Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China.
Immunology. 2018 Nov;155(3):387-395. doi: 10.1111/imm.12981. Epub 2018 Jul 26.
Although low-molecular-mass hyaluronan (LMMHA) has been implicated in pulmonary inflammatory diseases, the signalling pathway of LMMHA (200 000 molecular weight) that initiates the inflammatory response in lung is still unknown. In this study, we evaluate the role of phosphoinositide 3-kinase (PI3K) and its downstream signalling pathway in LMMHA-induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI3K or genetic deletion of Akt1 enhances neutrophil apoptosis, attenuates neutrophil influx into the lungs of mice and diminishes the expression of pro-inflammatory factors such as interleukin-6, keratinocyte cell-derived chemokine and pro-matrix metalloproteinase-9 in bronchoalveolar lavage fluid after intratracheal administration of LMMHA. More importantly, we found that PI3K/Akt1 participates in LMMHA-induced inflammatory responses, which are mainly mediated by the myeloid leukaemia cell differentiation protein (Mcl-1). Our study suggests that LMMHA induced significantly increased levels of inflammatory factors in bronchoalveolar lavage fluid and activation of the PI3K/Akt1 pathway, which up-regulates the expression of the anti-apoptotic protein Mcl-1 and inhibits the activation of caspase-3, thereby suppressing neutrophil apoptosis to trigger lung inflammation. These findings reveal a novel molecular mechanism underlying sterile inflammation and provides a new potential target for the treatment of pulmonary disease.
尽管低分子量透明质酸（LMMHA）与肺部炎症性疾病有关，但引发肺部炎症反应的 LMMHA（分子量 200000）的信号通路仍不清楚。在这项研究中，我们评估了磷酸肌醇 3-激酶（PI3K）及其下游信号通路在 LMMHA 诱导的肺部炎症反应中的作用。我们的结果表明，PI3K 的药理学抑制或 Akt1 的基因缺失增强了中性粒细胞的凋亡，减轻了 LMMHA 气管内给药后小鼠肺部中性粒细胞的浸润，并减少了支气管肺泡灌洗液中促炎因子（如白细胞介素 6、角质形成细胞衍生的趋化因子和促基质金属蛋白酶 9）的表达。更重要的是，我们发现 PI3K/Akt1 参与了 LMMHA 诱导的炎症反应，主要是通过髓样白血病细胞分化蛋白（Mcl-1）介导的。我们的研究表明，LMMHA 诱导了支气管肺泡灌洗液中炎症因子水平的显著增加和 PI3K/Akt1 通路的激活，上调了抗凋亡蛋白 Mcl-1 的表达，并抑制了 caspase-3 的激活，从而抑制了中性粒细胞的凋亡，引发了肺部炎症。这些发现揭示了无菌性炎症的新分子机制，并为肺部疾病的治疗提供了新的潜在靶点。
