Moderate Stress Protects Female Mice against Bacterial Infection of the Bladder by Eliciting Uroepithelial Shedding

Abstract

We have previously shown (M. Aronson, 0. Medalia, D. Amichay, and 0. Nativ, Infect. Immun. 56:1615-1617, 1988) that shedding of viable uroepithelial cells (elicited by invading microorganisms) constitutes an antimicrobial defense mechanism. The present study deals with two different stress-involving procedures, in which increased uroepithelial shedding rendered female mice resistant to vesical infection. Moderate stress was induced in female mice by exposing the animals either to constant illumination for 96 h or to 37°C heat for 24 h. In both cases, the rate of infection was considerably reduced as a result of increased epithelial shedding (P < 0.0001). Stress was manifested by both reduced thymic weight and increased blood corticosterone levels. Shedding was also elicited by intraperitoneal injection of norepinephrine together with hydrocortisone or by intravesical injection of corticosterone. Constant illumination as well as heat enormously facilitated the migration of polymorphonuclear cells into the bladder following the action of chemotactic stimuli. Male mice subjected to identical stress-generating conditions did not display considerable epithelial shedding or increased migration of polymorphonuclear cells, and they were not protected from intravesical infection.The phenomenon of uroepithelial shedding was originally described by Orikasa and Hinman as involving dying and dead cells, and these authors suggested that epithelial desquamation serves as a defense mechanism, since the adhering bacteria are washed out together with the cells (9).Our own independent studies, on the other hand, were carried out under conditions less injurious to the host's cells, employing radiation-killed cells of a nonvirulent strain. We were able to demonstrate that most of the shed cells are viable and that the active agent which induces shedding is the bacterial endotoxin (3). Our results also indicated that the uroepithelium is preprogrammed to respond by rapid shedding when required, as the process begins within 1 h of administration of lipopolysaccharide (LPS) to the bladder. The mechanism of shedding was shown to be mediated by the release of proteolytic enzymes, since pretreatment with aprotinin-the inhibitor of these enzymes-proved to considerably diminish the shedding. Since polymorphonuclear (PMN) cells do not begin to appear before 4 h following the LPS instillation, epithelial cells remain the sole candidates for being the source of the proteolytic enzymes. The phenomenon is apparently entirely local, not involving central mechanisms.The present studies were initiated in order to establish whether perturbation of circadian rhythms would affect the course of experimental vesical infection. It was expected that the spontaneous clearance of bacteria, which usually requires 2 to 3 weeks, would be prolonged under these conditions. However, the female mice which were exposed to 4 days of constant illumination, in order to develop a state of "free running" (i.e., state of unsynchronized circadian rhythms), failed altogeth...

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