Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, University of Sydney , Sydney , Australia.
Department of Respiratory Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
Am J Physiol Lung Cell Mol Physiol. 2018 Jun 1;314(6):L922-L935. doi: 10.1152/ajplung.00438.2017. Epub 2018 Jan 25.
Obesity is an important risk factor for developing severe asthma. Dietary fatty acids, which are increased in sera of obese individuals and after high-fat meals, activate the innate immune system and induce inflammation. This study investigated whether dietary fatty acids directly cause inflammation and/or synergize with obesity-induced cytokines in primary human pulmonary fibroblasts in vitro. Fibroblasts were challenged with BSA-conjugated fatty acids [ω-6 polyunsaturated fatty acids (PUFAs) and ω-3 PUFAs or saturated fatty acids (SFAs)], with or without TNF-α, and release of the proinflammatory cytokines, IL-6 and CXCL8, was measured. We found that the ω-6 PUFA arachidonic acid (AA), but not ω-3 PUFAs or SFAs, upregulates IL-6 and CXCL8 release. Combined AA and TNF-α challenge resulted in substantially greater cytokine release than either alone, demonstrating synergy. Synergistic upregulation of IL-6, but not CXCL8, was mainly mediated via cyclooxygenase (COX). Inhibition of p38 MAPK reduced CXCL8 release, induced by AA and TNF-α alone, but not in combination. Synergistic CXCL8 release, following AA and TNF-α challenge, was not medicated via a single signaling pathway (MEK1, JNK, phosphoinositide 3-kinase, and NF-κB) nor by hyperactivation of NF-κB or p38. To investigate if these findings occur in other airway cells, effects of AA in primary human airway smooth muscle (ASM) cells and human bronchial epithelial cells were also investigated. We found proinflammatory effects in ASM cells but not epithelial cells. This study suggests that diets rich in ω-6 PUFAs might promote airway inflammation via multiple pathways, including COX-dependent and -independent pathways, and in an obese person, may lead to more severe airway inflammation.
肥胖是导致严重哮喘的一个重要危险因素。血清中脂肪酸含量增加的肥胖个体和高脂餐后，会激活先天免疫系统并引发炎症。本研究旨在探讨膳食脂肪酸是否会直接引起人原代肺成纤维细胞炎症，以及是否会与肥胖诱导的细胞因子协同作用。体外将 BSA 结合的脂肪酸（ω-6 多不饱和脂肪酸（PUFA）和 ω-3 PUFAs 或饱和脂肪酸（SFAs））与 TNF-α 一起或不与 TNF-α 一起作用于成纤维细胞，测量促炎细胞因子 IL-6 和 CXCL8 的释放。我们发现，ω-6 PUFAA 花生四烯酸（AA）而非 ω-3 PUFAs 或 SFAs 可上调 IL-6 和 CXCL8 的释放。AA 和 TNF-α 联合刺激导致细胞因子释放显著增加，表明存在协同作用。协同上调 IL-6，但不是 CXCL8，主要通过环氧化酶（COX）介导。p38 MAPK 抑制可降低 AA 和 TNF-α 单独作用时，但不能降低联合作用时的 CXCL8 释放。AA 和 TNF-α 刺激后协同的 CXCL8 释放不是通过单一信号通路（MEK1、JNK、磷酸肌醇 3-激酶和 NF-κB）或 NF-κB 或 p38 的过度激活来介导的。为了研究这些发现是否发生在其他气道细胞中，还研究了 AA 在原代人气道平滑肌（ASM）细胞和人支气管上皮细胞中的作用。我们发现 AA 在 ASM 细胞中具有促炎作用，但在上皮细胞中没有。本研究表明，富含 ω-6 PUFAs 的饮食可能通过多种途径促进气道炎症，包括 COX 依赖性和非依赖性途径，并且在肥胖个体中可能导致更严重的气道炎症。
