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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Tennessee Health Science Center
Schools of Medicine
United States
Zip Code
Kirtikara, K; Morham, S G; Raghow, R et al. (1998) Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells. J Exp Med 187:517-23
Kanekura, T; Laulederkind, S J; Kirtikara, K et al. (1998) Cholecalciferol induces prostaglandin E2 biosynthesis and transglutaminase activity in human keratinocytes. J Invest Dermatol 111:634-9
Kirtikara, K; Laulederkind, S J; Raghow, R et al. (1998) An accessory role for ceramide in interleukin-1beta induced prostaglandin synthesis. Mol Cell Biochem 181:41-8
Solomon, S S; Mishra, S K; Palazzolo, M R et al. (1997) Identification of specific sites in the TNF-alpha molecule promoting insulin resistance in H-411E cells. J Lab Clin Med 130:139-46
Ballou, L R; Laulederkind, S J; Rosloniec, E F et al. (1996) Ceramide signalling and the immune response. Biochim Biophys Acta 1301:273-87
Higgins, G C; Postlethwaite, A E (1996) Synovial fluid from patients with rheumatoid arthritis contains a unique inhibitor of interleukin 1 alpha. J Rheumatol 23:965-73
Laulederkind, S J; Bielawska, A; Raghow, R et al. (1995) Ceramide induces interleukin 6 gene expression in human fibroblasts. J Exp Med 182:599-604
Postlethwaite, A E; Raghow, R; Stricklin, G et al. (1994) Osteogenic protein-1, a bone morphogenic protein member of the TGF-beta superfamily, shares chemotactic but not fibrogenic properties with TGF-beta. J Cell Physiol 161:562-70
Higgins, G C; Foster, J L; Postlethwaite, A E (1994) Interleukin 1 beta propeptide is detected intracellularly and extracellularly when human monocytes are stimulated with LPS in vitro. J Exp Med 180:607-14
Chao, C P; Laulederkind, S J; Ballou, L R (1994) Sphingosine-mediated phosphatidylinositol metabolism and calcium mobilization. J Biol Chem 269:5849-56

Showing the most recent 10 out of 25 publications