Fibrotic disorders (e.g. hepatic cirrhosis and interstitial lung diseases which can affect the functions of vital organs are problems encountered frequently in contemporary clinical medicine, however, knowledge concerning their pathogenesis is fragmentary. Immune and/or inflammatory reactions almost invariably precede fibrotic reactions. In this application, we propose to study several factors derived from serum, T cells, monocytes and the connective tissue matrix that modulate a variety of fibroblast functions, including chemotaxis, proliferation, and production of collagen, glycosaminoglycans and interstitial collagenase. Specific attention will be focused on the following: (1) Isolate, purify, and characterize the binding and physicochemical properties of the receptor for the chemoattractant, Alpha1(I); 2) Determine whether purified T cell-derived fibroblast proliferation factor (FPF) and interleukin 1 (IL1) act as """"""""competence"""""""" or """"""""progression"""""""" factors for fibroblasts; 3) Study the mechanisms by which the lymphokine collagen production protein (CDP) and collagen peptides stimulate and the lymphokine collagen production inhibitor and IL1 inhibit fibroblast collagen production; 4) Isolate, characterize and purify the lymphokine hyaluronate production inhibitor (HPI); 5) Characterize the nature of T cells that produce LDCF-F, FPF, CPP, CPI, and HPI; and 6) Study the role cAMP and P6E2 play in mediating the effects of IL1 on fibroblast proliferation, and collagen, hyaluronate and collagenase production. These studies should extend over basic knowledge of how inflammation and immune reactions trigger fibrosis. This knowledge may open new avenues of approach to the study of a variety of different human fibrosing diseases.
