Editing Kupffer cell (section)

==Clinical significance==
Kupffer cells are incredibly plastic cells that have the capability to polarize specific activation states and can perform different functions in different microenvironments. M1 (classical activation) and M2 (alternative activation) designate the two extremes of [[M1 macrophage|macrophage polarization]]. M1-polarized Kupffer cells produce a large amount of pro-inflammatory cytokines like TNF-alpha. On the other hand, M2-polarized Kupffer cells produce a large quantity of anti-inflammatory mediators, for example, IL-10.<ref>{{Cite journal|last1=Zeng|first1=Tao|last2=Zhang|first2=Cui-Li|last3=Xiao|first3=Mo|last4=Yang|first4=Rui|last5=Xie|first5=Ke-Qin|date=2016|title=Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials|journal=Frontiers in Immunology|language=en|volume=7|page=538|doi=10.3389/fimmu.2016.00538|pmid=27965666|pmc=5126119|issn=1664-3224|doi-access=free}}</ref><ref name=":2" />

Kupffer cells play a role in the pathogenesis of a damaged liver in response to sepsis. The macrophages in the liver activate and release both IL-1 and TNF-alpha. In turn, this activates leukocytes and sinusoidal endothelial cells to express [[ICAM-1]]. This results in tissue damage to the endothelium because of proteases, oxygen radicals, [[prostanoid]]s and other substances from leukocytes.

Kupffer cell activation contributes to pathogenesis of both chronic and acute [[alcoholic liver disease]] in response to ethanol-induced liver injury, common in chronic alcoholics. Chronic alcoholism and liver injury deal with a two-hit system.  While the first hit is direct, mediated by the direct toxicity of ethanol and its metabolic byproducts, the second hit is indirect, mediated by increased uptake of [[lipopolysaccharide]] (endotoxin) from the intestine.

Ethanol increases permeability of the intestinal epithelium, resulting in endotoxin produced by the [[intestinal flora]] leaking from the [[intestinal lumen]] into the liver via the [[portal vein]]. The presence of endotoxin induces a strong M1 polarization of Kupffer cells. A large amount of reactive oxygen species, pro-inflammatory cytokines and chemokines are produced by the activated Kupffer cells which lead to liver injury.

The cascade begins with endotoxin-mediated activation of the Toll-like receptor 4 ([[TLR4]]) and [[CD14]], receptors on the Kupffer cell that internalize endotoxin. This in turn activates the transcription of pro-inflammatory [[cytokine]]s and [[tumor necrosis factor-alpha]] (TNFα), with concurrent production of [[superoxide]]s. 

Cytokines and superoxides go on to cause inflammation and oxidizing damage respectively, while TNFα triggers the [[Ito cell|stellate cell]]s in the liver to initiate [[collagen]] synthesis. These processes result in [[fibrosis]], or scarring of the liver. Fibrosis will eventually cause [[cirrhosis]], a loss of function of the liver due to extensive scarring.<ref name="pmid15540801">{{cite journal | vauthors = Wheeler MD | title = Endotoxin and Kupffer cell activation in alcoholic liver disease | journal = Alcohol Research & Health | volume = 27 | issue = 4 | pages = 300–6 | date = 2003 | pmid = 15540801 | pmc = 6668869 }}</ref>