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 aM2 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 aM2-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.
Chronic liver damage can lead to fibrosis, marked by scarring of the liver tissue that can compromise liver function and for which treatments are very limited. Activation of the blood coagulation cascade is observed both in patients with liver fibrosis and in mice with experimental xenobiotic-induced liver fibrosis, and this is associated with deposition of fibrin polymers in the liver tissue. The primary goal of this research program is to uncover as yet undescribed mechanisms whereby fibrin polymers inhibit liver fibrosis, such that new therapies can be designed to promote resolution of liver fibrosis in patients.
| Pant, Asmita; Kopec, Anna K; Luyendyk, James P (2018) Role of the blood coagulation cascade in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 315:G171-G176 |
| Kopec, Anna K; Spada, Alfred P; Contreras, Patricia C et al. (2018) Caspase Inhibition Reduces Hepatic Tissue Factor-Driven Coagulation In Vitro and In Vivo. Toxicol Sci 162:396-405 |
| Lisman, Ton; Luyendyk, James P (2018) Platelets as Modulators of Liver Diseases. Semin Thromb Hemost 44:114-125 |
| Poole, Lauren G; Massey, Veronica L; Siow, Deanna L et al. (2017) Plasminogen Activator Inhibitor-1 Is Critical in Alcohol-Enhanced Acute Lung Injury in Mice. Am J Respir Cell Mol Biol 57:315-323 |
| Kopec, Anna K; Abrahams, Sara R; Thornton, Sherry et al. (2017) Thrombin promotes diet-induced obesity through fibrin-driven inflammation. J Clin Invest 127:3152-3166 |
| Joshi, Nikita; Kopec, Anna K; Ray, Jessica L et al. (2017) Von Willebrand factor deficiency reduces liver fibrosis in mice. Toxicol Appl Pharmacol 328:54-59 |
| Joshi, Nikita; Ray, Jessica L; Kopec, Anna K et al. (2017) Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis. J Biochem Mol Toxicol 31:1-7 |
| Joshi, Nikita; Kopec, Anna K; Cline-Fedewa, Holly et al. (2017) Lymphocytes contribute to biliary injury and fibrosis in experimental xenobiotic-induced cholestasis. Toxicology 377:73-80 |
| Ray, Jessica L; Kopec, Anna K; Joshi, Nikita et al. (2017) Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis. Toxicol Sci 156:428-437 |
| Trivedi, Priyanka; Kumar, Ramya K; Iyer, Ashwin et al. (2017) Targeting Phospholipase D4 Attenuates Kidney Fibrosis. J Am Soc Nephrol 28:3579-3589 |
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