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


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.
Austin
Paul F
PF
Division of Urology, St. Louis Children's Hospital, Missouri, USA.
Casale
Anthony J
AJ
Cain
Mark P
MP
Rink
Richard C
RC
Weintraub
Steven J
SJ
D002478:Cells, Cultured; D024061:Collagen Type III / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D005355:Fibrosis; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014552:Urinary Tract Infections / Q000378:metabolism / Q000473:pathology
D024061:Collagen Type III; D016207:Cytokines; D006146:Guanidines; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine