The role of lymphokines and monokines in fibrosis.

The close association of mononuclear inflammatory cells and fibroblasts within inflammatory loci during fibroplasia and fibrogenesis has prompted investigations seeking to identify potential intercellular signals linking inflammation and fibrosis. Lymphocytes and macrophages precede the influx of fibroblasts into these sites and exist within the lesion as fibroblasts infiltrate, divide, and generate components of the extracellular matrix. In vitro studies have revealed that activated lymphocytes and monocytes are capable of generating mediators that effect these fibroblast functions including stimulation of fibroblast chemotaxis, proliferation, and collagen and glycosaminoglycan synthesis (Figure 2). Furthermore, several of these mediators have been found to be spontaneously generated by lymphocytes and/or macrophages which have been isolated directly from an inflammatory site. Inflammatory cells are also the source of inhibitory factors which interrupt fibroblast motility, division, and collagen synthesis. Consequently, mononuclear cells appear to be instrumental in the cessation of fibrotic mechanisms after normal repair has occurred. The pronounced fibroplasia and fibrosis which often occur in association with certain immune-mediated disorders (schistosomiasis, pulmonary fibrosis, SCW-induced granuloma) may be the consequence of prolonged production of the lymphokines and monokines which enhance fibroblast function by chronically stimulated inflammatory cells or alternatively, of the failure to generate adequate levels of inhibitory molecules. The location and the phenotype of the target fibroblast must also be important since some organs (liver, lungs, dermis) frequently demonstrate preferential fibrotic sequelae in response to inflammatory stimuli, whereas others favor pronounced degradation of connective tissue (synovium). The regulation of these connective tissue events appears to involve multiple interdependent pathways with both positive and negative feedback control. Continued exploration of the lymphocyte and monocyte signals which converge on the fibroblast as the target cell will provide further insight into the mechanisms of connective tissue repair and pathologic fibrosis.