Sexual dimorphism in lung function responses to acute influenza A infection

Abstract

Background: Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females.

Objectives: To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza.

Methods: Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post-inoculation.

Results: Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness.

Conclusions: We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation.

Figure 1

Lung viral titre (pfu/g lung) for adult (left) and weanling (right) male and female BALB/c mice 4 days post‐inoculation with influenza A. No viral titre was measured in control mice, or 21 days after infection.

Figure 2

Dose–response curves for adult male (triangles) and female (circles) BALB/c mice 4 days (left panels) or 21 days (right panels) post‐inoculation with influenza A (closed symbols, solid lines) or control (open symbols, dashed lines). All data are expressed as mean ± SD (n = 7–8). Tests for significant differences were conducted at each dose using two‐way anova. * Significant effect of treatment (i.e. flu versus control), # Significant effect of sex, and + Significant interaction between treatment and sex. Significance was taken as P < 0·05 using the Holm‐Sidak post hoc test.

Figure 3

Dose–response curves for weanling male (triangles) and female (circles) BALB/c mice 4 days (left panels) or 21 days (right panels) post‐inoculation with influenza A (closed symbols, solid lines) or control (open symbols, dashed lines). All data are expressed as mean ± SD (n = 7–8). Tests for significant differences were conducted at all doses using two‐way anova. * Significant effect of treatment, # Significant effect of sex, and + Significant interaction between sex and treatment. Significance was taken as P < 0·05 using the Holm‐Sidak post hoc test.

Figure 4

Bronchoalveolar lavage fluid differential cell counts from adult male and female BALB/c mice 4 days (left) or 21 days (right) post‐inoculation with influenza A or control. Bars indicate significant differences in total cells between groups. *,# Significant differences in the number of macrophages and neutrophils, respectively, between infected and non‐infected mice.

Figure 5

Bronchoalveolar lavage fluid differential cell counts from weanling male and female BALB/c mice 4 days (left) or 21 days (right) post‐inoculation with influenza A or control. Bars indicate significant differences in total cells between groups. *,# Significant differences in the number of macrophages and neutrophils, respectively, between infected and non‐infected mice.

Figure 6

Bronchoalveolar lavage fluid levels of TNFα, IL‐6, IFNγ and MCP‐1 from adult (left) and weanling (right) male and female BALB/c mice 4 or 21 days post‐inoculation with influenza A or control. * Significant effect of influenza infection, # Significant difference between males and females.