Male Sex Hormones Exacerbate Lung Function Impairment after Bleomycin-Induced Pulmonary Fibrosis

Abstract

The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P , 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P , 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.

Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

“…With these caveats in mind, it is plausible that the observed differences in fibrosis, pulmonary inflammatory cell accumulation, and mortality between young male and female mice and aged male and female mice are reflective of authentic age-and sex-dependent differences. Consistent with this conclusion, Voltz et al (55) reported that young male mice display a greater decline in static lung compliance compared with young female mice following bleomycin instillation. Castrated male mice exhibited a similar response to female mice, whereas female mice that were virilized with testosterone showed a similar decline in static lung compliance to male mice.…”

“…While these environmental exposures can occur in both men and women, older men are more likely to have been lifelong smokers compared with women, and men more commonly occupy positions in the workforce associated with these types of occupational exposures (33,38). Second, studies conducted in rodents have suggested that androgens may contribute to enhanced injury to, and fibrosis of, the lung and other organs (10,19,37,51,55). However, the interactions between age and sex have not been systematically studied in animal models of pulmonary fibrosis.…”

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

“…In this study, BLM was administered at a dose of 7.5 U/kg; all the male rats survived, while a high mortality rate of 80±5% was calculated for the female animals. Whereas Voltz et al (2008), reported that androgens, too, play a worsening role in the BLM-induced pulmonary fibrosis model. However, invasive pulmonary function tests were used in this study and no significant difference could be shown between animals of either sex in terms of the results of frequently used biochemical and histological indices of pulmonary fi brosis.…”

“…There is, on the other hand, a generally shared expectation that female animals may enhance fi brosis by increasing both infl ammatory and immune responses through the estrogen hormones or a modifi ed cytokine expression, although several studies indicate the opposite (Gharaee-Kermani et al, 2005;Voltz et al, 2008).…”

Neglected evidence in idiopathic pulmonary fibrosis: from history to earlier diagnosis

“…A recent study was performed with bleomycin instilled intratracheally to young (8-12 weeks) and aged (52-54 weeks) male and female C57BL/6 mice [56]. In this model, aged male mice developed more severe lung disease with increased mortality compared to young mice [56] and young male mice developed more pulmonary fibrosis than young female mice [56,57], demonstrating that both advanced age and male sex contribute to fibrotic pathophysiology in the animal model. Furthermore, mice prone to accelerated senescence are also more susceptible to bleomycin-induced pulmonary fibrosis compared to control mice [58].…”