Role of endothelium in chronic inflammation.

The character of the immunologically stimulated chronic inflammatory infiltrate is to a considerable extent determined by nonspecific factors governing mononuclear cell traffic. The volume, composition and distribution of this traffic is strongly dependent on an initial adhesive interaction between circulating mononuclear cells and the EC of the PCV of the involved tissues. The emigration of lymphocytes from the PCV is preceded by binding of the lymphocytes to the endothelial lining cell. This binding is enhanced by lymphokines (IFN-gamma, TNF-beta) and monokines (IL-1, TNF-alpha), secreted by perivascular inflammatory cells and acting on the EC. This enhancement may permit an initial, immunologically generated small focus of mononuclear cells to amplify itself to a larger infiltrate. Movement of the EC-bound lymphocyte through the endothelium may be facilitated by IFN-gamma, as suggested by evidence that T cells, bound to the surface of EC monolayers overlying nitrocellulose filters, migrate through these monolayers in increased numbers in the presence of IFN-gamma. Movement of the lymphocyte through the wall of the PCV and subsequently through the perivascular space toward the inflammatory focus may be enhanced by the chemotactic action of IL-1, generated by the macrophages of the perivascular infiltrate. The lining layer of the synovial membrane may play an important role in the development of synovitis. Hyperplasia of the synovial lining layer is associated with the secretion of chemotactic agents which can attract monocytes from the PCV toward the lining. The continuous movement of monocytes from PCV to lining may establish a steady-state population of macrophage-like cells in the interstitium of the synovium. These may provide the accessory cell population required for the immune responses which give rise to the various chronic inflammatory synovitides. The sublining layer of the rheumatoid synovium does, in fact, contain large numbers of DR+macrophage+ cells which may represent this accessory cell population. Since the cytokines mediate the inflammatory effects of the cellular immune response, it follows that when injected intraarticularly they should produce synovial inflammation. Such inflammation has, in fact, been produced in experimental animals by the intraarticular injection of supernatants of antigen-stimulated PBMC or of rIL-1. A cytokine-mediated chronic inflammatory reaction may be expected to assemble a polyclonal population of lymphocytes around the PCV. However, the fraction of the accumulated T cells which is antigen reactive is not entirely a random one as indicated by the following.(ABSTRACT TRUNCATED AT 400 WORDS)