There has been considerable interest in the role of toll-like receptor (TLR) signaling in the host response to gastrointestinal injury. Cyclooxygenase-2 expression and PGE2 production are important downstream events in this process. The ligands typically associated with TLRs are microbial products;however, TLRs can also bind host molecules. In particular, TLR4 binds hyaluronic acid. Hyaluronic acid is a glycosaminoglycan that is produced by many cell types and is released into the extracellular space where it acts as a component of the extracellular matrix. An important role for hyaluronic acid binding to TLR4 has been described in non-microbial injury models in the lung and skin but the role of hyaluronic acid in the host response to gastrointestinal injury has not been explored. We have developed preliminary data demonstrating that: 1. Hyaluronic acid is produced in response to gastrointestinal injury in the DSS colitis model and in radiation injury in the small intestine. 2. Hyaluronic acid decreases the severity of DSS colitis. 3. In radiation injury in the small intestine, hyaluronic acid decreases radiation-induced apoptosis and increases crypt survival. These findings have lead to the following hypotheses. 1. Hyaluronic acid is generated in response to gastrointestinal mucosal injury and is a stimulus for epithelial proliferation and repair. Hyaluronic acid acts through TLR4 and perhaps TLR2 in mediating the protective response of the host in gastrointestinal injury. Moreover COX-2 expression and PGE2 production are important downstream signaling events in this process. 2. Administration of hyaluronic acid as a pharmacologic agent has preventive or therapeutic utility in gastrointestinal injury. Here we propose the following Specific Aims: 1) To define the mechanism by which HA synthesis is induced during gastrointestinal injury. 2) To define the mechanisms by which HA affects the host response to epithelial injury. 3) To define the potential role of exogenous HA as a preventive or therapeutic pharmacologic agent in models of gastrointestinal injury including DSS colitis and radiation injury in the small intestine.

Public Health Relevance

This proposal is most directly relevant to the development of radioprotective agents (agents that would protect normal intestine during radiation therapy) and the development of agents that would increase the growth of the intestine after resection. This proposal is also relevant to any disease that involves the host response to injuries to the intestinal epithelium including inflammatory bowel disease and enteric infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055753-14
Application #
8461662
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
1999-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
14
Fiscal Year
2013
Total Cost
$301,317
Indirect Cost
$103,082
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Stenson, William F (2014) The universe of arachidonic acid metabolites in inflammatory bowel disease: can we tell the good from the bad? Curr Opin Gastroenterol 30:347-51
Sundaresan, Sinju; Shahid, Rafiq; Riehl, Terrence E et al. (2013) CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin. FASEB J 27:1191-202
Ciorba, Matthew A; Riehl, Terrence E; Rao, M Suprada et al. (2012) Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut 61:829-38
Riehl, Terrence E; Foster, Lynne; Stenson, William F (2012) Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism. Am J Physiol Gastrointest Liver Physiol 302:G309-16
Riehl, T E; He, L; Zheng, L et al. (2011) COX-1(+/-)COX-2(-/-) genotype in mice is associated with shortened time to carotid artery occlusion through increased PAI-1. J Thromb Haemost 9:350-60
Walker, Monica R; Brown, Sarah L; Riehl, Terrence E et al. (2010) Growth factor regulation of prostaglandin-endoperoxide synthase 2 (Ptgs2) expression in colonic mesenchymal stem cells. J Biol Chem 285:5026-39
Zheng, Ling; Riehl, Terrence E; Stenson, William F (2009) Regulation of colonic epithelial repair in mice by Toll-like receptors and hyaluronic acid. Gastroenterology 137:2041-51
Alford, Shannon K; Longmore, Gregory D; Stenson, William F et al. (2008) CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells. J Immunol 181:2544-55
Brown, Sarah L; Riehl, Terrence E; Walker, Monica R et al. (2007) Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J Clin Invest 117:258-69
Ebach, Dawn R; Newberry, Rodney; Stenson, William F (2005) Differential role of tumor necrosis factor receptors in TNBS colitis. Inflamm Bowel Dis 11:533-40

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