Editing Inflammation

{{short description|Physical effects resulting from activation of the immune system}}
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{{More medical citations needed|date=March 2021}}
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{{Infobox medical condition
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 |image           = Allergy to Antibiotic Cefaclor.JPG
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 |caption         = An [[allergic reaction]] to [[cefaclor]] has led to inflammation of the skin on the foot. The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function. Some of these indicators can be seen here.
 |pronounce       =
 |specialty       = [[Immunology]], [[rheumatology]]
 |symptoms        = Heat, pain, redness, swelling
 |complications   = [[Asthma]], [[pneumonia]], [[autoimmune diseases]]
 |onset           =
 |duration        = '''Acute''': few days<br />'''Chronic''': up to many months, or years
 |types           =
 |causes          = Infection, [[physical injury]], [[autoimmune disorder]]
 |risks           =
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}}

'''Inflammation''' (from {{langx|la|[[wikt:en:inflammatio#Latin|inflammatio]]}}) is part of the biological response of body tissues to harmful stimuli, such as [[pathogen]]s, damaged cells, or [[Irritation|irritants]].<ref name="pmid17223962">{{Cite journal |vauthors=Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE |date=February 2007 |title=Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation |journal=Clinical and Experimental Immunology |volume=147 |issue=2 |pages=227–235 |doi=10.1111/j.1365-2249.2006.03261.x |pmc=1810472 |pmid=17223962}}</ref> The five [[cardinal signs]] are heat, pain, redness, swelling, and [[Functio laesa|loss of function]] (Latin ''calor'', ''dolor'', ''rubor'', ''tumor'', and ''functio laesa'').

Inflammation is a generic response, and therefore is considered a mechanism of [[innate immune system|innate immunity]], whereas [[adaptive immune system|adaptive immunity]] is specific to each pathogen.<ref name="ABBAS">{{Cite book |title=Basic Immunology. Functions and disorders of the immune system |vauthors=Abbas AB, Lichtman AH |publisher=Saunders/Elsevier |year=2009 |isbn=978-1-4160-4688-2 |edition=3rd |chapter=Ch.2 Innate Immunity}}</ref>

Inflammation is a protective response involving [[immune cells]], [[blood vessel]]s, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. However inflammation can also have negative effects.<ref>{{Cite web |title=Inflammation and Your Health |url=https://www.cedars-sinai.org/discoveries/inflammation.html |website=Cedars-Sinai}}</ref> Too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as [[hay fever]], [[periodontal disease]], [[atherosclerosis]], and [[osteoarthritis]].

Inflammation can be classified as ''acute'' or ''chronic''. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement of [[blood plasma|plasma]] and [[leukocyte]]s (in particular [[granulocyte]]s) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local [[vascular system]], the [[immune system]], and various cells in the injured tissue. Prolonged inflammation, known as ''chronic inflammation'', leads to a progressive shift in the type of cells present at the site of inflammation, such as [[Mononuclear cell infiltration|mononuclear cells]], and involves simultaneous destruction and [[healing]] of the tissue.

Inflammation has also been classified as Type 1 and Type 2 based on the type of [[cytokines]] and [[helper T cells]] (Th1 and Th2) involved.<ref>{{Cite journal |vauthors=Berger A |date=August 2000 |title=Th1 and Th2 responses: what are they? |url=https://www.bmj.com/content/321/7258/424.1 |url-status=live |journal=BMJ |volume=321 |issue=7258 |pages=424 |doi=10.1136/bmj.321.7258.424 |pmc=27457 |pmid=10938051 |archive-url=https://web.archive.org/web/20210712072427/https://www.bmj.com/content/321/7258/424.1 |archive-date=12 July 2021 |access-date=1 July 2021}}</ref>

== Meaning ==
The earliest known reference for the term inflammation is around the early 15th century. The word root comes from [[Old French]] ''inflammation'' around the 14th century, which then comes from [[Latin]] ''inflammatio'' or ''inflammationem''. Literally, the term relates to the word "flame", as the property of being "set on fire" or "to burn".<ref name="k027">{{Cite web |date=2017-09-28 |title=inflammation |url=https://www.etymonline.com/word/inflammation |access-date=2024-08-11 |website=Etymology of inflammation by etymonline}}</ref>

The term ''inflammation'' is not a synonym for ''infection''. ''Infection'' describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together in discussion of infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. ''Inflammation'', on the other hand, describes just the body's immunovascular response, regardless of cause. But, because the two are often [[correlation|correlated]], words ending in the suffix ''[[wikt:-itis|-itis]]'' (which means inflammation) are sometimes informally described as referring to infection: for example, the word ''[[urethritis]]'' strictly means only "urethral inflammation", but clinical [[health care provider]]s usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis. However, the inflammation–infection distinction is crucial in situations in [[pathology]] and [[medical diagnosis]] that involve inflammation that is not driven by microbial invasion, such as cases of [[atherosclerosis]], [[Trauma (medicine)|trauma]], [[ischemia]], and [[autoimmune diseases]] (including [[type III hypersensitivity]]).

== Causes ==
{{columns-list|colwidth=30em|
Physical:
* [[Burn (injury)|Burns]]<ref name="Hall">{{Cite book |title=Guyton and Hall textbook of medical physiology |vauthors=Hall J |date=2011 |publisher=Saunders/Elsevier |isbn=978-1-4160-4574-8 |edition=12th |location=Philadelphia, Pa. |page=428}}</ref>
* [[Frostbite]]
* [[Physical injury]], blunt or penetrating<ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK53373/ |title=Inflammation and the Microcirculation |vauthors=Granger DN, Senchenkova E |date=2010 |publisher=Morgan & Claypool Life Sciences |series=Integrated Systems Physiology—From Cell to Function |volume=2 |pages=1–87 |chapter=Leukocyte–Endothelial Cell Adhesion |doi=10.4199/C00013ED1V01Y201006ISP008 |pmid=21452440 |access-date=1 July 2017 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK53380/ |archive-url=https://web.archive.org/web/20210121004109/https://www.ncbi.nlm.nih.gov/books/NBK53373/ |archive-date=21 January 2021 |url-status=live}}</ref>
* Foreign bodies, including [[splinters]], dirt and debris
* Trauma<ref name=Hall/>
* [[Ionizing radiation]]
Biological:
* Infection by [[pathogen]]s<ref name=Hall/>
* Immune reactions due to [[hypersensitivity]]
* Stress

Chemical:<ref name=Hall/>
* Chemical [[Irritation|irritants]]
* [[Toxin]]s
* Alcohol

Psychological:
* Excitement<ref>{{Cite journal |vauthors=Piira OP, Miettinen JA, Hautala AJ, Huikuri HV, Tulppo MP |date=October 2013 |title=Physiological responses to emotional excitement in healthy subjects and patients with coronary artery disease |journal=Autonomic Neuroscience |volume=177 |issue=2 |pages=280–5 |doi=10.1016/j.autneu.2013.06.001 |pmid=23916871 |s2cid=19823098}}</ref>}}

== Types ==
{{Unreferenced section|date=April 2023}}
{{See also|List of inflammatory disorders|List of types of inflammation by location}}{{col-begin}}
{{Col-2}}
* [[Appendicitis]]
* [[Bursitis]]
* [[Colitis]]
* [[Cystitis]]
* [[Dermatitis]]
* [[Epididymitis]]
* [[Encephalitis]]
* [[Gingivitis]]
* [[Meningitis]]
* [[Myelitis]]
* [[Myocarditis]]
* [[Nephritis]]
* [[Neuritis]]
* [[Pancreatitis]]
* [[Periodontitis]]{{Col-2}}
* [[Pharyngitis]]
* [[Phlebitis]]
* [[Prostatitis]]
* [[RSD/CRPS]]
* [[Rhinitis]]
* [[Sinusitis]]
* [[Tendonitis]]
* [[Tonsillitis]]
* [[Urethritis]]
* [[Vasculitis]]
* [[Vaginitis]]
{{col-end}}

{| class="wikitable" style="text-align:center"
|+ Comparison between acute and chronic inflammation:
!width="150" | || Acute || Chronic
|-
| ''Causative agent'' || {{small|Bacterial pathogens, injured tissues}} || {{small|Persistent acute inflammation due to non-degradable pathogens, viral infection, persistent foreign bodies, or autoimmune reactions}}
|-
| ''Major cells involved'' || {{small|neutrophils (primarily), basophils (inflammatory response), and eosinophils (response to helminth worms and parasites), mononuclear cells (monocytes, macrophages)}} || {{small|Mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts}}
|-
| ''Primary mediators'' || {{small|Vasoactive amines, eicosanoids}} || {{small|IFN-γ and other cytokines, growth factors, reactive oxygen species, hydrolytic enzymes}}
|-
| ''Onset'' || {{small|Immediate}} || {{small|Delayed}}
|-
| ''Duration'' || {{small|Few days}} || {{small|Up to many months, or years}}
|-
| ''Outcomes'' || {{small|Resolution, abscess formation, chronic inflammation}} || {{small|Tissue destruction, fibrosis, necrosis}}
|}

=== Acute ===
Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus.<ref name="robspath" /> It involves a coordinated and systemic mobilization response locally of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases.<ref>{{Cite journal |vauthors=Kumar R, Clermont G, Vodovotz Y, Chow CC |date=September 2004 |title=The dynamics of acute inflammation |journal=Journal of Theoretical Biology |volume=230 |issue=2 |pages=145–55 |arxiv=q-bio/0404034 |bibcode=2004PhDT.......405K |doi=10.1016/j.jtbi.2004.04.044 |pmid=15321710 |s2cid=16992741}}</ref>

Acute inflammation occurs immediately upon injury, lasting only a few days.<ref name="pmid32310543">{{Cite journal |vauthors=Hannoodee S, Nasuruddin DN |year=2020 |title=Acute Inflammatory Response |url=https://www.ncbi.nlm.nih.gov/books/NBK556083/ |url-status=live |journal=[[EMedicine#History|StatPearls]] |pmid=32310543 |archive-url=https://web.archive.org/web/20220615132211/https://www.ncbi.nlm.nih.gov/books/NBK556083/ |archive-date=15 June 2022 |access-date=28 December 2020}}</ref> [[Cytokine]]s and [[chemokine]]s promote the migration of [[neutrophil]]s and [[macrophage]]s to the site of inflammation.<ref name="pmid32310543" /> Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation.<ref name="pmid32310543" /> [[Toll-like receptor]]s (TLRs) recognize microbial pathogens.<ref name="pmid32310543" /> Acute inflammation can be a defensive mechanism to protect tissues against injury.<ref name="pmid32310543" /> Inflammation lasting 2–6 weeks is designated subacute inflammation.<ref name="pmid32310543" /><ref name="pmid29630225" />

==== Cardinal signs ====
{| width="230" align="right" class="wikitable" style="text-align:center; margin-left:0.67em"
|+ The classic signs and symptoms of acute inflammation:{{efn|1=All these signs may be observed in specific instances, but no single sign must, as a matter of course, be present.<ref name="Stedman">{{Cite book |title=Stedman's Medical Dictionary |publisher=Williams & Wilkins |year=1990 |edition=Twenty-fifth}}</ref>
These are the original, or [[cardinal signs]] of inflammation.<ref name="Stedman" />}}
!English || Latin
|-
| Redness || ''[[Rubor]]''
|-
| Swelling || ''[[Swelling (medical)|Tumor]]''
|-
| Heat || ''[[Human body temperature|Calor]]''
|-
| Pain || ''[[Pain|Dolor]]''
|-
| style="border-bottom:2px solid grey;" | Loss of function|| style="border-bottom:2px solid grey;" | ''[[Functio laesa]]''{{efn|1=''Functio laesa'' is an antiquated notion, as it is not unique to inflammation and is a characteristic of many disease states.<ref name="Rather">{{Cite journal |vauthors=Rather LJ |date=March 1971 |title=Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Claudius Galen to the four cardinal signs of Celsus |journal=Bulletin of the New York Academy of Medicine |volume=47 |issue=3 |pages=303–22 |pmc=1749862 |pmid=5276838}}</ref>}}
|}

Inflammation is characterized by five [[cardinal signs]],<ref name="ConcisePathology-Signs">{{Cite book |url=http://www.accessmedicine.com/resourceTOC.aspx?resourceID=7 |title=Concise Pathology |vauthors=Chandrasoma P, Taylor CR |publisher=McGraw-Hill |year=2005 |isbn=978-0-8385-1499-3 |edition=3rd |chapter=Part A. "General Pathology", Section II. "The Host Response to Injury", Chapter 3. "The Acute Inflammatory Response", sub-section "Cardinal Clinical Signs" |oclc=150148447 |access-date=2008-11-05 |chapter-url=http://www.accessmedicine.com/content.aspx?aID=183351 |archive-url=https://web.archive.org/web/20081005091840/http://accessmedicine.com/resourceTOC.aspx?resourceID=7 |archive-date=5 October 2008 |url-status=live}}</ref><ref name="auto">{{cite journal | vauthors = Rather LJ | title = Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus | journal = Bulletin of the New York Academy of Medicine | volume = 47 | issue = 3 | pages = 303–322 | date = March 1971 | pmid = 5276838 | pmc = 1749862 }}</ref> (the traditional names of which  come from Latin):
* [[Pain|Dolor]] ([[pain]])
* Calor (heat)
* [[Rubor]] (redness)
* Tumor ([[swelling (medical)|swelling]])
* [[Functio laesa]] (loss of function)<ref>{{Cite book |url=http://thepoint.lww.com/Book/ShowWithResource/2931?resourceId=16419 |title=A massage Therapist Guide to Pathology |vauthors=Werner R |publisher=Wolters Kluwer |year=2009 |isbn=978-0-7817-6919-8 |edition=4th |access-date=6 October 2010 |archive-url=https://web.archive.org/web/20151221050601/http://thepoint.lww.com/Book/ShowWithResource/2931?resourceId=16419 |archive-date=21 December 2015 |url-status=live}}</ref>

The first four (classical signs) were described by [[Aulus Cornelius Celsus|Celsus]] ({{circa|30 BC}}–38 AD).<ref>{{Cite book |url=https://books.google.com/books?id=t_5pzrF1QocC&pg=PA97 |title=Brief History of Vision and Ocular Medicine |vauthors=Vogel WH, Berke A |publisher=Kugler Publications |year=2009 |isbn=978-90-6299-220-1 |page=97}}</ref>

[[Pain]] is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings.<ref name="ConcisePathology-Signs" /> Acute inflammation of the lung (usually in response to [[pneumonia]]) does not cause pain unless the inflammation involves the [[parietal pleura]], which does have [[nociceptor|pain-sensitive nerve endings]].<ref name="ConcisePathology-Signs" /> Heat and redness are due to increased blood flow at body core temperature to the inflamed site. Swelling is caused by accumulation of fluid.

=====Loss of function=====
The fifth sign, ''loss of function'', is believed to have been added later by [[Galen]],<ref name="isbn0-7817-7087-4">{{Cite book |title=Essentials of pahtophysiology: concepts of altered health states |vauthors=Porth C |publisher=Lippincott Williams & Wilkins |year=2007 |isbn=978-0-7817-7087-3 |location=Hagerstown, MD |pages=270}}</ref> [[Thomas Sydenham]]<ref name="isbn0-300-11322-6">{{Cite book |url=https://archive.org/details/worstofevilsmans00dorm/page/22 |title=The worst of evils: man's fight against pain |vauthors=Dormandy T |publisher=Yale University Press |year=2006 |isbn=978-0-300-11322-8 |location=New Haven, Conn |pages=[https://archive.org/details/worstofevilsmans00dorm/page/22 22] |url-access=registration}}</ref> or [[Rudolf Ludwig Karl Virchow|Rudolf Virchow]].<ref name="robspath">{{Cite book |title=Robbins Pathologic Basis of Disease |vauthors=Robbins SL, Cotran RS, Kumar V, Collins T |publisher=W.B Saunders Company |year=1998 |isbn=978-0-7216-7335-6 |location=Philadelphia}}</ref><ref name="ConcisePathology-Signs" /><ref name="auto" /> Examples of loss of function include  pain that inhibits mobility, severe swelling that prevents movement, having a worse sense of smell during a cold, or having difficulty breathing when bronchitis is present.<ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK279298/ |title=InformedHealth.org [Internet] |date=22 February 2018 |publisher=Institute for Quality and Efficiency in Health Care (IQWiG) |via=www.ncbi.nlm.nih.gov}}</ref><ref>{{Cite web |date=11 March 2024 |title=Inflammation &#124; Definition, Symptoms, Treatment, & Facts &#124; Britannica |url=https://www.britannica.com/science/inflammation |website=www.britannica.com}}</ref>  Loss of function has multiple causes.<ref name="ConcisePathology-Signs" />

==== Acute process ====
{{More medical citations needed|section|date=April 2023}}
[[File:Events in Acute Inflammation.pdf|thumb|569x569px|A flowchart depicting the events of acute inflammation.<ref>{{Cite book |title=Pathologic basis of disease |vauthors=Robbins S, Cotran R, Kumar V, Abbas A, Aster J |date=2020 |publisher=Saunders Elsevier |edition=10th |location=Philadelphia, PA}}</ref>]]
[[File:Granulation tissue low power.jpg|thumb|[[Micrograph]] showing granulation tissue. [[H&E stain]].]]
The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident [[macrophages]], [[dendritic cells]], [[histiocytes]], [[Kupffer cells]] and [[mast cell]]s. These cells possess surface receptors known as ''[[pattern recognition receptor]]s'' (PRRs), which recognize (i.e., bind) two subclasses of molecules: [[pathogen-associated molecular pattern]]s (PAMPs) and [[damage-associated molecular pattern]]s (DAMPs). PAMPs are compounds that are associated with various [[pathogen]]s, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.

At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (''rubor'') and increased heat (''calor''). Increased permeability of the blood vessels results in an exudation (leakage) of [[blood plasma|plasma]] proteins and fluid into the tissue ([[edema]]), which manifests itself as swelling (''tumor''). Some of the released mediators such as [[bradykinin]] increase the sensitivity to pain ([[hyperalgesia]], ''dolor''). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly [[neutrophils]] and [[macrophages]], to flow out of the blood vessels (extravasation) and into the tissue. The neutrophils migrate along a [[chemotactic]] gradient created by the local cells to reach the site of injury.<ref name="robspath" /> The loss of function (''functio laesa'') is probably the result of a neurological reflex in response to pain.

In addition to cell-derived mediators, several acellular biochemical cascade systems—consisting of preformed plasma proteins—act in parallel to initiate and propagate the inflammatory response. These include the [[complement system]] activated by bacteria and the [[coagulation system|coagulation]] and [[fibrinolysis system]]s activated by [[necrosis]] (e.g., burn, trauma).<ref name="robspath" />

Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed.<ref name="robspath" />

=== Chronic ===
{{main|Chronic inflammation}}
Chronic inflammation is inflammation that lasts for months or years.<ref name="pmid29630225">{{Cite web|vauthors=Pahwa R, Goyal A, Bansal P, Jialal I |date=7 August 2023 |title=Chronic inflammation |url=https://www.ncbi.nlm.nih.gov/books/NBK493173/ |publisher=StatPearls, US National Library of Medicine |pmid=29630225|access-date=29 December 2024}}</ref> Macrophages, [[lymphocytes]], and [[plasma cells]] predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation.<ref name="pmid29630225" /> [[Type 2 diabetes|Diabetes]], [[cardiovascular disease]], [[Allergy|allergies]], and [[chronic obstructive pulmonary disease]] are examples of diseases mediated by chronic inflammation.<ref name="pmid29630225" /> [[Obesity]], smoking, stress and insufficient diet are some of the factors that promote chronic inflammation.<ref name="pmid29630225" />

====Cardinal signs====
Common signs and symptoms that develop during chronic inflammation are:<ref name="pmid29630225"/>
* Body pain, [[arthralgia]], [[myalgia]]
* Chronic fatigue and insomnia
* Depression, anxiety and mood disorders
* Gastrointestinal complications such as constipation, diarrhea, and acid reflux
* Weight gain or loss
* Frequent infections

== Vascular component ==
{{More medical citations needed|section|date=March 2021}}

=== Vasodilation and increased permeability ===

As defined, acute inflammation is an immunovascular response to inflammatory stimuli, which can include infection or trauma.<ref name=":1">{{Cite journal |vauthors=Raiten DJ, Sakr Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, Brabin BJ, Suchdev PS, van Ommen B |date=May 2015 |title=Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) |journal=The Journal of Nutrition |volume=145 |issue=5 |pages=1039S–1108S |doi=10.3945/jn.114.194571 |pmc=4448820 |pmid=25833893}}</ref><ref>{{Cite journal |vauthors=Taams LS |date=July 2018 |title=Inflammation and immune resolution |journal=Clinical and Experimental Immunology |volume=193 |issue=1 |pages=1–2 |doi=10.1111/cei.13155 |pmc=6037995 |pmid=29987840}}</ref> This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid [[granulocytes]] in the acute setting).<ref name=":1" /> The vascular component of acute inflammation involves the movement of [[Blood plasma|plasma fluid]], containing important [[protein]]s such as [[fibrin]] and [[immunoglobulin]]s ([[antibodies]]), into inflamed tissue.

Upon contact with PAMPs, tissue [[macrophages]] and [[mastocytes]] release vasoactive amines such as [[histamine]] and [[serotonin]], as well as [[eicosanoids]] such as [[prostaglandin E2]] and [[leukotriene B4]] to remodel the local vasculature.<ref name=":2">{{Cite journal |vauthors=Medzhitov R |date=July 2008 |title=Origin and physiological roles of inflammation |journal=Nature |volume=454 |issue=7203 |pages=428–435 |bibcode=2008Natur.454..428M |doi=10.1038/nature07201 |pmid=18650913 |s2cid=205214291}}</ref> Macrophages and endothelial cells release [[nitric oxide]].<ref>{{Cite journal |vauthors=Mantovani A, Garlanda C |date=February 2023 |title=Humoral Innate Immunity and Acute-Phase Proteins |journal=The New England Journal of Medicine |volume=388 |issue=5 |pages=439–452 |doi=10.1056/NEJMra2206346 |pmc=9912245 |pmid=36724330 |veditors=Longo DL}}</ref> These mediators vasodilate and permeabilize the [[blood vessel]]s, which results in the net distribution of [[blood plasma]] from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell ([[edema]]).<ref name=":2" /> This exuded tissue fluid contains various antimicrobial mediators from the plasma such as [[complement system|complement]], [[lysozyme]], [[antibodies]], which can immediately deal damage to microbes, and [[Opsonin|opsonise]] the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded [[platelet]]s, [[coagulation system|coagulant]]s, [[plasmin]] and [[kinin]]s can [[clot]] the wounded area using vitamin K-dependent mechanisms<ref>{{cite book | vauthors = Ferland G | chapter = Vitamin K |date=2020 | title = Present Knowledge in Nutrition |pages=137–153 | chapter-url = https://linkinghub.elsevier.com/retrieve/pii/B9780323661621000081 |access-date=2023-02-17 |publisher=Elsevier |language=en |doi=10.1016/b978-0-323-66162-1.00008-1 |isbn=978-0-323-66162-1}}</ref> and provide [[haemostasis]] in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a [[fibrin]] lattice – as would construction [[scaffolding]] at a construction site – for the purpose of aiding phagocytic debridement and [[wound healing|wound repair]] later on. Some of the exuded tissue fluid is also funneled by [[lymphatics]] to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the [[adaptive immune system]].

[[File:Toe.JPG|thumb|right|230px|Infected [[ingrown toenail]] showing the characteristic redness and swelling associated with acute inflammation]]

Acute inflammation is characterized by marked vascular changes, including [[vasodilation]], increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators.<ref name=":2" /> Vasodilation occurs first at the [[arteriole]] level, progressing to the [[capillary]] level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of [[blood plasma|plasma]] into the tissues, with resultant [[Venous stasis|stasis]] due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows [[leukocytes]] to marginate (move) along the [[endothelium]], a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the [[Shear stress|shearing force]] along the periphery of the vessels moves cells in the blood into the middle of the vessel.

=== Plasma cascade systems ===
* The [[complement system]], when activated, creates a cascade of chemical reactions that promotes [[Antibody opsonization|opsonization]], [[chemotaxis]], and [[agglutination (biology)|agglutination]], and produces the [[Membrane attack complex|MAC]].
* The [[kinin system]] generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
* The [[coagulation system]] or ''clotting cascade'', which forms a protective protein mesh over sites of injury.
* The [[fibrinolysis system]], which acts in opposition to the ''coagulation system'', to counterbalance clotting and generate several other inflammatory mediators.

=== Plasma-derived mediators ===
{{small|''* non-exhaustive list''}}
{| class="wikitable"
! Name || Produced by || Description
|-
| align="center" | '''[[Bradykinin]]''' || align="center" | ''[[Kinin system]]'' || A vasoactive protein that is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.
|-
| align="center" | '''[[C3 (complement)|C3]]''' || align="center" | ''[[Complement system]]'' || Cleaves to produce ''C3a'' and ''C3b''. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an [[opsonin]], which marks the invader as a target for [[phagocytosis]].
|-
| align="center" | '''[[Complement component 5a|C5a]]'''  || align="center" | ''[[Complement system]]'' || Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as a [[chemoattractant]] to direct cells via chemotaxis to the site of inflammation.
|-
| align="center" | '''[[Factor XII]]''' (''Hageman Factor'') || align="center" | ''[[Liver]]'' || A protein that circulates inactively, until activated by collagen, platelets, or exposed [[basement membrane]]s via [[conformational change]]. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.
|-
| align="center" | '''[[Membrane attack complex]]''' || align="center" | ''[[Complement system]]'' || A complex of the complement proteins [[C5b]], [[Complement component 6|C6]], [[Complement component 7|C7]], [[C8 complex|C8]], and multiple units of [[Complement component 9|C9]]. The combination and activation of this range of complement proteins forms the ''membrane attack complex'', which is able to insert into bacterial cell walls and causes cell lysis with ensuing bacterial death.
|-
| align="center" | '''[[Plasmin]]''' || align="center" | ''[[Fibrinolysis system]]'' || Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.
|-
| align="center" | '''[[Thrombin]]''' || align="center" | ''[[Coagulation system]]'' || Cleaves the soluble plasma protein [[fibrinogen]] to produce insoluble [[fibrin]], which aggregates to form a [[blood clot]]. Thrombin can also bind to cells via the [[Protease-activated receptor|PAR1]] receptor to trigger several other inflammatory responses, such as production of [[chemokine]]s and [[nitric oxide]].
|}

== Cellular component ==
The ''cellular component'' involves [[leukocyte]]s, which normally reside in blood and must move into the inflamed tissue via ''extravasation'' to aid in inflammation.<ref name=":1" /> Some act as [[phagocyte]]s, ingesting bacteria, viruses, and cellular debris. Others release enzymatic [[granule (cell biology)|granules]] that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by [[granulocyte]]s, whereas chronic inflammation is mediated by mononuclear cells such as [[monocyte]]s and [[lymphocyte]]s.

=== Leukocyte extravasation ===
[[File:NeutrophilerAktion.svg|200px|thumb|right|Neutrophils migrate from blood vessels to the infected tissue via chemotaxis, where they remove pathogens through phagocytosis and degranulation]]
[[File:Immune response.svg|thumb|Inflammation is a process by which the body's white blood cells and substances they produce protect us from infection with foreign organisms, such as bacteria and viruses. The (phagocytes) white blood cells are a nonspecific immune response, meaning that they attack any foreign bodies. However, in some diseases, like arthritis, the body's defense system the immune system triggers an inflammatory response when there are no foreign invaders to fight off. In these diseases, called autoimmune diseases, the body's normally protective immune system causes damage to its own tissues. The body responds as if normal tissues are infected or somehow abnormal.]]
{{Main|Leukocyte extravasation}}
Various [[leukocyte]]s, particularly neutrophils, are critically involved in the initiation and maintenance of inflammation. These cells must be able to move to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as ''extravasation'' and can be broadly divided up into a number of steps:
# '''Leukocyte margination and endothelial adhesion:''' The white blood cells within the vessels which are generally centrally located move peripherally towards the walls of the vessels.<ref name=":0">{{Cite book |title=Muir's Textbook of Pathology |vauthors=Herrington S |publisher=CRC Press |year=2014 |isbn=978-1-4441-8499-0 |edition=15th |pages=59}}</ref> Activated macrophages in the tissue release [[cytokines]] such as [[Interleukin 1|IL-1]] and [[TNFα]], which in turn leads to production of [[chemokine]]s that bind to [[proteoglycan]]s forming gradient in the inflamed tissue and along the [[endothelial]] wall.<ref name=":2" /> Inflammatory cytokines induce the immediate expression of [[P-selectin]] on endothelial cell surfaces and P-selectin binds weakly to carbohydrate ligands on the surface of leukocytes and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines released from injured cells induce the expression of [[E-selectin]] on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of [[integrin]] ligands such as [[ICAM-1]] and [[VCAM-1]] on endothelial cells, which mediate the adhesion and further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue after [[signal transduction]] via respective [[G protein-coupled receptors]] that activates integrins on the leukocyte surface for firm adhesion. Such activation increases the affinity of bound integrin receptors for ICAM-1 and VCAM-1 on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
# '''Migration across the endothelium, known as'' transmigration, ''via the process of [[diapedesis]]:''' Chemokine gradients stimulate the adhered leukocytes to move between adjacent endothelial cells. The endothelial cells retract and the leukocytes pass through the basement membrane into the surrounding tissue using adhesion molecules such as ICAM-1.<ref name=":0" />
# '''Movement of leukocytes within the tissue via [[chemotaxis]]:''' Leukocytes reaching the tissue interstitium bind to [[extracellular matrix]] proteins via expressed integrins and [[CD44]] to prevent them from leaving the site. A variety of molecules behave as [[chemoattractant]]s, for example, C3a or C5a (the [[anaphylatoxins]]), and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.

=== Phagocytosis ===
{{Main|Phagocyte}}
Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue. [[Phagocyte]]s express cell-surface endocytic [[pattern recognition receptors]] (PRRs) that have affinity and efficacy against non-specific [[microbe-associated molecular patterns]] (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate [[phagocytosis]] are cell wall components, including complex carbohydrates such as [[mannans]] and β-[[glucans]], [[lipopolysaccharides]] (LPS), [[peptidoglycans]], and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with [[C-type lectin]] receptors binding to mannans and β-glucans, and [[scavenger receptor (immunology)|scavenger receptor]]s binding to LPS.

Upon endocytic PRR binding, [[actin]]-[[myosin]] [[cytoskeletal]] rearrangement adjacent to the plasma membrane occurs in a way that [[endocytosis|endocytoses]] the plasma membrane containing the PRR-PAMP complex, and the microbe. [[Phosphatidylinositol]] and [[Vps34]]-[[PIK3R4|Vps15]]-[[BECN1|Beclin1]] signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular [[lysosomes]], where fusion of the phagosome and the lysosome produces a phagolysosome. The [[reactive oxygen species]], [[superoxides]] and [[hypochlorite]] bleach within the phagolysosomes then kill microbes inside the phagocyte.

Phagocytic efficacy can be enhanced by [[opsonization]]. Plasma derived complement [[C3b]] and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express [[opsonin]] receptors [[Fc receptor]] and [[complement receptor 1]] (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the [[lysosomal]] elimination of the infective agent.

=== Cell-derived mediators ===
{{small|''* non-exhaustive list''}}
{| class="wikitable"
!Name || Type || Source || Description
|-
| align="center" | '''[[Granule (cell biology)|Lysosome granules]]''' || align="center" | ''[[Enzyme]]s'' || align="center" | [[Granulocyte]]s || These cells contain a large variety of enzymes that perform a number of functions. Granules can be classified as either ''[[Specific granules|specific]]'' or ''[[azurophil]]ic'' depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins that allow these enzymes to act as inflammatory mediators.
|-
| align="center" | '''[[Granulocyte-macrophage colony-stimulating factor|GM-CSF]]''' || align="center" | ''[[Glycoprotein]]'' || align="center" | Macrophages, monocytes, T-cells, B-cells, and tissue-resident cells || Elevated GM-CSF has been shown to contribute to inflammation in [[inflammatory arthritis]], [[osteoarthritis]], [[colitis]] [[asthma]], [[obesity]], and [[Coronavirus disease 2019|COVID-19]].
|-
| align="center" | '''[[Histamine]]''' || align="center" | ''[[Monoamine]]'' || align="center" | Mast cells and basophils || Stored in preformed granules, histamine is released in response to a number of stimuli. It causes [[arteriole]] dilation, increased [[venous]] permeability, and a wide variety of organ-specific effects.
|-
| align="center" | '''[[Interferon gamma|IFN-γ]]''' || align="center" | ''[[Cytokine]]'' || align="center" | T-cells, NK cells || Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.
|-
| align="center" | '''[[Interleukin 6|IL-6]]''' || align="center" | ''[[Cytokine]]'' and ''[[Myokine]]'' || align="center" | Macrophages, osteoblasts, adipocytes, and smooth muscle cells (cytokine) Skeletal muscle cells (myokine) || Pro-inflammatory cytokine secreted by macrophages in response to [[pathogen-associated molecular pattern]]s (PAMPs); pro-inflammatory cytokine secreted by adipocytes, especially in obesity; anti-inflammatory myokine secreted by skeletal muscle cells in response to exercise.
|-
| align="center" | '''[[Interleukin 8|IL-8]]''' || align="center" | ''[[Chemokine]]'' || align="center" | Primarily [[macrophage]]s || Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.
|-
| align="center" | '''[[Leukotriene B4]]''' || align="center" | ''[[Eicosanoid]]'' || align="center" | [[Leukocytes]], cancer cells || Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.
|-
| align="center" | '''[[LTC4]]''', '''[[LTD4]]''' || align="center" | ''[[Eicosanoid]]'' || align="center" | [[eosinophils]], [[mast cells]], [[macrophages]] || These three [[Cysteine]]-containing leukotrienes contract lung airways, increase micro-vascular permeability, stimulate mucus secretion, and promote eosinophil-based inflammation in the lung, skin, nose, eye, and other tissues.
|-
| align="center" | '''[[5-oxo-eicosatetraenoic acid]]''' || align="center" | ''[[Eicosanoid]]'' || align="center" | [[Leukocytes]], cancer cells || Potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and with even greater potency eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.
|-
| align="center" | '''[[5-HETE]]''' || align="center" | ''[[Eicosanoid]]'' || align="center" | [[Leukocytes]] || Metabolic precursor to 5-Oxo-eicosatetraenoic acid, it is a less potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.
|-
| align="center" | '''[[Prostaglandin]]s''' || align="center" | ''[[Eicosanoid]]'' || align="center" | Mast cells || A group of lipids that can cause vasodilation, fever, and pain.
|-
| align="center" | '''[[Nitric oxide]]''' || align="center" | ''Soluble gas'' || align="center" | Macrophages, endothelial cells, some neurons || Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.
|-
| align="center" | '''[[Tumor necrosis factor-alpha|TNF-α]] and [[Interleukin 1|IL-1]]''' || align="center" | ''[[Cytokine]]s'' || align="center" | Primarily macrophages || Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation of [[fibroblast]]s. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF-α inhibits osteoblast differentiation.
|-
| align="center" | '''[[Tryptase]]''' || align="center" | ''[[Enzyme]]s'' || align="center" | Mast Cells || This serine protease is believed to be exclusively stored in mast cells and secreted, along with histamine, during mast cell activation.<ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK200913/ |title=Itch: Mechanisms and Treatment |vauthors=Carstens E, Akiyama T, Cevikbas F, Kempkes C, Buhl T, Mess C, Buddenkotte J, Steinhoff M |date=2014 |publisher=CRC Press/Taylor & Francis |isbn=978-1-4665-0543-8 |veditors=Carstens M, Akiyama T |series=Frontiers in Neuroscience |location=Boca Raton (FL) |chapter=Role of Interleukin-31 and Oncostatin M in Itch and Neuroimmune Communication |pmid=24830021}}</ref><ref>{{Cite journal |vauthors=Caughey GH |date=June 2007 |title=Mast cell tryptases and chymases in inflammation and host defense |journal=Immunological Reviews |volume=217 |issue=1 |pages=141–54 |doi=10.1111/j.1600-065x.2007.00509.x |pmc=2275918 |pmid=17498057}}</ref><ref>{{Cite journal |vauthors=Caughey GH |date=May 2016 |title=Mast cell proteases as pharmacological targets |journal=European Journal of Pharmacology |series=Pharmacological modulation of Mast cells and Basophils |volume=778 |pages=44–55 |doi=10.1016/j.ejphar.2015.04.045 |pmc=4636979 |pmid=25958181}}</ref>
|}

== Morphologic patterns ==
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an [[epithelial]] surface, or [[pyogenic]] bacteria are involved.
* '''Granulomatous inflammation:''' Characterised by the formation of [[granuloma]]s, they are the result of a limited but diverse number of diseases, which include among others [[tuberculosis]], [[leprosy]], [[sarcoidosis]], and [[syphilis]].
* '''Fibrinous inflammation:''' Inflammation resulting in a large increase in vascular permeability allows [[fibrin]] to pass through the blood vessels. If an appropriate ''procoagulative'' stimulus is present, such as cancer cells,<ref name="robspath" /> a fibrinous exudate is deposited. This is commonly seen in [[serous membrane|serous cavities]], where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine ([[pseudomembranous colitis]]), pseudomembranous tubes can be formed.
* '''Purulent inflammation:''' Inflammation resulting in large amount of [[pus]], which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as [[staphylococci]] is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called [[abscess]]es.
* '''Serous inflammation:''' Characterised by the copious effusion of non-viscous serous fluid, commonly produced by [[mesothelial]] cells of [[serous membrane]]s, but may be derived from blood plasma. Skin [[blister]]s exemplify this pattern of inflammation.
* '''Ulcerative inflammation:''' Inflammation occurring near an epithelium can result in the [[necrotic]] loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an [[ulcer (dermatology)|ulcer]].

== Disorders ==
[[File:Asthma (Lungs).png|thumb|215x215px|Asthma is considered an inflammatory-mediated disorder. On the right is an inflamed airway due to asthma.]]
[[File:CD colitis 2.jpg|thumb|209x209px|Colitis (inflammation of the colon) caused by [[Crohn's disease]].]]
Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, as demonstrated in both [[allergic reaction]]s and some [[myopathies]], with many [[immune system disorder]]s resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer, [[atherosclerosis]], and [[ischaemic heart disease|ischemic heart disease]].<ref name="robspath" />

Examples of disorders associated with inflammation include:
{{div col|colwidth=25em}}
* [[Acne vulgaris]]
* [[Asthma]]
* [[Autoimmune disease]]s
* [[Autoinflammatory disease]]s
* [[Celiac disease]]
* [[Asymptomatic inflammatory prostatitis|Chronic prostatitis]]
* [[Ulcerative colitis|Colitis]]
* [[Diverticulitis]]
* [[Familial Mediterranean Fever]]
* [[Glomerulonephritis]]
* [[Hidradenitis suppurativa]]
* [[Hypersensitivity|Hypersensitivities]]
* [[Inflammatory bowel disease]]s
* [[Interstitial cystitis]]
* [[Lichen planus]]
* [[Mast Cell Activation Syndrome]]
* [[Mastocytosis]]
* [[Otitis]]
* [[Pelvic inflammatory disease]]
* [[Peripheral ulcerative keratitis]]
* [[Pneumonia]]
* [[Reperfusion injury]]
* [[Rheumatic fever]]
* [[Rheumatoid arthritis]]
* [[Rhinitis]]
* [[Sarcoidosis]]
* [[Transplant rejection]]
* [[Vasculitis]]
{{div col end}}

=== Atherosclerosis ===

{{main|Atherosclerosis}}
Atherosclerosis, formerly considered a [[lipid]] storage disorder, is now understood as a chronic inflammatory condition involving the arterial walls.<ref name="libby2021">{{cite journal |vauthors=Libby P |title=Inflammation during the life cycle of the atherosclerotic plaque |journal=Cardiovascular Research |volume=117 |issue=13 |pages=2525–2536 |date=November 2021 |pmid=34550337 |pmc=8783385 |doi=10.1093/cvr/cvab303}}</ref> Research has established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it.<ref name=libby2021/> These new findings reveal links between traditional risk factors like cholesterol levels and the underlying mechanisms of [[atherogenesis]].

Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to people.<ref name="libby2021" /> For instance, elevation in markers of inflammation predicts outcomes of people with [[acute coronary syndrome]]s, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker [[C-reactive protein]], prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors, such as LDL levels.<ref>{{cite journal | vauthors = Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A | title = Role of inflammation in atherosclerosis | journal = Journal of Nuclear Medicine | volume = 48 | issue = 11 | pages = 1800–1815 | date = November 2007 | pmid = 17942804 | doi = 10.2967/jnumed.107.038661 }}</ref><ref name=libby2021/>

Moreover, certain treatments that reduce coronary risk also limit inflammation. Notably, lipid-lowering medications such as [[statin]]s have shown anti-inflammatory effects, which may contribute to their efficacy beyond just lowering LDL levels.<ref>{{cite journal | vauthors = Morofuji Y, Nakagawa S, Ujifuku K, Fujimoto T, Otsuka K, Niwa M, Tsutsumi K | title = Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer | journal = Pharmaceuticals | volume = 15 | issue = 2 | pages = 151 | date = January 2022 | pmid = 35215263 | pmc = 8877351 | doi = 10.3390/ph15020151 | doi-access = free }}</ref> This emerging understanding of inflammation's role in atherosclerosis has had significant clinical implications, influencing both risk stratification and therapeutic strategies.

==== Emerging treatments ====

Recent developments in the treatment of atherosclerosis have focused on addressing inflammation directly. New anti-inflammatory drugs, such as monoclonal antibodies targeting IL-1β, have been studied in large clinical trials, showing promising results in reducing cardiovascular events.<ref>{{cite journal | vauthors = Szekely Y, Arbel Y | title = A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today? | journal = Cardiology and Therapy | volume = 7 | issue = 1 | pages = 25–44 | date = June 2018 | pmid = 29417406 | pmc = 5986669 | doi = 10.1007/s40119-018-0104-3 }}</ref> These drugs offer a potential new avenue for treatment, particularly for patients who do not respond adequately to statins. However, concerns about long-term safety and cost remain significant barriers to widespread adoption.

==== Connection to depression ====
Inflammatory processes can be triggered by negative cognition or their consequences, such as stress, violence, or deprivation. Negative cognition may therefore contribute to inflammation, which in turn can lead to depression. A 2019 meta-analysis found that chronic inflammation is associated with a 30% increased risk of developing [[major depressive disorder]], supporting the link between inflammation and [[mental health]].<ref>{{cite journal | vauthors = Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD | title = Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls | journal = Brain, Behavior, and Immunity | volume = 87 | pages = 901–909 | date = July 2020 | pmid = 32113908 | pmc = 7327519 | doi = 10.1016/j.bbi.2020.02.010 }}</ref>

=== Allergy ===
An allergic reaction, formally known as [[Type I hypersensitivity|type 1 hypersensitivity]], is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is [[hay fever]], which is caused by a hypersensitive response by [[mast cell]]s to [[allergen]]s. Pre-sensitised mast cells respond by [[degranulation|degranulating]], releasing [[vasoactive]] chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes.<ref name="robspath" /> Severe inflammatory response may mature into a systemic response known as [[anaphylaxis]].

=== Myopathies ===
[[Inflammatory myopathy|Inflammatory myopathies]] are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as [[systemic sclerosis]], and include [[dermatomyositis]], [[polymyositis]], and [[inclusion body myositis]].<ref name="robspath" />

=== Leukocyte defects ===
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection.<ref name="robspath" /> Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria ([[Chédiak–Higashi syndrome]]), or produce [[microbicide]]s ([[chronic granulomatous disease]]). In addition, diseases affecting the [[bone marrow]] may result in abnormal or few leukocytes.

=== Pharmacological ===
Certain drugs or exogenous chemical compounds are known to affect inflammation. [[Vitamin A]] deficiency, for example, causes an increase in inflammatory responses,<ref>{{Cite journal |vauthors=Wiedermann U, Chen XJ, Enerbäck L, Hanson LA, Kahu H, Dahlgren UI |date=December 1996 |title=Vitamin A deficiency increases inflammatory responses |journal=Scandinavian Journal of Immunology |volume=44 |issue=6 |pages=578–84 |doi=10.1046/j.1365-3083.1996.d01-351.x |pmid=8972739 |s2cid=3079540}}</ref> and [[anti-inflammatory]] drugs work specifically by inhibiting the enzymes that produce inflammatory [[eicosanoids]]. Additionally, certain illicit drugs such as [[cocaine]] and [[Ecstasy (drug)|ecstasy]] may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. [[NF-κB]]).<ref>{{Cite journal |vauthors=Hargrave BY, Tiangco DA, Lattanzio FA, Beebe SJ |year=2003 |title=Cocaine, not morphine, causes the generation of reactive oxygen species and activation of NF-kappaB in transiently cotransfected heart cells |journal=Cardiovascular Toxicology |volume=3 |issue=2 |pages=141–51 |doi=10.1385/CT:3:2:141 |pmid=14501032 |s2cid=35240781}}</ref><ref>{{Cite journal |vauthors=Montiel-Duarte C, Ansorena E, López-Zabalza MJ, Cenarruzabeitia E, Iraburu MJ |date=March 2004 |title=Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine ("Ecstasy") on hepatic stellate cells |journal=Biochemical Pharmacology |volume=67 |issue=6 |pages=1025–33 |doi=10.1016/j.bcp.2003.10.020 |pmid=15006539}}</ref>

=== Cancer ===
Inflammation orchestrates the [[Tumor microenvironment|microenvironment]] around tumours, contributing to proliferation, survival and migration.<ref>{{Cite journal |vauthors=Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R |date=September 2011 |title=Interaction of tumor cells with the microenvironment |journal=Cell Communication and Signaling |volume=9 |pages=18 |doi=10.1186/1478-811X-9-18 |pmc=3180438 |pmid=21914164 |doi-access=free}}</ref> Cancer cells use [[selectins]], [[chemokines]] and their receptors for invasion, migration and metastasis.<ref name="Coussens" /> On the other hand, many cells of the immune system contribute to [[cancer immunology]], suppressing cancer.<ref name="pmid22914051">{{Cite journal |vauthors=Gunn L, Ding C, Liu M, Ma Y, Qi C, Cai Y, Hu X, Aggarwal D, Zhang HG, Yan J |date=September 2012 |title=Opposing roles for complement component C5a in tumor progression and the tumor microenvironment |journal=Journal of Immunology |volume=189 |issue=6 |pages=2985–94 |doi=10.4049/jimmunol.1200846 |pmc=3436956 |pmid=22914051}}</ref>
Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as [[NF-κB]], may mediate some of the most critical effects of inflammatory stimuli on cancer cells.<ref name="pmid19382224">{{Cite journal |vauthors=Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA |date=June 2009 |title=Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? |journal=BioEssays |volume=31 |issue=6 |pages=629–41 |doi=10.1002/bies.200800138 |pmid=19382224 |s2cid=205469320}}</ref> This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. On the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.

There is some evidence from 2009 to suggest that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.<ref name="pmid19468060">{{Cite journal |vauthors=Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A |date=July 2009 |title=Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability |journal=Carcinogenesis |type=review |volume=30 |issue=7 |pages=1073–81 |doi=10.1093/carcin/bgp127 |pmid=19468060 |doi-access=free}}</ref>{{Update needed|date=October 2024}}

====Role in cancer====

In 1863, [[Rudolf Virchow]] hypothesized that the origin of cancer was at sites of chronic inflammation.<ref name="Coussens">{{Cite journal |vauthors=Coussens LM, Werb Z |year=2002 |title=Inflammation and cancer |journal=Nature |volume=420 |issue=6917 |pages=860–7 |bibcode=2002Natur.420..860C |doi=10.1038/nature01322 |pmc=2803035 |pmid=12490959}}</ref><ref name="Chiba">{{Cite journal |vauthors=Chiba T, Marusawa H, Ushijima T |date=September 2012 |title=Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation |url=http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |url-status=live |journal=Gastroenterology |volume=143 |issue=3 |pages=550–563 |doi=10.1053/j.gastro.2012.07.009 |pmid=22796521 |s2cid=206226588 |archive-url=https://web.archive.org/web/20220829232437/https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |archive-date=29 August 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2433/160134}}</ref> As of 2012, chronic inflammation was estimated to contribute to approximately 15% to 25% of human cancers.<ref name="Chiba" /><ref name="pmid18650914">{{Cite journal |vauthors=Mantovani A, Allavena P, Sica A, Balkwill F |date=July 2008 |title=Cancer-related inflammation |url=https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |url-status=live |journal=Nature |volume=454 |issue=7203 |pages=436–44 |bibcode=2008Natur.454..436M |doi=10.1038/nature07205 |pmid=18650914 |s2cid=4429118 |archive-url=https://web.archive.org/web/20221030195610/https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |archive-date=30 October 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2434/145688}}</ref>

====Mediators and DNA damage in cancer====

An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.<ref name="pmid6399978">{{Cite journal |vauthors=Larsen GL, Henson PM |year=1983 |title=Mediators of inflammation |journal=Annual Review of Immunology |volume=1 |pages=335–59 |doi=10.1146/annurev.iy.01.040183.002003 |pmid=6399978}}</ref> Inflammatory mediators that contribute to neoplasia include [[prostaglandin]]s, inflammatory [[cytokine]]s such as [[Interleukin 1 beta|IL-1β]], [[tumor necrosis factor alpha|TNF-α]], [[Interleukin 6|IL-6]] and [[Interleukin 15|IL-15]] and [[chemokine]]s such as [[Interleukin 8|IL-8]] and [[CXCL1|GRO-alpha]].<ref name="Shacter">{{Cite journal |vauthors=Shacter E, Weitzman SA |date=February 2002 |title=Chronic inflammation and cancer |journal=Oncology |volume=16 |issue=2 |pages=217–26, 229; discussion 230–2 |pmid=11866137}}</ref><ref name="Chiba" /> These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.<ref name="Coussens" /><ref name="Shacter" />

Inflammation also causes DNA damages due to the induction of [[reactive oxygen species]] (ROS) by various intracellular inflammatory mediators.<ref name="Coussens" /><ref name="Shacter" /><ref name="Chiba" /> In addition, [[White blood cell|leukocytes]] and other [[Phagocyte|phagocytic cells]] attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and [[reactive nitrogen species]] (RNS). ROS and RNS are normally produced by these cells to fight infection.<ref name="Coussens" /> ROS, alone, cause more than 20 types of DNA damage.<ref name="pmid27989142">{{Cite journal |vauthors=Yu Y, Cui Y, Niedernhofer LJ, Wang Y |date=December 2016 |title=Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage |journal=Chemical Research in Toxicology |volume=29 |issue=12 |pages=2008–2039 |doi=10.1021/acs.chemrestox.6b00265 |pmc=5614522 |pmid=27989142}}</ref> Oxidative DNA damages cause both [[mutation]]s<ref name="pmid22293091">{{Cite journal |vauthors=Dizdaroglu M |date=December 2012 |title=Oxidatively induced DNA damage: mechanisms, repair and disease |journal=Cancer Letters |volume=327 |issue=1–2 |pages=26–47 |doi=10.1016/j.canlet.2012.01.016 |pmid=22293091}}</ref> and epigenetic alterations.<ref name="pmid24281019">{{Cite journal |vauthors=Nishida N, Kudo M |year=2013 |title=Oxidative stress and epigenetic instability in human hepatocarcinogenesis |journal=Digestive Diseases |volume=31 |issue=5–6 |pages=447–53 |doi=10.1159/000355243 |pmid=24281019 |doi-access=free}}</ref><ref name="Chiba" /><ref name="Ding">{{Cite journal |vauthors=Ding N, Maiuri AR, O'Hagan HM |year=2017 |title=The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases |journal=Mutation Research |volume=780 |pages=69–81 |doi=10.1016/j.mrrev.2017.09.005 |pmc=6690501 |pmid=31395351}}</ref> RNS also cause mutagenic DNA damages.<ref name="pmid28050219">{{Cite journal |vauthors=Kawanishi S, Ohnishi S, Ma N, Hiraku Y, Oikawa S, Murata M |year=2016 |title=Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells |journal=Genes and Environment |volume=38 |issue=1 |pages=26 |bibcode=2016GeneE..38...26K |doi=10.1186/s41021-016-0055-7 |pmc=5203929 |pmid=28050219 |doi-access=free}}</ref>

A normal cell may undergo [[carcinogenesis]] to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic [[mutation]]s due to [[DNA repair#Translecion synthesis|inaccurate repair]]. In addition, mistakes in the DNA repair process may cause [[Cancer epigenetics|epigenetic]] alterations.<ref name="Chiba" /><ref name="Shacter" /><ref name="Ding" /> Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic.

Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in [[coding region]]s, 10–20 of which are [[carcinogenesis|"driver mutations"]] that contribute to cancer development.<ref name="Chiba" /> However, chronic inflammation also causes epigenetic changes such as [[DNA methylation in cancer|DNA methylation]]s, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see [[DNA methylation in cancer]]). Sites of oxidative damage in [[chromatin]] can recruit complexes that contain [[DNA methyltransferase]]s (DNMTs), a histone deacetylase ([[sirtuin 1|SIRT1]]), and a [[EZH2|histone methyltransferase (EZH2)]], and thus induce DNA methylation.<ref name="Chiba" /><ref name="pmid22094255">{{Cite journal |vauthors=O'Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB |date=November 2011 |title=Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands |journal=Cancer Cell |volume=20 |issue=5 |pages=606–19 |doi=10.1016/j.ccr.2011.09.012 |pmc=3220885 |pmid=22094255}}</ref><ref name="pmid28522752">{{Cite journal |vauthors=Maiuri AR, Peng M, Podicheti R, Sriramkumar S, Kamplain CM, Rusch DB, DeStefano Shields CE, Sears CL, O'Hagan HM |date=July 2017 |title=Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis |journal=Cancer Research |volume=77 |issue=13 |pages=3467–3478 |doi=10.1158/0008-5472.CAN-17-0056 |pmc=5516887 |pmid=28522752}}</ref> DNA methylation of a [[CpG site|CpG island]] in a [[Promoter (genetics)|promoter region]] may cause silencing of its downstream gene (see [[CpG site]] and [[regulation of transcription in cancer]]). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see [[DNA methylation in cancer#Likely role of hypermethylation of DNA repair genes in cancer|hypermethylation of DNA repair genes in cancer]]). A 2018 report<ref name="pmid29358395">{{Cite journal |vauthors=Yamashita S, Kishino T, Takahashi T, Shimazu T, Charvat H, Kakugawa Y, Nakajima T, Lee YC, Iida N, Maeda M, Hattori N, Takeshima H, Nagano R, Oda I, Tsugane S, Wu MS, Ushijima T |date=February 2018 |title=Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=6 |pages=1328–1333 |bibcode=2018PNAS..115.1328Y |doi=10.1073/pnas.1717340115 |pmc=5819434 |pmid=29358395 |doi-access=free}}</ref> evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation).<ref name="pmid24664859">{{Cite journal |vauthors=Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, Khan S, Kazi JI, Bernstein C, Kazmi SU |date=October 2014 |title=Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis |journal=Pathology & Oncology Research |volume=20 |issue=4 |pages=839–46 |doi=10.1007/s12253-014-9762-1 |pmid=24664859 |s2cid=18727504}}</ref> However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with [[Cigarette#Smokers|tobacco chemicals]] and [[Acetaldehyde#Carcinogenicity|acetaldehyde]], a product of alcohol metabolism).

=== HIV and AIDS ===

It has long been recognized that infection with [[HIV]] is characterized not only by development of profound [[immunodeficiency]] but also by sustained inflammation and immune activation.<ref name="Deeks 141–155">{{Cite journal |vauthors=Deeks SG |date=2011-01-01 |title=HIV infection, inflammation, immunosenescence, and aging |journal=Annual Review of Medicine |volume=62 |pages=141–55 |doi=10.1146/annurev-med-042909-093756 |pmc=3759035 |pmid=21090961}}</ref><ref>{{Cite journal |vauthors=Klatt NR, Chomont N, Douek DC, Deeks SG |date=July 2013 |title=Immune activation and HIV persistence: implications for curative approaches to HIV infection |journal=Immunological Reviews |volume=254 |issue=1 |pages=326–42 |doi=10.1111/imr.12065 |pmc=3694608 |pmid=23772629}}</ref><ref>{{Cite journal |vauthors=Salazar-Gonzalez JF, Martinez-Maza O, Nishanian P, Aziz N, Shen LP, Grosser S, Taylor J, Detels R, Fahey JL |date=August 1998 |title=Increased immune activation precedes the inflection point of CD4 T cells and the increased serum virus load in human immunodeficiency virus infection |journal=The Journal of Infectious Diseases |volume=178 |issue=2 |pages=423–30 |doi=10.1086/515629 |pmid=9697722 |doi-access=free}}</ref> A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.<ref name="Deeks 141–155" /><ref>{{Cite journal |vauthors=Ipp H, Zemlin A |date=February 2013 |title=The paradox of the immune response in HIV infection: when inflammation becomes harmful |journal=Clinica Chimica Acta; International Journal of Clinical Chemistry |volume=416 |pages=96–9 |doi=10.1016/j.cca.2012.11.025 |pmid=23228847}}</ref> Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease.<ref>{{Cite journal |vauthors=Nasi M, Pinti M, Mussini C, Cossarizza A |date=October 2014 |title=Persistent inflammation in HIV infection: established concepts, new perspectives |journal=Immunology Letters |volume=161 |issue=2 |pages=184–8 |doi=10.1016/j.imlet.2014.01.008 |pmid=24487059}}</ref> Even after the introduction of [[Antiretroviral therapy, highly active|effective antiretroviral therapy]] (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of its natural nonhuman primate hosts, the [[sooty mangabey]], causes high-level viral replication but limited evidence of disease.<ref>{{Cite journal |vauthors=Milush JM, Mir KD, Sundaravaradan V, Gordon SN, Engram J, Cano CA, Reeves JD, Anton E, O'Neill E, Butler E, Hancock K, Cole KS, Brenchley JM, Else JG, Silvestri G, Sodora DL |date=March 2011 |title=Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells |journal=The Journal of Clinical Investigation |volume=121 |issue=3 |pages=1102–10 |doi=10.1172/JCI44876 |pmc=3049370 |pmid=21317533}}</ref><ref>{{Cite journal |vauthors=Rey-Cuillé MA, Berthier JL, Bomsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, Chakrabarti LA |date=May 1998 |title=Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease |journal=Journal of Virology |volume=72 |issue=5 |pages=3872–86 |doi=10.1128/JVI.72.5.3872-3886.1998 |pmc=109612 |pmid=9557672}}</ref> This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of [[rhesus macaque]] produces immune activation and AIDS-like disease with many parallels to human HIV infection.<ref>{{Cite journal |vauthors=Chahroudi A, Bosinger SE, Vanderford TH, Paiardini M, Silvestri G |date=March 2012 |title=Natural SIV hosts: showing AIDS the door |journal=Science |volume=335 |issue=6073 |pages=1188–93 |bibcode=2012Sci...335.1188C |doi=10.1126/science.1217550 |pmc=3822437 |pmid=22403383}}</ref>

Delineating how [[CD4]] T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis{{emdash}}one of the top priorities for HIV research by the Office of AIDS Research, [[National Institute of Allergy and Infectious Diseases|National Institutes of Health]]. Recent studies demonstrated that [[Caspase 1|caspase-1]]-mediated [[pyroptosis]], a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.<ref name="Doitsh 509–514">{{Cite journal |vauthors=Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC |date=January 2014 |title=Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection |journal=Nature |volume=505 |issue=7484 |pages=509–14 |bibcode=2014Natur.505..509D |doi=10.1038/nature12940 |pmc=4047036 |pmid=24356306}}</ref><ref>{{Cite journal |vauthors=Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC |date=January 2014 |title=IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV |journal=Science |volume=343 |issue=6169 |pages=428–32 |bibcode=2014Sci...343..428M |doi=10.1126/science.1243640 |pmc=3976200 |pmid=24356113}}</ref><ref>{{Cite journal |vauthors=Galloway NL, Doitsh G, Monroe KM, Yang Z, Muñoz-Arias I, Levy DN, Greene WC |date=September 2015 |title=Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells |journal=Cell Reports |volume=12 |issue=10 |pages=1555–1563 |doi=10.1016/j.celrep.2015.08.011 |pmc=4565731 |pmid=26321639}}</ref> These are the two signature events that propel HIV disease progression to [[HIV/AIDS|AIDS]]. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury.<ref>{{Cite journal |vauthors=Doitsh G, Greene WC |date=March 2016 |title=Dissecting How CD4 T Cells Are Lost During HIV Infection |journal=Cell Host & Microbe |volume=19 |issue=3 |pages=280–91 |doi=10.1016/j.chom.2016.02.012 |pmc=4835240 |pmid=26962940}}</ref> Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflammatory cytokines such as [[Interleukin 1 beta|IL-1β]] and [[Interleukin 18|IL-18]] can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,<ref name="Doitsh 509–514" /> which has already proven to be safe and well tolerated in phase II human clinical trials.<ref>{{Cite journal |date=19 December 2013 |title=Study of VX-765 in Subjects With Treatment-resistant Partial Epilepsy – Full Text View – ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT01048255 |url-status=live |archive-url=https://web.archive.org/web/20220926164557/https://clinicaltrials.gov/ct2/show/NCT01048255 |archive-date=26 September 2022 |access-date=2016-05-21 |website=clinicaltrials.gov}}</ref> These findings could propel development of an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting "tolerance" of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.

=== Resolution ===
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.<ref name="robspath" /> Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues.
Mechanisms that serve to terminate inflammation include:<ref name="robspath" /><ref>{{Cite journal |vauthors=Eming SA, Krieg T, Davidson JM |date=March 2007 |title=Inflammation in wound repair: molecular and cellular mechanisms |journal=The Journal of Investigative Dermatology |volume=127 |issue=3 |pages=514–25 |doi=10.1038/sj.jid.5700701 |pmid=17299434 |doi-access=free}}</ref>

{{columns-list|colwidth=30em|
* Short [[half-life]] of [[inflammatory mediators]] ''in vivo''.
* Production and release of [[transforming growth factor (TGF) beta]] from [[macrophages]]<ref>{{Cite journal |vauthors=Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB |date=September 1999 |title=Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response |journal=Nature Cell Biology |volume=1 |issue=5 |pages=260–6 |doi=10.1038/12971 |pmid=10559937 |s2cid=37216623}}</ref><ref>{{Cite journal |vauthors=Ashcroft GS |date=December 1999 |title=Bidirectional regulation of macrophage function by TGF-beta |url=https://zenodo.org/record/1260212 |url-status=live |journal=Microbes and Infection |volume=1 |issue=15 |pages=1275–82 |doi=10.1016/S1286-4579(99)00257-9 |pmid=10611755 |archive-url=https://web.archive.org/web/20200110215702/https://zenodo.org/record/1260212 |archive-date=10 January 2020 |access-date=11 September 2019}}</ref><ref>{{Cite journal |vauthors=Werner F, Jain MK, Feinberg MW, Sibinga NE, Pellacani A, Wiesel P, Chin MT, Topper JN, Perrella MA, Lee ME |date=November 2000 |title=Transforming growth factor-beta 1 inhibition of macrophage activation is mediated via Smad3 |journal=The Journal of Biological Chemistry |volume=275 |issue=47 |pages=36653–8 |doi=10.1074/jbc.M004536200 |pmid=10973958 |doi-access=free}}</ref>
* Production and release of [[interleukin 10]] (IL-10)<ref>{{Cite journal |vauthors=Sato Y, Ohshima T, Kondo T |date=November 1999 |title=Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing |journal=Biochemical and Biophysical Research Communications |volume=265 |issue=1 |pages=194–9 |doi=10.1006/bbrc.1999.1455 |pmid=10548513}}</ref>
* Production of anti-inflammatory [[specialized proresolving mediators]], i.e. [[lipoxin]]s, [[resolvin]]s, [[maresin]]s, and [[neuroprotectin]]s<ref>{{Cite journal |vauthors=Serhan CN |date=August 2008 |title=Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators |journal=Journal of Periodontology |volume=79 |issue=8 Suppl |pages=1520–6 |doi=10.1902/jop.2008.080231 |pmid=18673006}}</ref><ref name="pmid25911383">{{Cite journal |vauthors=Headland SE, Norling LV |date=May 2015 |title=The resolution of inflammation: Principles and challenges |journal=Seminars in Immunology |volume=27 |issue=3 |pages=149–60 |doi=10.1016/j.smim.2015.03.014 |pmid=25911383}}</ref>
* Downregulation of pro-inflammatory molecules, such as [[leukotrienes]].
* Upregulation of anti-inflammatory molecules such as the [[interleukin 1 receptor antagonist]] or the soluble [[tumor necrosis factor receptor]] (TNFR)
* [[Apoptosis]] of pro-inflammatory cells<ref>{{Cite journal |vauthors=Greenhalgh DG |date=September 1998 |title=The role of apoptosis in wound healing |journal=The International Journal of Biochemistry & Cell Biology |volume=30 |issue=9 |pages=1019–30 |doi=10.1016/S1357-2725(98)00058-2 |pmid=9785465}}</ref>
* Desensitization of receptors.
* Increased survival of cells in regions of inflammation due to their interaction with the [[extracellular matrix]] (ECM)<ref>{{Cite journal |vauthors=Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW |date=November 2005 |title=Regulation of lung injury and repair by Toll-like receptors and hyaluronan |journal=Nature Medicine |volume=11 |issue=11 |pages=1173–9 |doi=10.1038/nm1315 |pmid=16244651 |s2cid=11765495}}</ref><ref>{{Cite journal |vauthors=Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Puré E, Henson PM, Noble PW |date=April 2002 |title=Resolution of lung inflammation by CD44 |journal=Science |volume=296 |issue=5565 |pages=155–8 |bibcode=2002Sci...296..155T |doi=10.1126/science.1069659 |pmid=11935029 |s2cid=7905603}}</ref>
* Downregulation of receptor activity by high concentrations of [[ligands]]
* Cleavage of [[chemokine]]s by [[matrix metalloproteinases]] (MMPs) might lead to production of anti-inflammatory factors.<ref>{{Cite journal |vauthors=McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I, Overall CM |date=August 2000 |title=Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 |journal=Science |volume=289 |issue=5482 |pages=1202–6 |bibcode=2000Sci...289.1202M |doi=10.1126/science.289.5482.1202 |pmid=10947989}}</ref>
}}
{{Cquote|Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, [[granulocyte]]s promote the switch of [[arachidonic acid]]–derived [[prostaglandin]]s and [[leukotriene]]s to lipoxins, which initiate the termination sequence. [[Neutrophil]] recruitment thus ceases and programmed death by [[apoptosis]] is engaged. These events coincide with the biosynthesis, from [[omega-3 fatty acid|omega-3 polyunsaturated fatty acids]], of [[resolvins]] and [[Neuroprotectin|protectins]], which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo [[phagocytosis]] by [[macrophage]]s, leading to neutrophil clearance and release of anti-inflammatory and reparative [[cytokines]] such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the [[Lymphatic system|lymphatics]].<ref name="pmid16369558">{{Cite journal |vauthors=Serhan CN, Savill J |date=December 2005 |title=Resolution of inflammation: the beginning programs the end |journal=Nature Immunology |volume=6 |issue=12 |pages=1191–7 |doi=10.1038/ni1276 |pmid=16369558 |s2cid=22379843}}</ref>|30px|30px|[[Charles N. Serhan]]
}}

=== Connection to depression ===
There is evidence for a link between [[Depression and immune function#Depression and inflammation|inflammation and depression]].<ref>{{Cite journal |vauthors=Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, Maes M |date=September 2013 |title=So depression is an inflammatory disease, but where does the inflammation come from? |journal=BMC Medicine |volume=11 |pages=200 |doi=10.1186/1741-7015-11-200 |pmc=3846682 |pmid=24228900 |doi-access=free}}</ref> Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.<ref name="Cox et al. (2012)">{{Cite journal |vauthors=Cox WT, Abramson LY, Devine PG, Hollon SD |date=September 2012 |title=Stereotypes, Prejudice, and Depression: The Integrated Perspective |journal=Perspectives on Psychological Science |volume=7 |issue=5 |pages=427–49 |doi=10.1177/1745691612455204 |pmid=26168502 |s2cid=1512121}}</ref><ref>{{Cite journal |vauthors=Kiecolt-Glaser JK, Derry HM, Fagundes CP |date=November 2015 |title=Inflammation: depression fans the flames and feasts on the heat |journal=The American Journal of Psychiatry |volume=172 |issue=11 |pages=1075–91 |doi=10.1176/appi.ajp.2015.15020152 |pmc=6511978 |pmid=26357876}}</ref>{{Dubious|Depression|reason=Implausible claim apparently not supported by citation.|date=July 2013}}
In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode".<ref>{{Cite news |date=2015-01-04 |title=Is depression a kind of allergic reaction? |url=https://www.theguardian.com/lifeandstyle/2015/jan/04/depression-allergic-reaction-inflammation-immune-system |url-status=live |archive-url=https://web.archive.org/web/20221021202426/https://www.theguardian.com/lifeandstyle/2015/jan/04/depression-allergic-reaction-inflammation-immune-system |archive-date=21 October 2022 |access-date=11 December 2016 |work=The Guardian |vauthors=Williams C}}</ref>

Classical symptoms of being physically sick, such as lethargy, show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during the depressive episodes of people with bipolar disorder and drop off during remission.<ref>{{Cite journal |vauthors=Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M, Mascarenhas M, Escosteguy Vargas A, Chies JA, Kapczinski F |date=August 2009 |title=Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder |journal=Journal of Affective Disorders |volume=116 |issue=3 |pages=214–7 |doi=10.1016/j.jad.2008.12.001 |pmid=19251324}}</ref> Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment.<ref>{{Cite journal |vauthors=Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M |date=July 2006 |title=The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine |journal=Molecular Psychiatry |volume=11 |issue=7 |pages=680–4 |doi=10.1038/sj.mp.4001805 |pmid=16491133 |doi-access=free}}</ref>
Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.<ref>{{Cite journal |vauthors=Canli T |year=2014 |title=Reconceptualizing major depressive disorder as an infectious disease |journal=Biology of Mood & Anxiety Disorders |volume=4 |pages=10 |doi=10.1186/2045-5380-4-10 |pmc=4215336 |pmid=25364500 |doi-access=free}}</ref>

=== Connection to delirium ===
There is evidence for a link between inflammation and [[delirium]] based on the results of a recent longitudinal study investigating CRP in COVID-19 patients.<ref>{{Cite journal |vauthors=Saini A, Oh TH, Ghanem DA, Castro M, Butler M, Sin Fai Lam CC, Posporelis S, Lewis G, David AS, Rogers JP |date=October 2022 |title=Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study |url=https://discovery.ucl.ac.uk/id/eprint/10136824/ |url-status=live |journal=Aging & Mental Health |volume=26 |issue=10 |pages=2054–2061 |doi=10.1080/13607863.2021.1989375 |pmid=34651536 |s2cid=238990849 |archive-url=https://web.archive.org/web/20211022093940/https://discovery.ucl.ac.uk/id/eprint/10136824/ |archive-date=22 October 2021 |access-date=20 February 2023 |doi-access=free}}</ref>

== Systemic effects ==
An [[infectious organism]] can escape the confines of the immediate tissue via the [[circulatory system]] or [[lymphatic system]], where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation, it may gain access to the lymphatic system via nearby [[lymph vessel]]s. An infection of the lymph vessels is known as [[lymphangitis]], and infection of a lymph node is known as [[lymphadenitis]]. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.

When inflammation overwhelms the host, [[systemic inflammatory response syndrome]] is diagnosed. When it is due to infection, the term [[sepsis]] is applied, with the terms [[bacteremia]] being applied specifically for bacterial sepsis and [[viremia]] specifically to viral sepsis. [[Vasodilation]] and organ dysfunction are serious problems associated with widespread infection that may lead to [[septic shock]] and death.<ref>{{Cite book |title=StatPearls |vauthors=Ramanlal R, Gupta V |date=2021 |publisher=StatPearls Publishing |location=Treasure Island (FL) |chapter=Physiology, Vasodilation |pmid=32491494 |access-date=22 September 2021 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK557562/ |archive-url=https://web.archive.org/web/20210511162804/https://www.ncbi.nlm.nih.gov/books/NBK557562/ |archive-date=11 May 2021 |url-status=live}}</ref>

=== Acute-phase proteins ===
Inflammation also is characterized by high systemic levels of [[acute-phase protein]]s. In acute inflammation, these proteins prove beneficial; however, in chronic inflammation, they can contribute to [[amyloidosis]].<ref name="robspath" /> These proteins include [[C-reactive protein]], [[serum amyloid A]], and [[serum amyloid P]], which cause a range of systemic effects including:<ref name="robspath" />
{{div col|colwidth=25em}}
* Fever
* Increased [[blood pressure]]
* Decreased [[sweating]]
* [[Malaise]]
* [[Anorexia (symptom)|Loss of appetite]]
* [[Somnolence]]
{{div col end}}

=== Leukocyte numbers ===
Inflammation often affects the numbers of leukocytes present in the body:
* [[Leukocytosis]] is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per microliter, but extreme cases can see it approach 100 000 cells per microliter.<ref name="robspath" /> Bacterial infection usually results in an increase of [[neutrophil]]s, creating [[neutrophilia]], whereas diseases such as [[asthma]], [[hay fever]], and parasite infestation result in an increase in [[eosinophil]]s, creating [[eosinophilia]].<ref name="robspath" />
* [[Leukopenia]] can be induced by certain infections and diseases, including viral infection, ''[[Rickettsia]]'' infection, some [[protozoa]], [[tuberculosis]], and some cancers.<ref name="robspath" />

=== Interleukins and obesity ===
With the discovery of [[interleukin]]s (IL), the concept of [[systemic inflammation]] developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the [[endothelium]] and other organ systems.

Chronic inflammation is widely observed in [[obesity]].<ref name="ParimisettyDorsemans2016">{{Cite journal |vauthors=Parimisetty A, Dorsemans AC, Awada R, Ravanan P, Diotel N, Lefebvre d'Hellencourt C |date=March 2016 |title=Secret talk between adipose tissue and central nervous system via secreted factors-an emerging frontier in the neurodegenerative research |journal=Journal of Neuroinflammation |type=Review |volume=13 |issue=1 |pages=67 |doi=10.1186/s12974-016-0530-x |pmc=4806498 |pmid=27012931 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Kershaw EE, Flier JS |date=June 2004 |title=Adipose tissue as an endocrine organ |journal=The Journal of Clinical Endocrinology and Metabolism |volume=89 |issue=6 |pages=2548–56 |doi=10.1210/jc.2004-0395 |pmid=15181022 |doi-access=free}}</ref> Obese people commonly have many elevated markers of inflammation, including:<ref>{{Cite journal |vauthors=Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, Vidal H, Hainque B |date=September 2000 |title=Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss |journal=The Journal of Clinical Endocrinology and Metabolism |volume=85 |issue=9 |pages=3338–42 |doi=10.1210/jcem.85.9.6839 |pmid=10999830 |doi-access=free}}</ref><ref>{{Cite journal |vauthors=Mohamed-Ali V, Flower L, Sethi J, Hotamisligil G, Gray R, Humphries SE, York DA, Pinkney J |date=December 2001 |title=beta-Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies |journal=The Journal of Clinical Endocrinology and Metabolism |volume=86 |issue=12 |pages=5864–9 |doi=10.1210/jcem.86.12.8104 |pmid=11739453 |s2cid=73100391 |doi-access=free}}</ref>
* [[Interleukin-6|IL-6 (Interleukin-6)]]<ref name="Loffreda S 1998">{{Cite journal |vauthors=Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM |date=January 1998 |title=Leptin regulates proinflammatory immune responses |journal=FASEB Journal |volume=12 |issue=1 |pages=57–65 |doi=10.1096/fasebj.12.1.57 |pmid=9438411 |doi-access=free}}</ref><ref name="Esposito K 2002">{{Cite journal |vauthors=Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D |date=October 2002 |title=Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress |journal=Circulation |volume=106 |issue=16 |pages=2067–72 |doi=10.1161/01.CIR.0000034509.14906.AE |pmid=12379575 |doi-access=free}}</ref>

{{columns-list|colwidth=30em|
* [[Interleukin-8|IL-8 (Interleukin-8)]]
* [[Interleukin-18|IL-18 (Interleukin-18)]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
* [[Tumor necrosis factor-alpha|TNF-α (Tumor necrosis factor-alpha)]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
* [[C-reactive protein|CRP (C-reactive protein)]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
* [[Insulin]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
* [[Blood sugar|Blood glucose]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
* [[Leptin]]<ref name="Loffreda S 1998" /><ref name="Esposito K 2002" />
}}

Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP.<ref>{{Cite journal |vauthors=Petersen AM, Pedersen BK |date=April 2005 |title=The anti-inflammatory effect of exercise |journal=Journal of Applied Physiology |volume=98 |issue=4 |pages=1154–62 |doi=10.1152/japplphysiol.00164.2004 |pmid=15772055 |s2cid=4776835}}</ref> Waist circumference correlates significantly with systemic inflammatory response.<ref>{{Cite journal |vauthors=Rogowski O, Shapira I, Bassat OK, Chundadze T, Finn T, Berliner S, Steinvil A |date=July 2010 |title=Waist circumference as the predominant contributor to the micro-inflammatory response in the metabolic syndrome: a cross sectional study |journal=Journal of Inflammation |volume=7 |pages=35 |doi=10.1186/1476-9255-7-35 |pmc=2919526 |pmid=20659330 |doi-access=free}}</ref>

Loss of [[white adipose tissue]] reduces levels of inflammation markers.<ref name="ParimisettyDorsemans2016" /> As of 2017 the association of systemic inflammation with [[insulin resistance]] and [[type 2 diabetes]], and with [[atherosclerosis]] was under preliminary research, although rigorous [[clinical trial]]s had not been conducted to confirm such relationships.<ref name="Goldfine">{{Cite journal |vauthors=Goldfine AB, Shoelson SE |date=January 2017 |title=Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk |journal=The Journal of Clinical Investigation |volume=127 |issue=1 |pages=83–93 |doi=10.1172/jci88884 |pmc=5199685 |pmid=28045401 |doi-access=free}}</ref>

[[C-reactive protein]] (CRP) is generated at a higher level in obese people, and may increase the risk for [[cardiovascular diseases]].<ref name="Choi">{{Cite journal |vauthors=Choi J, Joseph L, Pilote L |date=March 2013 |title=Obesity and C-reactive protein in various populations: a systematic review and meta-analysis |journal=Obesity Reviews |volume=14 |issue=3 |pages=232–44 |doi=10.1111/obr.12003 |pmid=23171381 |s2cid=206227739}}</ref>

== Outcomes ==

The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred—and the injurious agent that is causing it. Here are the possible outcomes to inflammation:<ref name="robspath" />

# '''Resolution'''<br />The complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged [[parenchyma]]l cells regenerate. Such is usually the outcome when limited or short-lived inflammation has occurred.
# '''[[Fibrosis]]'''<br />Large amounts of tissue destruction, or damage in tissues unable to regenerate, cannot be regenerated completely by the body. Fibrous [[scarring]] occurs in these areas of damage, forming a scar composed primarily of [[collagen]]. The scar will not contain any specialized structures, such as [[parenchyma]]l cells, hence functional impairment may occur.
# '''Abscess formation'''<br />A cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
# '''Chronic inflammation'''<br />In acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a [[chronic wound]]. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the [[toxin]]s they release—including [[reactive oxygen species]]—are injurious to the organism's own tissues as well as invading agents. As a consequence, chronic inflammation is almost always accompanied by tissue destruction.

== Examples ==
Inflammation is usually indicated by adding the suffix "[[wikt:-itis|itis]]", as shown below. However, some conditions, such as [[asthma]] and [[pneumonia]], do not follow this convention. More examples are available at [[List of types of inflammation]].

<gallery>
 File:Acute_Appendicitis.jpg|Acute [[appendicitis]]
 File:Dermatitis.jpg|Acute [[dermatitis]]
 File:Streptococcus pneumoniae meningitis, gross pathology 33 lores.jpg|Acute infective [[meningitis]]
 File:Tonsillitis.jpg|Acute [[tonsillitis]]
</gallery>

== See also ==
{{columns-list|colwidth=30em|
* [[Anaphylatoxin]]
* [[Anti-inflammatory|Anti-inflammatories]]
* [[Essential fatty acid interactions]]
* [[Healing]]
* [[Inflammaging]]
* [[Inflammatory cytokine]]
* [[Inflammatory reflex]]
* [[Interleukin]]
* [[Lipoxin]]
* [[Neurogenic inflammation]]
* [[Substance P]]
* [[Stress (biology)]]
* [[Endothelial Cell Tropism]]}}

== Notes ==
{{notelist}}

== References ==
{{reflist}}

== External links ==
{{commons category|Inflammations}}
* {{MeshName|Inflammation}}

{{Inflammation}}
{{Immune system}}
{{Pathology}}

{{Authority control}}

[[Category:Immunology]]
[[Category:Animal physiology]]
[[Category:Inflammations]]
[[Category:Human physiology]]