Gender Differences in Murine Airway Responsiveness and Lipopolysaccharide-Induced Inflammation

Abstract

The roles of gender and sex hormones in lung function and disease are complex and not completely understood. The present study examined the influence of gender on lung function and respiratory mechanics in naive mice and on acute airway inflammation and hyperresponsiveness induced by intratracheal LPS administration. Basal lung function characteristics did not differ between naive males and females, but males demonstrated significantly greater airway responsiveness than females following aerosolized methacholine challenge as evidenced by increased respiratory system resistance and elastance (p < 0.05). Following LPS administration, males developed more severe hypothermia and greater airway hyperresponsiveness than females (p < 0.05). Inflammatory indices including bronchoalveolar lavage fluid total cells, neutrophils, and TNF-α content were greater in males than in females 6 h following LPS administration (p < 0.05), whereas whole-lung TLR-4 protein levels did not differ among treatment groups, suggesting that differential expression of TLR-4 before or after LPS exposure did not underlie the observed inflammatory outcomes. Gonadectomy decreased airway inflammation in males but did not alter inflammation in females, whereas administration of exogenous testosterone to intact females increased their inflammatory responses to levels observed in intact males. LPS-induced airway hyperresponsiveness was also decreased in castrated males and was increased in females administered exogenous testosterone. Collectively, these data indicate that airway responsiveness in naive mice is influenced by gender, and that male mice have exaggerated airway inflammatory and functional responses to LPS compared with females. These gender differences are mediated, at least in part, by effects of androgens.

Male sex hormones promote vagally mediated reflex airway responsiveness to cholinergic stimulation

“…In particular, total lung capacity and enhanced pause (Penh) responses to methacholine aerosol have been reported to differ in naïve male and female mice (19,22,24). Importantly, we recently observed a considerable sex difference in murine airway responsiveness to cholinergic stimulation, as assessed by invasive measurement of respiratory mechanics, wherein the airways of naïve male C57BL/6 and BALB/c mice were found to be considerably more sensitive to methacholine aerosol than were those of naïve females (4). Furthermore, the minimal airway responsiveness of female mice to methacholine is not likely due to effects mediated by female sex hormones, as alteration of circulating levels via ovariectomy or exogenous administration of estradiol fails to alter responsiveness (5).…”

“…Invasive analysis of lung function was performed with the FlexiVent mechanical ventilator system (SCIREQ, Montreal, Québec, Canada) as described previously (4). Briefly, mice were anesthetized with urethane (1.5 g/kg ip), and once surgical anesthesia was established, a tracheostomy was performed, and a 19-gauge stainless-steel cannula was inserted into the trachea.…”

Preclinical SPECT/CT Imaging of αvβ6 Integrins for Molecular Stratification of Idiopathic Pulmonary Fibrosis

“…Male 6-wk-old C57BL/6 mice received 60IU bleomycin or saline via oropharyngeal dosing, as previously described (32), before nano-SPECT/CT imaging and image analysis. For integrin-blocking experiments in mice exposed to bleomycin or saline 4 wk previously, animals received either anti-avb6 (10D5; Millipore) or IgG2a isotype control antibody at a dose of 2.5 mg/kg, 24 h before nanoSPECT/CT imaging.…”

Contributions of Age and Sex to Heterogeneity of Symptoms and Effectiveness of Secondary Prevention Strategies in Asthma as Modeled in the Guinea Pig

“…In young guinea pigs, airway hyperresponsiveness after antigen sensitization and challenge was apparent in the males, but not females. In a study of adult mice using endotoxin to cause airway hyperresponsiveness, males had significantly greater methacholine-induced increases in Rn, G and H after LPS treatment (Card et al, 2006). Baseline measurements of Rn, G and H were not different for mice of either sex.…”