Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans

Abstract

Sex-specific differences in pulmonary morbidity in humans are well documented. Hyperoxia contributes to lung injury in experimental animals and humans. The mechanisms responsible for sex differences in the susceptibility towards hyperoxic lung injury remain largely unknown. In this investigation, we tested the hypothesis that mice will display sex-specific differences in hyperoxic lung injury. Eight week-old male and female mice (C57BL/6J) were exposed to 72 h of hyperoxia (FiO2>0.95). After exposure to hyperoxia, lung injury, levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF 2α) (LC-MS/MS), apoptosis (TUNEL) and inflammatory markers (suspension bead array) were determined. CytochromeP450 (CYP)1A expression in the lung was assessed using immunohistochemistry and western blotting. After exposure to hyperoxia, males showed greater lung injury, neutrophil infiltration and apoptosis, compared to air-breathing controls than females. Pulmonary 8-iso-PGF 2α levels were higher in males than females after hyperoxia exposure. Sexually dimorphic increases in levels of IL-6 (F>M) and VEGF (M>F) in the lungs were also observed. CYP1A1 expression in the lung was higher in female mice compared to males under hyperoxic conditions. Overall, our results support the hypothesis that male mice are more susceptible than females to hyperoxic lung injury and that differences in inflammatory and oxidative stress markers contribute to these sex-specific dimorphic effects. In conclusion, this paper describes the establishment of an animal model that shows sex differences in hyperoxic lung injury in a temporal manner and thus has important implications for lung diseases mediated by hyperoxia in humans.

NLRP3 Protein Deficiency Exacerbates Hyperoxia-induced Lethality through Stat3 Protein Signaling Independent of Interleukin-1β

“…We exposed mice to 90% O 2 to induce hyperoxia, whereas Zhang et al exposed mice to 100% O 2 . The survival time during hyperoxia reported here is longer than that reported by Zhang et al Furthermore, Lingappan et al (35) reported that male mice are more susceptible than female mice to HALI, suggesting genderspecific differences in responses of mice with HALI. Moreover, the responses to hyperoxia and subsequent HALI are influenced by the ambient housing temperature (2).…”

TRPA1: Acrolein meets its target

“…While it is possible that sex-specific regulation of TRPA1 expression is responsible for the observed difference, other sexually dimorphic mechanisms may play a role such as the differential production of antioxidant defense systems, protective enzymes, cytokines and other mediators. Increased male susceptibility has been reported for other types of lung injury, including hypoxic lung injury where female mice of the same strain (C57BL/6) displayed higher recovery rates (Lingappan et al, 2013). Differences in acrolein-induced mortality also exist between inbred mouse strains, however, the Trpa1 gene was absent in the list of polymorphic genes linked to strain-specific acrolein susceptibility (Leikauf et al, 2011).…”

The effect of 17β-estradiol on sex-dimorphic cytochrome P450 expression patterns induced by hyperoxia in the liver of male CBA/H mice

“…Resistance to hyperoxia is found to be female predominant in adult animals [19], We found that hyperoxia induced significant sex-related changes in liver oxidative/antioxidative status which were reflected in higher mortality rate of adult male mice [13], and also found that treatment of male mice with E2 could efficiently boost antioxidative system in the liver [14]. In this study…”