Pancreatitis is an inflammatory disease of the pancreas which results in significant morbidity and mortality. When exposed to a noxious stimulus, pancreas initially responds with an acute reaction characterized by intense local and systemic inflammation termed acute pancreatitis (AP). While in most patients the pancreas recovers from AP without any residual deficit, in some patients, due to ongoing injury or for unclear reasons, continued inflammation leads to chronic fibro-inflammatory changes in the pancreas, an entity termed chronic pancreatitis (CP). Despite decades of research there is no specific therapy for acute or chronic pancreatitis. Since acute and chronic pancreatitis represent two ends of a continuum of inflammation, strategies targeting inflammation should lead to development of novel therapies for this disease. In this regards pirfenidone, a novel small anti-inflammatory molecule has been developed as a treatment for Idiopathic Pulmonary Fibrosis (IPF). While pirfenidone is approved for clinical use only in IPF, preclinical studies have shown that it has anti-fibrotic activity in models of liver and kidney fibrosis as well. Furthermore, by virtue of its anti-inflammatory properties, pirfenidone has demonstrated protective activity in models of acute inflammation as well. However, the efficacy of pirfenidone against acute or chronic pancreatitis has never been evaluated. Intriguingly our preliminary data suggest that therapeutic treatment with pirfenidone, i.e. when delivered after initiation of injury, attenuates local and systemic inflammation in acute pancreatitis and decreases fibrosis in chronic pancreatitis. In the translational aims of the current proposal the efficacy of pirfenidone will be evaluated in multiple models of acute and chronic pancreatitis to generate pre-clinical data for future clinical trial. Given that no specific therapy for AP or CP exists and that pirfenidone is already in clinical use, these studies have immediate clinical relevance. The mechanism of action of pirfenidone is unclear. Our preliminary data suggest that pirfenidone increases regulatory T cells (Tregs). In multiple acute and chronic inflammatory diseases, Tregs have been shown to attenuate inflammation, improve disease severity and help in recovery. Based on our preliminary data we have put forward a novel hypothesis that pirfenidone attenuates severity of acute and chronic pancreatitis by augmenting Treg population. The role of Tregs in pathophysiology of acute and chronic pancreatitis and their role in the efficacy of pirfenidone have never been studied before. Successful execution of the proposed studies will provide novel insight into pathogenesis of pancreatitis and identification of novel drug targets.
Pancreatitis is an inflammatory disease of pancreas. Our data suggest that pirfenidone, an anti-inflammatory compound which is approved for treatment of idiopathic pulmonary fibrosis, reduces severity of acute and chronic pancreatitis. In the translational aims of the current proposal the efficacy of pirfenidone will be evaluated in multiple models of acute and chronic pancreatitis to generate pre-clinical data for future clinical trial. In the mechanistic aim of the grant the mechanism of action of pirfenidone will be explored. We strongly believe that the studies proposed in the current grant proposal will lead to emergence of pirfenidone as a new drug for treatment of acute and chronic pancreatitis. Furthermore, mechanistic studies will elucidate novel mechanisms with emergence of novel targets for therapy of acute and chronic pancreatitis.
| Garg, Bharti; Giri, Bhuwan; Modi, Shrey et al. (2018) NF?B in Pancreatic Stellate Cells Reduces Infiltration of Tumors by Cytotoxic T Cells and Killing of Cancer Cells, via Up-regulation of CXCL12. Gastroenterology 155:880-891.e8 |
| Sethi, Vrishketan; Kurtom, Saba; Tarique, Mohammad et al. (2018) Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response. Gastroenterology 155:33-37.e6 |
