Role of monocytes and macrophages in experimental and human acute liver failure

Table 1 Literature summary on the effect of hepatic macrophage depletion on the extent of liver injury in experimental models of ALF

Study	Model	Method of macrophage depletion/inhibition	Affect on severity of acute liver injury	Conclusion
Laskin et al[18], 1995	APAP (rat)	Gadolinium chloride/dextran sulphate	Decreased ALT at 24 h in treated groups; Decreased necrosis	Macrophage depletion was protective
Michael et al[19], 1999	APAP (mouse)	Gadolinium chloride/dextran sulphate	Decreased ALT at 8 h in treated groups	Macrophage depletion was protective
Hogaboam et al[12], 2000	APAP (mouse)	CCR2 -/-	ALT at 24 and 48 h, hepatic necrosis and TUNEL staining all increased in KO; Increase in IFN-γ and TNF-α	CCR2 KO - macrophage depletion worsened liver injury
Dambach et al[13], 2002	APAP (mouse)	CCR2 -/-	ALT levels similar in WT and KO mice; Histologically KO mice showed less inflammation at 72 h	CCR2 KO - macrophage depletion, caused less inflammation at 72 h but no overall difference in outcome
Ju et al[20], 2002	APAP (mouse)	Liposome/clodronate	Increased ALT at 8 and 24 h in treated group	Macrophage depletion increased liver damage
Holt et al[6], 2008	APAP (mouse)	CCR2 -/-	ALT same at 10 and 24 h; Comparable histological necrosis at 24 h but delayed recovery at 48 and 72 h in CCR2 -/-	Reduction in infiltrating macrophage population causes delayed recovery
Karlmark et al[5], 2009	CCl4 (mouse)	Liposome/clodronate	Unaltered ALT level at 4 and 24 h post-CCl4	Reduction in infiltrating macrophages had no effect on severity of liver damage

ALF: Acute liver failure; ALT: Alanine transaminase; WT: Wild-type; KO: Knockout; APAP: Acetaminophen induced hepatotoxicity; CCl₄: Carbon tetrachloride; CCR2: Chemokine (C-C motif) receptor 2.

Table 2 Pro- and anti-inflammatory cytokines in experimental models of ALF

Cytokine	Model	Source	Mechanism of action
TNF-α	Murine hepatic ischaemia[21,22]	Macrophage	Hepatocellular apoptosis
	Murine α-amanitin or actinomycin D[23]		Cellular recruitment
	Murine Gal/LPS[24]
	Murine Con-A[25]
	Rat Gal/LPS[26]
IFN-γ	Murine Gal/LPS[27]	Macrophages	Induce iNOS
	Murine APAP[28]	NK and T cells	Upregulates Fas, sensitising hepatocytes to apoptosis
	Murine Con-A[29,30]		Upregulates adhesion molecules and chemokines resulting in leucocyte accumulation
MIF	Guinea pig halothane[31]	Preformed stores released from hepatocytes and KCs early in injury	Stimulate release of proinflammatory cytokines
	Murine APAP[31]		Counter-act glucocorticoid anti-inflammatory effects
	Murine LPS in BCG-primed mice[32]		Cellular recruitment
	Rat ethanol[33]
IL-6	Murine APAP[22,34,35]	Released from macrophages and T cells	Reduced TNF-α secretion
	Murine alcohol and TNF-α[36]		Activation of STAT3 signalling pathway
	Murine Con-A[37,38]		Induction of anti-apoptotic proteins e.g. Bcl-2, Bcl-XL, FLIP
	Murine Acute CCl4[39]
	Murine Fas-mediated apoptosis[40]
	Murine ischemia/reperfusion[41]
IL-10	Murine Gal/LPS[27,42,43]	Macrophages/monocytes and injured hepatocytes	Inhibition of TNF-α, IFN-γ secretion
	Murine CCl4[44]
	Rat CCl4[45]
	Murine APAP[46]
	Murine Con-A[47]

Con-A: Concanavalin-A; Gal/LPS: Galactosamine lipopolysaccharide; TNF-α: Tumour necrosis factor-α; IFN-γ: Interferon-γ; MIF: Macrophage migration inhibitory factor; IL-6: Interleukin-6.