Sex Differences in Airway Inflammation and Structural Properties in a Mouse Model of House Dust Mite Challenge

Abstract

BackgroundAsthma is a chronic airway disease that leads to compromised lung function and affects more than 300 million patients worldwide, leading to >180,000 deaths each year, many of which are avoidable with proper treatment and care. Despite significant advances in diagnostic and treatment of the disease, asthma continues to be a significant health problem and an economic burden. Epidemiological studies in adult populations have revealed sex differences in asthma morbidity, with higher incidence in females than males. The causes of this disparity are still unclear, but studies have shown that sex‐specific signaling pathways regulated by hormones contribute to differences in immune cell activation and airway reactivity in response to different environmental stimuli.MethodsWith the goal of understanding the mechanisms associated with the observed sex disparities in allergen‐induced asthma, we challenged both male and female adult C57BL/6J mice with a house dust mite (HDM) solution from two species, Dermatophagoides pteronyssinus and Dermatophagoides farinae. The protocol consisted of five consecutive intranasal challenges with 25μg of HDM or control (PBS) followed by two days off, repeated for five weeks. The asthma phenotype was assessed by testing airway hyperresponsiveness (AHR) to methacholine challenge, and airway inflammation was characterized by cell differential assessment of bronchoalveolar lavage fluid obtained from experimental animals. Lung tissue was harvested for inflammatory mRNA expression determinations and histology. Airway remodeling was characterized using the two‐photon imaging technique, second harmonic generation (SHG), on lung tissue sections to determine collagen content in mouse airways (Velocity, imaging quantification software).ResultsWe found that HDM promoted alterations in respiratory mechanics in challenged animals, including alterations in lung function measures that led to airway hyperresponsiveness (AHR) and increased parenchymal elastance in both males and females. While HDM‐challenged male mice showed higher AHR, airway collagen & elastin content, and BALF eosinophilia than females, challenged females displayed higher BALF neutrophilia and expression of type II pro‐inflammatory cytokines than males.ConclusionOur results indicate sex differences in both inflammatory and immune responses, as well as in airway structural changes induced by HDM exposure in mice. Characterization of the mechanisms leading to these sex differences will provide better insight into the causes of sex disparities observed in asthma prevalence and severity.Support or Funding InformationThis work was supported by NIH grants HL133520 (PS) and HL141618 (PS) and the APS Porter Fellowship (NF)