Role of toll like receptors (TLRs)in Gd contrast agent induced skin fibrosis

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DESCRIPTION (provided by applicant): Nephrogenic Systemic Fibrosis (NSF) is a rare condition occurring in a small subset of patients with renal insufficiency following exposure to Gadolinium based contrast agents (GdBCA). This disorder is characterized by severe dermal and systemic fibrosis with the presence of large numbers of activated macrophages, fibrocytes and fibroblasts in affected tissues. Several published studies have reported the development of skin lesions in sub-total nephrectomized rodents injected with high doses of GdBCA, however, these lesions do not demonstrate many of the histopathological characteristics of human NSF lesions. To overcome this flaw, we propose to develop a more realistic and informative animal model of NSF by utilizing mice with adenine-induced renal failure that have either been injected intravenously with high dose GdBCA or that have been exposed to GdBCA via subdermally implanted osmotic pumps or by intratracheal instillation. Given the intense interest in the role of macrophages and, in particular, of the Toll-like receptor (TLR) pathway in the development of fibrosis, we will perform extensive mechanistic studies to examine the role of macrophages and TLRs in the development of GdBCA induced fibrosis in this new model. The hypotheses to be tested will be: 1) GdBCA exposure induces NSF-like fibrotic lesions, 2) activated macrophages are required to induce these lesions; and 3) the induction requires engagement of TLR4 and/or TLR7. To test these hypotheses, the following specific aims are proposed: SPECIFIC AIM 1: Induce fibrosis by GdBCA administration in C57BL/6J mice with adenine induced renal failure. SPECIFIC AIM 2: Investigate the role of macrophages and of TLR4 and TLR7 in the development of fibrosis in mice with adenine induced renal disease. The studies proposed here will provide valuable information regarding the initial molecular events that couple exogenous or environmental etiologic factors with inflammation and fibrosis focusing on the participation of the innate immunity system and TLR responses in these processes. Furthermore, these studies will provide important clues regarding the pathogenesis of idiopathic systemic fibrotic disorders such as SSc and may allow the identification of novel potential therapeutic targets for these diseases. PUBLIC HEALTH RELEVANCE: Nephrogenic Systemic Fibrosis (NSF) is a fibrotic disease induced by exposure of patients with renal insufficiency to gadolinium-based contrast agents (GdBCA) employed for magnetic resonance scanning. Current animal models of GdBCA induced skin lesions fail to demonstrate many relevant components of human NSF lesions. The research studies proposed here will use GdBCA to cause fibrosis in mice in which renal failure which closely resembles human renal failure in induced by administration of a special diet. These studies will elucidate the mechanisms involved in the initiation and progression of inflammation and fibrosis as well as the role of specialized cells known as macrophages and their cell surface receptors known as Toll-like receptors. The results obtained will be novel and, most importantly, they may allow us to identify promising molecular targets for the development of novel and effective therapies for other fibrotic disorders including Systemic Sclerosis (Scleroderma).