Multiple lines of evidence suggest that Th2 inflammation and the remodeling are essential components in the pathogenesis of asthma and anti-parasite responses. Chitin, the second most abundant glycopolymer in biology, is an integral component of the walls of parasites and fungi where it protects them from potentially deleterious aspects of their environment. Chitin containing organisms also produce chitinases to allow them to molt and grow. As a result, chitinase production is an essential part of the immune response to parasites and infectious agents in lower life forms. Interestingly, chitin and chitin synthase do not exist in man. However, a number of chitinase and chitinase-like genes have recently been appreciated in man. This includes true chitinases such as acidic mammalian chitinase (AMCase) and members that lack chitinase activity like breast regression protein-39 (BRP-39). Interestingly, AMCase and BRP-39 are both potently induced at sites of Th2 inflammation. However, very little is known about the effects of AMCase and virtually nothing is known about the role(s) of BRP-39 in human biology. We speculated that elements that are critical in anti-parasite Th2 inflammation and remodeling also play essential roles in asthmatic Th2 responses. To test this we studied the regulation and roles of AMCase and BRP-39 in allergic inflammation and remodeling. Our studies demonstrate that AMCase and BRP-39 are prominently induced in macrophages and epithelial cells at sites of Th2 inflammation. They also demonstrate that AMCase has prominent chitinase activity, is induced in a Th2-specific manner and that treatment with anti-AMCase antiserum markedly decreases aeroallergen-induced Th2 inflammation and IL-13 effector pathway activation. In contrast, BRP-39 induction was not Th2 specific and treatment with anti-BRP-39 antiserum did not alter IL-13 induced inflammation. It did, however, decrease IL-13 induced tissue remodeling. These observations led us to the following hypotheses: (1) the prototypic chitinase, AMCase, and the prototypic chitinase-like protein, BRP-39 are prominent gene products at sites of Th2 inflammation; (2) AMCase plays a key role in the pathogenesis of Th2 inflammation where it is required for optimal IL-13 effector pathway activation and (3) BRP-39 plays a key role in the pathogenesis of Th2-induced tissue remodeling. To test these hypotheses we propose to:
AIM I. Characterize the expression, localization, and regulation of AMCase and BRP-39 in the antigen challenged and transgenic lung.
AIM II. Characterize the role(s) of AMCase in Th2 inflammation, physiologic dysregulation and remodeling.
AIM III. Characterize the role(s) of BRP-39 in Th2 inflammation, physiologic dysregulation and remodeling.
Showing the most recent 10 out of 16 publications
