NOVEL ROLES FOR CHEMOKINES AND FIBROBLASTS IN INTERSTITIAL FIBROSIS

Background. Regardless of its involvement in either wound healing or e xcessive fibrosis, the interstitial fibroblast can now be considered a n important early participant in inflammatory responses. Although it i s recognized that certain immune cells and proinflammatory mediators a re intricately linked to fibrotic disease, little is presently known a bout the manner in which these mediators and cells are orchestrated to a fibrotic finale. Experimental studies have shown that interstitial fibroblasts are capable of participating in an inflammatory response b y promoting direct fibroblast-to-immune cell communication and/or modu lating the release of soluble mediators chat are mutually recognized b y both types of cells. Methods. Primary cultures of murine fibroblasts were recovered from either normal tissue or tissue undergoing a cell- mediated inflammatory response. These stromal cells were assessed for the expression of various cytokines and chemokines indicative of a typ e 1 or type 2 response. In addition, the fibroblasts were co-cultured with mononuclear cells to assess the cell-to-cell communication. Resul ts. Fibroblasts recovered from different cell-mediated inflammatory re sponses demonstrated a dramatic alteration in their cytokine profile. Fibroblasts recovered from the type 2 immune response produced high le vels of monocyte chemotactic protein-1 (MCP-I), as compared to the nor mal fibroblasts and fibroblasts recovered from the type I lesion. Mono nuclear cells co-cultured with fibroblasts induced a contact-dependent expression of elevated levels of chemokines, especially the macrophag e-derived MIP-I alpha. Thus, both fibroblasts themselves and fibroblas ts co-cultured with immune-inflammatory cells have the ability to part icipate in the maintenance of an inflammatory response via the express ion of chemokines. Conclusions Our laboratory and others have addresse d the role of chemotactic cytokines or chemokines in the fibrotic proc ess, and have demonstrated that fibroblasts are capable of modulating the activation of various immune cells that have been implicated in fi brotic disease. In addition, the interstitial fibroblast is capable of regulating its own behavior within the interstitial environment via t he expression of chemokines and chemokine receptors. Thus, novel strat egies aimed al:preventing fibrotic disease will likely need to address the early engagement of inflammatory cells by fibroblasts, and possib ly modulate the ability of fibroblasts to generate and/or recognize pr ofibrotic signals supplied by chemokines.