Immunohistochemical observations on the kinetics of macrophages and myofibroblasts in rat renal interstitial fibrosis induced by cis-diamminedichloroplatinum.

It has been speculated elsewhere that growth factors produced by macrophages in response to tissue damage induce a modulation of pre-existing fibroblasts into myofibroblasts, leading to fibrosis. The development of these cells in cis-diamminedichloroplatinum (CDDP)-induced rat renal interstitial fibrosis was observed immunohistochemically. In the cortico-medullary junction, nuclear changes and epithelial necrosis of the proximal renal tubule (mainly the P3 segment) were seen on days 1 and 4 after a single dose (6 mg/kg body weight) of CDDP, and regenerating epithelium appeared on day 7. Gradually developing fibrosis was observed around the affected tubules on days 14 and 28. The increase in fibrosis was confirmed by histometrical analysis. The number of ED-1 (primary antibody) positive macrophages reached a peak in the affected cortico-medullary junction on day 7 and this was accompanied by an increase in muscle actin-positive myofibroblasts. On days 14 and 28, macrophages had declined in number, but the number of muscle actin-positive myofibroblasts in the fibrotic area was still high as compared with control values. Cytoplasmic myofilaments were observed in myofibroblasts by electron microscopy. These findings suggest that the myofibroblasts participate in renal interstitial fibrosis in the rat, and that their appearance may be related to macrophage infiltration in response to tubular injury, at least in the early stages of fibrosis.