784 Impaired Resolution of Inflammation and Tissue Regeneration in Corticotropin Releasing Hormone (CRH)- Deficient Mice Following DSS-Colitis

Inflammatory bowel disease (IBD) is a chronic, relapsing disease owing its development on complex interactions between genetic and environmental factors. It is currently accepted that innate immunity and indigenous pathogens play a critical role in the pathophysiology of IBD by compromising the function of the epithelial barrier. In previous studies we have demonstrated immunomodulatory actions of Corticotropin Releasing Hormone, or Factor, (CRH or CRF), a neuropeptide acting as the major mediator of the stress response, in intestinal inflammation in rodents. CRH and its receptors are expressed in a variety of tissues in humans and rodents including the intestine. Using an experimental model of innate immunity-dependent ulcerative colitis, the DSS model, we have recently shown that Crh deficiency is associated with increased susceptibility to disease development, indicating new roles for CRH in innate immune responses. To extend our understanding on the role of CRH in experimental IBD, we followed the course of DSS-colitis during the phase of repair of the tissue injury. To our surprise the disease was progressed in the Crh-/mice 5 days following cessation of DSS treatment resulting in their severely compromised survival, while all wild-type mice recovered. The progressive disease in the Crh-/mice was characterized by significant body weight loss, lack of regeneration of the epithelial barrier, and signs of increased fibrosis. Preliminary findings suggest that recovery of the vascularization and the innervation of the injured tissue follow an abnormal pattern. Thus, we identified prominent expression of beta III tubulin, a neuron specific cytoskeletal protein, and synaptophysin, a major synaptic vesicle protein, during the early phase of the disease unlike the late expression in the normal mice. The significance of these findings for the adverse course of the disease in the Crh-/mice, given recent reports on the significant correlation between gut innervation and inflammation, is under investigation. Our findings demonstrate the requirement of CRH for the intestinal epithelial repair in colitis and raise the hypothesis of the critical contribution of “appropriate” tissue stress response for the resolution of inflammation and return to tissue homeostasis in the gut.