Involvements of p38 MAPK and oxidative stress in the ozone-induced enhancement of AHR and pulmonary inflammation in an allergic asthma model

Abstract

BackgroundExposure to ambient ozone (O3) increases the susceptivity to allergens and triggers exacerbations in patients with asthma. However, the detailed mechanisms of action for O3 to trigger asthma exacerbations are still unclear.MethodsAn ovalbumin (OVA)-established asthmatic mouse model was selected to expose to filtered air (OVA-model) or 1.0 ppm O3 (OVA-O3 model) during the process of OVA challenge. Next, the possible involvements of p38 MAPK and oxidative stress in the ozone actions on the asthma exacerbations were investigated on the mice of OVA-O3 model by treating them with SB239063 (a p38 MAPK inhibitor), and/or the α-tocopherol (antioxidant). Biological measurements were conducted including airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL), inflammation in the airway lumen and lung parenchyma, the phosphorylation of p38 MAPK and heat shock protein (HSP) 27 in the tracheal tissues, and the malondialdehyde (MDA) content and the glutathione peroxidase (GSH-Px) activity in lung tissues.ResultsIn OVA-allergic mice, O3 exposure deteriorated airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL) and pulmonary inflammation, accompanied by the increased oxidative stress in lung tissues and promoted p38 MAPK and HSP27 phosphorylation in tracheal tissues. Administration of SB239063 (a p38 MAPK inhibitor) on OVA-O3 model exclusively mitigated the Raw, the CL, and the BAL IL-13 content, while α-tocopherol (antioxidant) differentially reduced the BAL number of eosinophils and macrophages, the content of BAL hyaluronan, the peribronchial inflammation, as well as the mRNA expression of TNF-α and IL-5 in the lung tissues of OVA-O3 model. Administration of these two chemical inhibitors similarly inhibited the AHR, the BAL IFN-γ and IL-6 production, the perivascular lung inflammation and the lung IL-17 mRNA expression of OVA-O3 model. Interestingly, the combined treatment of both compounds together synergistically inhibited neutrophil counts in the BALF and CXCL-1 gene expression in the lung.ConclusionsO3 exposure during the OVA challenge process promoted exacerbation in asthma. Both p38 MAPK and oxidative stress were found to play a critical role in this process and simultaneous inhibition of these two pathways significantly reduced the O3-elicited detrimental effects on the asthma exacerbation.

Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma

“…IL-17A signaling controls neutrophilic airway inflammation (172) mainly through stimulating the release of IL-8 and other pro-neutrophilic factors in the airways (131,(137)(138)(139)(140)(141)(142)(143)(144)(145)(146) (Figure 1B). The importance of this cytokine in O 3 exposure-induced exacerbation of allergic airway inflammation was supported in a mouse model in which significant inhibition of IL-17A gene expression by the combined targeting of p38 MAPK activation and oxidative stress was critical in synergistically attenuating airway hyperresponsiveness, eosinophilic and neutrophilic inflammation (107).…”

“…Amongst the environmental causes our review is focused on inhalational exposure to the toxic air pollutant, ozone (O 3 ) as it was found to be a significant contributor to respiratory illness. Specifically, O 3 induces airway hyperreactivity in mouse models of asthma (6,86,87,89,91,(98)(99)(100)(101)(102)(103)(104)(105)(106)(107), in Th2 low asthma in rhesus macaques (94,108) and in healthy human subjects and patients with asthma and COPD (6,7,59,(109)(110)(111)(112)(113)(114)(115)(116). Ground-level (tropospheric) O 3 is generated by the action of sunlight's UV rays from precursors (mostly air pollutants containing hydrocarbons, volatile organic compounds [VOC] and nitrogen oxides emitted during fossil fuel combustion).…”

Transcriptional Effects of Ozone and Impact on Airway Inflammation

“…These responses to ozone are relatively corticosteroid insensitive but combination of dexamethasone with a p38 MAPK inhibitor (SB239063) suppressed ozone effects on inflammation and AHR suggesting that p38 MAPK activation is involved in the corticosteroid insensitivity seen in this model. SB239063 alone prevented ozone-induced airway resistance (Raw), lung compliance (CL), and BAL IL-13 levels when given in the context of an ovalbumin challenge (25). In addition, the anti-oxidant α-tocopherol alone reduced BAL eosinophils and macrophages and peribronchial inflammation.…”

Naturally Oxidized Olive Oil Promotes Active Cutaneous Anaphylaxis and Th2 Cytokine Production

“…9) Oxidized soybean oil intake has been reported to enhance the production of antibodies 10) and inflammatory mediators and to promote lymphocytes proliferation, 11) but little information is available on the relationship between oxidized oil intake and the increased incidence or exacerbation of allergic diseases. As oxidative stress is associated with a variety of allergic diseases, such as asthma, bronchitis, and dermatitis, [12][13][14] increased oxidative stress due to the ingestion of oxidized dietary oils may increase allergic symptoms.…”