Sex Differences in Pulmonary Eicosanoids and Specialized Pro-Resolving Mediators in Response to Ozone Exposure

Abstract

Ozone (O3) is a criteria air pollutant known to increase the morbidity and mortality of cardiopulmonary diseases. This occurs through a pulmonary inflammatory response characterized by increased recruitment of immune cells into the airspace, pro-inflammatory cytokines, and pro-inflammatory lipid mediators. Recent evidence has demonstrated sex-dependent differences in the O3-induced pulmonary inflammatory response. However, it is unknown if this dimorphic response is evident in pulmonary lipid mediator metabolism. We hypothesized that there are sex-dependent differences in lipid mediator production following acute O3 exposure. Male and female C57BL/6J mice were exposed to 1 part per million O3 for 3 hours and were necropsied at 6 or 24 hours following exposure. Lung lavage was collected for cell differential and total protein analysis, and lung tissue was collected for mRNA analysis, metabololipidomics, and immunohistochemistry. Compared to males, O3-exposed female mice had increases in airspace neutrophilia, neutrophil chemokine mRNA, pro-inflammatory eicosanoids such as prostaglandin E2, and specialized pro-resolving mediators (SPMs) such as resolvin D5 in lung tissue. Likewise, precursor fatty acids (arachidonic and docosahexaenoic acid; DHA) were increased in female lung tissue following O3 exposure compared to males. Experiments with ovariectomized females revealed that loss of ovarian hormones exacerbates pulmonary inflammation and injury. However, eicosanoid and SPM production were not altered by ovariectomy despite depleted pulmonary DHA concentrations. Taken together, these data indicate that O3 drives an increased pulmonary inflammatory and bioactive lipid mediator response in females. Furthermore, ovariectomy increases susceptibility to O3-induced pulmonary inflammation and injury, as well as decreases pulmonary DHA concentrations.

Sex Hormone–Dependent Lipid Mediator Formation in Male and Female Mice During Peritonitis

“…Similarly, plasma levels of 18-HEPE, 14-HDHA, and 17-HDHA were lower in male metabolic syndrome patients, although SPM levels were not different ( Barden et al, 2015 ). Of interest, not only SPMs (i.e., RvD5) but also PGE 2 were lower in the lungs of male mice after exposure to ozone along with reduced AA and DHA levels compared with females, but ovariectomy had no impact on eicosanoid and SPM production despite depleted pulmonary DHA concentrations ( Yaeger et al, 2021 ). Conversely, in healthy volunteers treated with dexamethasone, the plasma levels of 17-HDHA, RvD1, AT-RvD1, and RvE2 were higher in males ( Barden et al, 2018 ).…”

“…2020). However, there is currently no consistent sex bias in the levels of SPM and their precursors, which in some studies dominate in males (English et al, 2017;Barden et al, 2018;Pullen et al, 2020), while in other studies, they preponderate in female subjects (Barden et al, 2015;Rathod et al, 2017;Halade et al, 2020;Trotta et al, 2021;Yaeger et al, 2021). Moreover, the influence of sex hormones on the SPM biosynthesis is rather elusive.…”

“…There is obviously no consisting pattern of sex differences that unequivocally proves preponderances of all different LMs in males or females. With some few exceptions ( English et al, 2017 ; Rathod et al, 2017 ; Yaeger et al, 2021 ), most studies addressing sex differences and/or the impact of sex hormones related to the LM biosynthesis focused on single selected pathways, namely, either 5-LOX/LTs or COX/prostanoids, or SPM, and neglected the others. Here, we aimed at obtaining comprehensive LM signature profiles including pro-inflammatory LT and PG/TX and inflammation-resolving SPM in inflammatory exudates and plasma from male and female mice at the peak (4 h) and the resolution (24 h) of acute inflammation employing zymosan-induced peritonitis as an appropriate experimental model ( Cash et al, 2009 ).…”

Acute and Repeated Ozone Exposures Differentially Affect Circadian Clock Gene Expression in Mice

“…[ 34 ] A more recent report validated some of these findings and identified increased expression of pro‐inflammatory eicosanoids and resolvins in female mice. [ 56 ]…”

Modeling human heterogeneity of obesity with diversity outbred mice reveals a fat mass‐dependent therapeutic window for resolvin E1

“…It is entirely possible that administration for longer periods of time would lead to a larger fraction of the entire population that would be classified as a positive responder. Finally, we did not study sex‐specific effects and there are likely strong differences between male and female DO mice in response to RvE1 11,35,36 …”