Testosterone alleviates inflammation but increases the methacholine response in male mice with allergic lung inflammation.

Abstract

Testosterone seems protective against asthma, but the underlying mechanisms are uncertain. Although several of its anti-inflammatory properties have been described, its effect on respiratory mechanics and the methacholine response are incompletely understood. Herein, the effect of testosterone was investigated on several features of experimental asthma with a special focus on respiratory mechanics and the methacholine response. Systemic testosterone was first altered to subphysiological, physiological, or supraphysiological levels in male BALB/c mice through orchiectomy and testosterone supplementation. Testosterone (0.25 mg/day/30 g of body weight) was delivered continuously during 20 days using an implanted pump. At day 10, each group was exposed intranasally to either saline or house dust mite (HDM) once daily for 10 consecutive days to induce allergic lung inflammation. The day after the last exposure, respiratory mechanics were measured at baseline and in response to nebulized methacholine. Bronchoalveolar lavages (BAL) and lung tissues were also collected to quantify inflammation. Baseline respiratory mechanics were altered in mice with subphysiological levels of testosterone, with signs of small airway narrowing heterogeneity and closure. Testosterone drastically inhibited the HDM-induced inflammation. Yet, testosterone also increased the methacholine response, which occurred to the same extent in mice with and without experimental asthma. It is concluded that testosterone improves baseline respiratory mechanics and, although it increases the methacholine response, it does not synergistically amplify hyperresponsiveness in a context of experimental asthma, probably because it concurrently decreases inflammation.NEW & NOTEWORTHY Male mice with three distinct levels of testosterone were evaluated in a common mouse model of asthma induced by house dust mite exposures. Although testosterone decreased allergic lung inflammation, it also increased the response to nebulized methacholine. This mismatch between inflammation and the methacholine response informed about how different features of experimental asthma can be swayed in different directions by a single molecular mediator.