Null mutation in macrophage migration inhibitory factor prevents muscle cell loss and fibrosis in partial bladder outlet obstruction

Abstract

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.

Antagonism of macrophage migration inhibitory factor decreases cyclophosphamide cystitis in mice

“…In addition to mediating bladder inflammation, recent evidence showed that MIF is involved in detrusor muscle loss and fibrosis associated with outlet obstruction in mice, 56 suggesting that MIF antagonism may be a prominent target in treating detrusor underactivity and urinary retention. Therefore, our results show that blocking MIF's tautomerase activity with ISO-1, prevented (or greatly decreased) inflammatory changes in a well-described model of rodent cystitis.…”

Endogenous macrophage migration inhibitory factor reduces the accumulation and toxicity of misfolded SOD1 in a mouse model of ALS

“…MIF KO mice have been developed in which exons 2 and 3 of MIF are disrupted (23). These MIF KO mice, backcrossed onto a C57BL6 background (24), were used in this study. Importantly, all mouse lines were on a pure C57BL6 background to eliminate confounding genetic influences.…”

“…MIF knockout (KO) mice, in which exons 2 and 3 of MIF are disrupted (23), did not develop obvious phenotypes when backcrossed onto a C57BL6 background (24). In the present study, we used these MIF KO mice and the transgenic mutant SOD1 G85R mice (25) to study how endogenous MIF affects the course of Significance Amyotrophic lateral sclerosis (ALS) can be caused by mutations in superoxide dismutase (SOD1), which lead to the accumulation of misfolded SOD1 proteins and to the death of motor neurons.…”

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

“…23 There is also evidence that MIF promotes apoptotic cell death in primary bladder muscle cells, B lymphocytes, tumor cell lines, cardiomyocytes and neurons. [24][25][26][27] The mechanism of apoptosis induction by MIF is not well understood. There is some circumstantial evidence that suggests the involvement of mitochondrial dysfunction in MIF-mediated apoptosis.…”