Effect of ozone exposure and infection on bronchoalveolar lavage: Sex differences in response patterns

Abstract

Female mice exhibit a better survival rate than males after infection, but if infection follows an ozone-induced oxidative stress, male survival exceeds that of females. Our goal was to study bronchoalveolar lavage factors that contribute to these sex differences in outcome. We studied parameters at 4, 24, and 48 hours after ozone exposure and infection, including markers of inflammation, oxidative stress, and tissue damage, and surfactant phospholipids and surfactant protein A (SP-A). A multianalyte immunoassay at the 4 hr time point measured 59 different cytokines, chemokines, and other proteins. We found that: 1) Although some parameters studied revealed sex differences, no sex differences were observed in LDH, total protein, MIP-2, and SP-A. Males showed more intragroup significant differences in SP-A between filtered air- and ozone-exposed mice compared to females. 2) Oxidized dimeric SP-A was higher in FA-exposed female mice. 3) Surfactant phospholipids were typically higher in males. 4) The multianalyte data revealed differences in the exuberance of responses under different conditions - males in response to infection and females in response to oxidative stress. These more exuberant, and presumably less well-controlled responses associate with the poorer survival. We postulate that the collective effects of these sex differences in response patterns of lung immune cells may contribute to the clinical outcomes previously observed.

Association between Air Pollutants and Asthma Emergency Room Visits and Hospital Admissions in Time Series Studies: A Systematic Review and Meta-Analysis

“…hormonal levels, lung size and growth and airway inflammation) are different. Furthermore, greater effects of ozone on females were consistent with those in a previous report [ 108 ].…”

Single-cell analysis reveals differential regulation of the alveolar macrophage actin cytoskeleton by surfactant proteins A1 and A2: implications of sex and aging

“…5 ) experiments. These results come as a continuation of a long series of studies that have demonstrated such differences in both the molecular and the physiological level [ 3 , 4 , 15 , 17 , 39 , 40 ]. Hormonal regulation of the actin cytoskeleton in AMs could be an important factor in the generation of sex differences.…”

“…Functionally, the regulation of the distribution of subpopulations of AMs by SP-A variants may explain differences observed in their phagocytic activity [ 11 – 13 ] and the course of lung disease [ 4 , 39 , 40 , 47 ]. Sex differences concerning susceptibility in lung disease, such as asthma [ 48 ], chronic obstructive pulmonary disorder [ 49 ], and even lung cancer [ 50 ], have been widely reported, although the latter remains controversial [ 51 ].…”

SP-A2 contributes to miRNA-mediated sex differences in response to oxidative stress: pro-inflammatory, anti-apoptotic, and anti-oxidant pathways are involved

“…We found miR-191-5p, shown previously to regulate IL-6 [ 44 ], to be downregulated and this could increase the levels of IL-6, which is consistent with our experimental findings. IL-6 was found to be expressed in the BAL of males after O 3 exposure, but not in females [ 38 ]. IL-6 has been shown to have both pro- and anti-inflammatory functions [ 52 ], and in mice, IL-6 overexpression has been shown to protect against hyperoxia-induced lung mitochondrial damage [ 53 ].…”

“…In our studies, we observed differences in survival rates between males and females after bacterial infection. Females appeared to resolve the bacterial respiratory infection more readily than males, but when OxS was introduced prior to infection, the outcome was reversed, i.e., females showed lower survival rates than males [ 13 , 17 , 35 – 38 ]. Moreover, these sex differences were further accentuated in SP-A KO mice or when SP-A was oxidized, highlighting once again the important role of SP-A as a regulatory innate immune molecule [ 13 , 17 ].…”