Lipopolysaccharide and inflammatory cytokines cause an inducible nitric oxide synthase-dependent bladder smooth muscle fibrotic response

Purpose: Bladder wall fibrosis is a sequela of recurrent urinary tract infection (UTI). Inducible nitric oxide synthase (iNOS) has been shown to mediate the fibrotic response to inflammation in other tissues. We determined if iNOS could be involved in the fibrotic response to recurrent UTI. Materials and Methods: Human bladder smooth muscle cells (SMC) were treated with bacterial lipopolysaccharides (LPS) and a mixture of inflammatory cytokines. The level of collagen type III, and the levels of iNOS mRNA, protein and activity were determined. The effect of the iNOS inhibitor aminoguanidine on collagen type III expression was then assessed. Results: Expression of collagen type III, iNOS mRNA and iNOS protein as well as iNOS activity were increased in bladder SMC treated with the combination of LPS, and cytokines. The increase in collagen type III expression was inhibited by pretreatment of cells with aminoguanidine. Conclusions: LPS and inflammatory cytokines induce collagen type III expression in an iNOS dependent manner in human bladder SMC. This finding suggests that iNOS may be a critical mediator of the bladder wall fibrotic response to chronic UTI and iNOS inhibitors may be of therapeutic value in patients with chronic UTI.