Abstract
BackgroundAcute ozone (O3) exposure has known deleterious effects on the respiratory system and has been linked with respiratory disease and infection. Inflammatory lung disease induced by air pollution has demonstrated greater severity and poorer prognosis in women vs. men. Both severe damage to the bronchial-alveolar epithelium and malfunctioning of bronchial-blood barrier have been largely attributed to the pathobiology of O3-induced inflammatory response, but the associated mechanisms in the male and female lung remain unknown.MethodsHere, we investigated sex-based differential regulation of lung interleukin-6 (IL-6) and its downstream signaling pathways JAK2/STAT3 and AKT1/NF-κB in response to O3 exposure in a mouse model. We exposed male and female mice (in different stages of the estrous cycle) to 2 ppm of O3 or filtered air (FA) for 3 h, and we harvested lung tissue for protein expression analysis by Western blot.ResultsWe found significant up-regulation of IL-6 and IL-6R in females and IL-6 in males in response to O3 vs. FA. Ozone exposure induced a significant increase in STAT3-Y705 phosphorylation in both females and males. Males exposed to O3 had decreased levels of JAK2, but increased JAK2 (Y1007+Y1008) phosphorylation, while females exposed to O3 showed significant up-regulation of both proteins. Both NF-κB (p105/p50) and AKT1 protein levels were significantly increased only in females exposed to O3. In addition, females exposed to O3 during proestrus displayed increased expression of selected genes when compared to females exposed to O3 in other estrous cycle stages.ConclusionsTogether, our observations indicate a sex-based and estrous cycle-dependent differential lung inflammatory response to O3 and involvement of two converging JAK2/STAT3 and AKT1/NF-κB pathways. To our knowledge, this is the first study specifically addressing the impact of the estrous cycle in O3-associated lung inflammatory pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0069-7) contains supplementary material, which is available to authorized users.
Highlights
Acute ozone (O3) exposure has known deleterious effects on the respiratory system and has been linked with respiratory disease and infection
In an effort to study the overall effects of O3 in mediating acute inflammation and oxidative stress in the lungs of males and females, the present study evaluates a possible role of JAK2/STAT3 and AKT1/NF-κB signaling in relation to IL-6 and IL-6R response and the effects of the female estrous cycle in O3-induced lung inflammation
Ozone-associated lung inflammation and up-regulation of IL-6 and IL-6R expression With one-way analysis of variance, ozone exposure resulted in a significant increase in the expression levels of IL-6 in both male and female mice compared to the matched controls exposed to filtered air (FA) (Fig. 1a, b, Additional file 1: Figure S1-a)
Summary
Acute ozone (O3) exposure has known deleterious effects on the respiratory system and has been linked with respiratory disease and infection. Inflammatory lung disease induced by air pollution has demonstrated greater severity and poorer prognosis in women vs men. Both severe damage to the bronchial-alveolar epithelium and malfunctioning of bronchial-blood barrier have been largely attributed to the pathobiology of O3-induced inflammatory response, but the associated mechanisms in the male and female lung remain unknown. Acute O3 exposure is toxic to the respiratory system and has been linked with respiratory tract infections, asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer, and cardiovascular disease, with relatively poor prognosis and higher mortality in women than in men [5,6,7,8,9,10,11]. The mechanisms associated with the differential lung disease outcomes in men and women are still poorly understood
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