Effects of lipopolysaccharide on the appearance of macrophage populations and fibrogenesis in cisplatin-induced rat renal injury.

Macrophages play an important role in renal interstitial fibrosis via production of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha); these fibrogenic factors mediate induction of myofibroblastic cells capable of producing extracellular matrices. We investigated the effects of lipopolysaccharide (LPS), a macrophage activator, on the appearance of macrophage populations and subsequent fibrogenesis in cisplatin (CDDP)-induced rat renal lesions. In keeping with the progression of interstitial fibrosis, alpha-smooth muscle actin (alpha-SMA)-immunopositive myofibroblastic cell number began to increase on day 4 and continued gradually until day 16 after CDDP injection. Cells immunoreactive for ED1 (for exudate macrophages), ED2 (for resident macrophages) and ED3 (for activated resident macrophages) showed the highest number on day 4 or day 7, and thereafter, the numbers were gradually decreased up to day 16. On the other hand, the number of cells immunoreactive for OX6 (rat MHC class II-recognizing antibody) was increased on day 7 and remained elevated up to day 16. LPS was injected on day 7 after CDDP injection when the greatest number of ED1-positive macrophages were present. In CDDP/LPS-injected rats, the numbers of macrophages reacting to ED1, ED2, ED3, and OX6 were higher than those in CDDP-injected rats during the observation period between days 7 and 16; ED3- and OX6-positive cells were more prominently increased than ED1- and ED2-postive cells. By RT-PCR analysis, the expression of TGF-beta1 and TNF-alpha mRNAs in CDDP/LPS-injected rats on day 7 was markedly increased in contrast to those in CDDP-injected rats. These findings indicate that LPS treatment enhanced the macrophage expression of fibrogenic factors. However, there was no marked difference in the fibrogenesis between CDDP/LPS- and CDDP-injected rats. These findings suggest that the macrophage populations appearing in CDDP-induced rat renal lesions should be investigated further, to address the complicated pathogenesis of renal interstitial fibrosis.