Null mutation in macrophage migration inhibitory factor prevents muscle cell loss and fibrosis in partial bladder outlet obstruction.
Idiopathic detrusor underactivity (DU) and detrusor decompensation which develops following partial bladder outlet obstruction (pBOO) are both associated with smooth muscle degeneration and fibrosis. Macrophage migration inhibitory factor (MIF), an important mediator of bladder inflammation, has been shown to promote fibroblast survival and muscle death in other tissues. We evaluated the hypothesis that MIF has similar actions in the bladder by studying detrusor responses to pBOO or sham surgery in anesthetized female mice rendered null for the mif gene (MIF KO) and in wild-type (WT) controls, all killed 3 wk after surgery. WT mice revealed intense MIF immunoreactivity in urothelial cells which decreased, without change in overall mif mRNA levels. Stereologically sound quantitative morphometric measurements were performed in the middetrusor region of each bladder. MIF KO bladders were normal in appearance, yet were 30-40% heavier, with increased middetrusor collagen and muscle, compared with WT controls. In WT mice, pBOO increased the collagen-to-muscle ratio 1.9-fold and middetrusor collagen 1.8-fold, while nucleated muscle counts were 22% lower. In MIF KO mice, by contrast, pBOO had no significant effect on any of these parameters. In primary bladder muscle cultures, treatment with rMIF protein increased TUNEL staining, raising the proportion of early and late apoptotic cells on flow cytometry. Our studies implicate MIF in the sequence of events leading to detrusor muscle loss and fibrosis in obstruction. They raise the possibility that strategies designed to antagonize MIF synthesis, release, or biological activity could prevent or delay DU and urinary retention.
Taylor
John A
JA
UConn Center on Aging, University of Connecticut Health Center, 263 Farmington Ave., MC-5215, Farmington, CT 06030-5215, USA.
Zhu
Qing
Q
Irwin
Brian
B
Maghaydah
Yazeed
Y
Tsimikas
John
J
Pilbeam
Carol
C
Leng
Lin
L
Bucala
Richard
R
Kuchel
George A
GA
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D001748:Urinary Bladder Neck Obstruction / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016055:Urinary Retention / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
D008263:Macrophage Migration-Inhibitory Factors; D003094:Collagen; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse