1 Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia.
2 Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and University of Newcastle, Newcastle, Australia.
Am J Respir Cell Mol Biol. 2019 May;60(5):554-568. doi: 10.1165/rcmb.2018-0215OC.
Obesity is an important risk factor for severe asthma exacerbations, which are mainly caused by respiratory infections. Dietary fatty acids, which are increased systemically in obese patients and are further increased after high-fat meals, affect the innate immune system and may contribute to dysfunctional immune responses to respiratory infection. In this study we investigated the effects of dietary fatty acids on immune responses to respiratory infection in pulmonary fibroblasts and a bronchial epithelial cell line (BEAS-2B). Cells were challenged with BSA-conjugated fatty acids (ω-6 polyunsaturated fatty acids [PUFAs], ω-3 PUFAs, or saturated fatty acids [SFAs]) +/- the viral mimic polyinosinic:polycytidylic acid (poly[I:C]) or bacterial compound lipoteichoic acid (LTA), and release of proinflammatory cytokines was measured. In both cell types, challenge with arachidonic acid (AA) (ω-6 PUFA) and poly(I:C) or LTA led to substantially greater IL-6 and CXCL8 release than either challenge alone, demonstrating synergy. In epithelial cells, palmitic acid (SFA) combined with poly(I:C) also led to greater IL-6 release. The underlying signaling pathways of AA and poly(I:C)- or LTA-induced cytokine release were examined using specific signaling inhibitors and IB. Cytokine production in pulmonary fibroblasts was prostaglandin dependent, and synergistic upregulation occurred via p38 mitogen-activated protein kinase signaling, whereas cytokine production in bronchial epithelial cell lines was mainly mediated through JNK and p38 mitogen-activated protein kinase signaling. We confirmed these findings using rhinovirus infection, demonstrating that AA enhances rhinovirus-induced cytokine release. This study suggests that during respiratory infection, increased levels of dietary ω-6 PUFAs and SFAs may lead to more severe airway inflammation and may contribute to and/or increase the severity of asthma exacerbations.
肥胖是严重哮喘恶化的一个重要危险因素，而严重哮喘恶化主要是由呼吸道感染引起的。肥胖患者体内系统性增加的膳食脂肪酸，以及高脂肪餐后进一步增加的脂肪酸，会影响先天免疫系统，并可能导致对呼吸道感染的免疫功能失调反应。在这项研究中，我们研究了膳食脂肪酸对肺成纤维细胞和支气管上皮细胞系（BEAS-2B）中呼吸道感染免疫反应的影响。用 BSA 结合脂肪酸（ω-6 多不饱和脂肪酸[PUFA]、ω-3 PUFA 或饱和脂肪酸[SFA]） +/- 病毒模拟物多聚肌苷酸：多聚胞苷酸（poly[I:C]）或细菌复合脂磷壁酸（LTA）刺激细胞，测量促炎细胞因子的释放。在这两种细胞类型中，与花生四烯酸（AA）（ω-6 PUFA）和 poly[I:C]或 LTA 的联合刺激导致 IL-6 和 CXCL8 的释放明显大于单一刺激，表明存在协同作用。在上皮细胞中，棕榈酸（SFA）与 poly[I:C]联合也导致了更大的 IL-6 释放。使用特定的信号通路抑制剂和 IB 研究了 AA 和 poly[I:C]或 LTA 诱导细胞因子释放的潜在信号通路。肺成纤维细胞中细胞因子的产生依赖于前列腺素，协同上调通过 p38 丝裂原活化蛋白激酶信号发生，而支气管上皮细胞系中的细胞因子产生主要通过 JNK 和 p38 丝裂原活化蛋白激酶信号发生。我们使用鼻病毒感染证实了这些发现，表明 AA 增强了鼻病毒诱导的细胞因子释放。本研究表明，在呼吸道感染期间，膳食 ω-6 PUFAs 和 SFAs 水平的增加可能导致更严重的气道炎症，并可能导致和/或加重哮喘恶化。
