Figure 611

TIN showing early phase with focal (A) and more severe and diffuse (B) interstitial inflammatory cell infiltrates. Late phase showing thickened tubular basement membrane, distorted tubular shape, and cellular infiltration of the tubules, called tubulitis (C). The extent and severity of interstitial cellular infiltrates show a direct correlation with the severity of tubular atrophy and interstitial fibrosis. Experimental studies show the sequential accumulation of T cells and monocytes after the initial insult. Accumulation of these cells implicates their important role both in the early inflammatory stage of the disease and in the progression of subsequent injury.

Immunohistologic examination utilizing monoclonal antibodies, coupled with conventional and electron microscopy, indicates that most of the mononuclear inflammatory cells comprising renal interstitial infiltrates are T cells. These T cells are immunologically activated in the absence of any evidence of tubulointerstitial immune deposits, even in classic examples of immune complex-mediated diseases such as systemic lupus erythematosus. The profile of immunocompetent cells suggests a major role for cell-mediated immunity in the tubulointerstitial lesions. The infiltrating cells may be of the helper-inducer subset or the cyotoxic-suppressor subset, although generally there seems to be a selective prevalence for the former variety. Lymphocytes that are peritubular and are seen invading the tubular epithelial cells, so-called tubulitis, are generally of the cytotoxic (CD8+) variety.

The interstitial accumulation of monocytes and macrophages involves osteopontin (uropontin). Osteopontin is a secreted cell attachment glycoprotein whose messenger RNA expression becomes upregulated, and its levels are increased at the sites of tubular injury in proportion to the severity of tubular damage. The expression of other cell adhesion molecules (intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin) also is increased at the sites of tubular injury. This increased expression may contribute to the recruitment of mononuclear cells and increase the susceptibility of renal cells to cell-mediated injury.

Fibroblastic (type I) interstitial cells, which normally produce and maintain the extracellular matrix, begin to proliferate in response to injury. They increase their well-developed rough endoplasmic reticulum and acquire smooth muscle phenotype (myofibroblast). Growth kinetic studies of these cells reveal a significant increase in their proliferating capacity and generation time, indicating hyper-proliferative growth.

Mechanisms Involved in Renal Interstitial Fibrosis



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