Acute liver failure (ALF) is a devastating condition that affects patients with and without prior liver disease, including the veteran patients served by the Veterans Administration. Although the causal factors for ALF are generally known, there is a lack of effective pharmacologic treatment as the intra- and intercellular mechanisms of ALF are poorly understood. Kupffer cells (KCs), neutrophils, monocytes, and T cell-mediated immune reactions have been implicated as critical components of the pathogenesis of various types of liver damage. Yet, the morbidity and mortality due to acute liver injury of various etiologies continue to be high (>20,000 deaths/year in the USA) with liver transplantation as the only life-saving option. However, organ shortage, increasing costs, as well as associated complications that cause delay, or even rapid failure, of the graft function are major limitations. Thus despite extensive research, there are as yet unknown mechanisms responsible for ALF, which must be identified. Our work established that perisinusoidal hepatic stellate cells (HSCs) play an important role in endotoxin- as well as ischemia/reperfusion-induced liver injury by producing cytokines and chemokines and by recruiting neutrophils. Our new results show that depletion of HSCs imparts almost complete protection against concanavalin A (ConA)-induced liver injury, a model that has been consistently used to investigate immune cell-mediated liver damage in vivo. Even more important, we found that ConA- stimulated HSCs elicit a direct effect on hepatocytes, illustrated by high oxidative stress and death by apoptosis and necrosis Based on these findings, we hypothesize that HSCs play a central role in various types of acute liver injury from the initial stages. We propose to use the ConA-challenged HSC-depleted mouse and complementary in vitro cell culture systems as models to identify the mechanisms of ALF in 3 Specific Aims- Aim 1: To determine the role of HSCs in ConA-induced acute liver injury.
Aim 2 : To define the mechanisms of the direct effect of ConA on HSCs and then hepatocytes.
Aim 3 : To dissect the mechanisms regulating interactions between ConA-stimulated HSCs and cells of the immune system. We contend that understanding of the precise mechanisms by which HSCs orchestrate excessive liver damage directly via soluble mediators and indirectly by interacting with cells of the immune system including KCs is very critical. Such knowledge will be highly significant for the development of new therapies to target HSCs or factor(s) thereof in order to arrest the ongoing hepatic damage responsible for morbidity and mortality of ALF and to prevent a need for transplantation that would otherwise be necessary.

Public Health Relevance

Acute liver failure (ALF) is a devastating condition that affects patients, including the veterans served by the Veterans Administration, with and without prior liver disease. ALF accounts for >20,000 deaths/year in the USA. Despite extensive research, the morbidity and mortality due to ALF of various etiologies continue to be high. However, due to the lack of effective pharmacologic treatment, liver transplantation remains the only life-saving option. This is because the precise mechanisms of ALF are poorly understood. The current research, based on strong evidence from our laboratory, will apply a new approach to discover as yet unknown but critical mechanisms of ALF. It focuses on hepatic stellate cells and their interactions with other liver cells in orchestrating liver damage. Such knowledge will be highly significant for the development of new therapies to target HSCs or factor(s) thereof in order to arrest the ongoing hepatic damage responsible for morbidity/mortality of ALF and/or its progression to chronic disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Gastroenterology (GAST)
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Cincinnati VA Medical Center Research
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Rani, Richa; Kumar, Sudhir; Sharma, Akanksha et al. (2018) Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury. J Biol Chem 293:18466-18476
Sharma, Akanksha; Gandhi, Chandrashekhar R (2018) ""CHOP""ing intestinal stem cells on way to cholestatic liver injury. Hepatology 67:1216-1218
Yao, Lu; Chen, Weina; Song, Kyoungsub et al. (2017) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury. PLoS One 12:e0176106
Gandhi, Chandrashekhar R (2017) Hepatic stellate cell activation and pro-fibrogenic signals. J Hepatol 67:1104-1105
Nalesnik, Michael A; Gandhi, Chandrashekhar R; Starzl, Thomas E (2017) Augmenter of liver regeneration: A fundamental life protein. Hepatology 66:266-270
Kumar, Sudhir; Wang, Jiang; Thomson, Angus W et al. (2017) Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation. J Leukoc Biol 101:429-438
Rani, Richa; Tandon, Ashish; Wang, Jiang et al. (2017) Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage. Am J Pathol 187:2008-2019
Kumar, Sudhir; Wang, Jiang; Shanmukhappa, Shiva Kumar et al. (2017) Toll-Like Receptor 4-Independent Carbon Tetrachloride-Induced Fibrosis and Lipopolysaccharide-Induced Acute Liver Injury in Mice: Role of Hepatic Stellate Cells. Am J Pathol 187:1356-1367
Vodovotz, Yoram; Simmons, Richard L; Gandhi, Chandrashekhar R et al. (2017) ""Thinking"" vs. ""Talking"": Differential Autocrine Inflammatory Networks in Isolated Primary Hepatic Stellate Cells and Hepatocytes under Hypoxic Stress. Front Physiol 8:1104
Shoukry, Naglaa H; Fabre, Thomas; Gandhi, Chandrashekhar R (2016) A novel role for hepatic stellate cells in pathogenesis of visceral leishmaniasis. Hepatology 63:375-6

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