Hormonal Influences on Airway Biology and Naphthalene‐ Mediated Clara Cell Injury

Abstract

Women have a greater chance of developing adult onset asthma, COPD, and some forms of lung cancer than men. Naphthalene (NA), a bioactivated cytotoxicant, is used to model distal Clara cell airway injury and repair. Our laboratory has shown that female mice are more sensitive than male mice to NA toxicity. The objective of the current study was to evaluate the role of hormones in normal airway biology and in NA mediated injury. This was achieved by 1) measuring estrogen receptors (ESR) gene expression by RT PCR in airways by estrus cycle stage, 2) measuring glutathione levels in airways by cycle stage, and 3) comparing airway damage in response to NA in intact vs. gonadectomized animals. Airway level specific responses were defined in microdissected airways. In comparison to non‐cycling mice, ESR expression was decreased in both diestrus and proestrus and increased in the estrus phase of the cycle. Glutathione levels were decreased in the airways of mice during diestrus and metestrus compared to male mice. Depletion of glutathione within the Clara cell plays a major role in NA cytotoxity. Confocal microscopy of microdissected airways as well as high resolution resin sections showed less extensive injury in ovariectomized mice compared to intact female mice. These findings support the hypothesis that sex differences in lung injury are influenced by hormones. Funded by NIH grants ES012720, HL007013‐29, and TRDRP 14RT‐0191.