Human Monocyte Regulation of Connective Tissue Growth

Accelerated fibroblast accumulation, mitosis, and depositionof collagen during fibrotic processes are frequently precededby intense inflammatory exudates of mononuclear cells whichare derived from the peripheral blood. In vitro, we examinedthe role of human peripheral blood mononuclear cells in activationof human fibroblasts. The adherent mononuclear phagocyte, ormonocyte, was found to release mediators which stimulate fibroblastproliferation and enhance collagen production. Adherence totissue culture dishes in vitro was found to activate the releaseof these monocyte products, and represents a process which mimicsin vivo extravasation of monocytes from the blood vessel intothe connective tissue. The release of these mediators is dependenton monocyte protein synthesis, metabolism, and protease activity.Little is known of the role that immunologic sensitization toautologous connective tissue components might play in inducing such inflammatory responses which can result in pathologicfibrotic sequelae. In beginning to explore these possibilities,we have found that levels of antibodies to types I (interstitial)and IV (basement membrane) collagen correlate directly withthe extent of pulmonary fibrosis in patients with scleroderma.Furthermore, we can sensitize mice to homologous types I orIV collagen, or laminin (a basement membrane attachment protein),and elicit a delayed type hypersensitivity response which ismarked by mononuclear cell infiltration. Cell-mediated immunityto these antigens can be transferred to normal recipients withsensitized T-lymphocytes. We discuss these data and proposea hypothesis for mechanisms of monocyte extravasation fibroblastactivation fibrosis.