Novel anti-fibrotic mechanisms in chemical-induced liver injury

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Liver fibrosis is a devastating outcome of numerous liver diseases associated with xenobiotic exposure, and accounts for approximately one million deaths annually owing to liver failure and certain cancers. Patients with liver fibrosis would most likely benefit from therapies aimed at maximizing activity of endogenous anti-fibrotic pathways, such as natural killer (NK) cell activation, in order to delay the onset of liver failure. Increase activity of the blood coagulation cascade and conversion of soluble fibrinogen to insoluble fibrin polymers in liver are prominent features of liver fibrosis in humans and experimental xenobiotic-induced liver fibrosis in mice. Although frequently implicated as pathologic, an increase in tissue fibrin deposition is not synonymous with increasing fibrotic changes (i.e., collagen deposition). Indeed, the exact role of fibrin polymer deposition in the pathogenesis of liver fibrosis is largel unknown. Our strong preliminary analysis supports the novel concept that fibrin polymer has an inhibitory effect on fibrosis development in the liver. Identifying the precise role of fibrin polyers in liver fibrosis is critical, because this could reveal specific functions of fibrin polymers as putative therapeutic targets to treat liver fibrosis. Our strong preliminary studies suggest that fibrin polymers inhibit xenobiotic-induced liver fibrosis in mice by engaging specific cellular integrin's. The central hypothesis framing these studies is that fibrin polymers inhibit liver fibrosis by engaging the integrin aMß2 on resident liver NK cells to enhance their expression of anti-fibrotic mediators. Our approach includes genetically-modified mice expressing fibrinogen proteins with specific functional mutations, a unique primary NK cell culture system to study in vitro cell activation by fibrin, and a novel small molecule that allosterically enhances aMß2-dependent cell adhesion to fibrin polymers. The investigative team comprises experts in toxic liver injury and fibrosis, coagulation and fibrinogen biochemistry/function, and novel mouse models. Specifically, in our proposed studies we will: (Aim 1) Determine the mechanism by which fibrin inhibits experimental liver fibrosis; (Aim 2) Determine the mechanisms whereby fibrin enhances NK cell activation in vitro; and (Aim 3) Determine the contribution of the fibrin-NK cell axis to experimental liver fibrosis in vivo. The insights gained will significantly advance the current understanding of coagulation in liver fibrosis and highlight putative targets and novel therapeutic strategies to inhibit liver fibrosis. Potential strategies could include mechanism-based translation of drugs targeting specific non-hemostatic functions of fibrin that could reduce fibrosis without simultaneously inducing a bleeding risk.