Figure 6 summarizes a proposed model for the role of multiple mediators in the pathogenesis of LPS hepatotoxicity. This model is based on evidence reviewed above but is not meant to be exclusive. Exposure to LPS is associated with the accumulation of PMNs in the liver and increased levels of circulating TNF-α, which is probably derived, at least in part, from hepatic Kupffer cells. The mechanism of recruitment of PMNs in the liver remains unknown. However, it does not appear to be mediated solely by TNF-α or the coagulation system because hepatic PMN accumulation was not prevented by antiserum to TNF-α or by heparin. Both blood PMNs and TNF-α appear to be required for activation of the coagulation system after LPS exposure. Because TNF-α stimulates PMNs to release oxygen metabolites in vitro and because reactive oxygen metabolites have been implicated in the activation of the coagulation system after LPS exposure, TNF-α might contribute to the activation of the coagulation system by stimulating PMNs to release reactive oxygen metabolites; however, this remains to be demonstrated. The coagulation system mediates liver injury by an unknown mechanism that might involve thrombin but is independent of the thrombin-catalyzed conversion of fibrinogen to fibrin. Thrombin has a number of biological activities that appear to be independent of its proteolytic action on circulating fibrinogen. Among these is the stimulation of thromboxane A2 release from platelets. Evidence from several studies suggests that this potent, vasoactive arachidonic acid metabolite may contribute to the pathogenesis of LPS- induced liver injury (see section IV.D.). Although the source of thromboxane A2 is not known, it seems possible that it arises from activated platelets. Indeed, an early morphological change in the hepatic sinusoids after LPS administration is the appearance of aggregates of activated platelets. Thus, the elaboration of thrombin during activation of the coagulation system after LPS exposure could result in liver injury by a mechanism that is dependent on platelet-derived thromboxane A2. This hypothesis, although consistent with available evidence, is incomplete at best and not the only picture that might be drawn.
|Original language||English (US)|
|Number of pages||31|
|State||Published - Dec 1 1993|
ASJC Scopus subject areas
- Molecular Medicine