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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI PI 3K/Akt1 pathway
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Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI PI 3K/Akt1 pathway

机译：低分子量透明质酸通过PI PI 3K / AKT1途径诱导MCL-1的上调抑制中性粒细胞凋亡的肺炎

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Summary 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 ( PI 3K) and its downstream signalling pathway in LMMHA ‐induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI 3K 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 PI 3K/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 PI 3K/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.
机译：发明内容虽然低分子量透明质酸（LMMHA）涉及肺炎炎症疾病，但启动肺部炎症反应的LMMHA（200 000分子量）的信号通路仍然未知。在这项研究中，我们评估磷酸阳性3-激酶（PI 3K）及其下游信号通路在LMMHA诱导的肺炎反应中的作用。我们的研究结果表明，PI 3K或AKT1遗传缺失的药理抑制增强了中性粒细胞凋亡，将嗜中性粒细胞流入小鼠的肺部衰减，并减少了促蛋白-6，角质形成细胞衍生的趋化因子和亲基质的促炎因子等表达金属蛋白酶-9在腹腔血管血液施用后的支气管肺泡灌洗液中。更重要的是，我们发现PI 3K / AKT1参与LMMHA诱导的炎症反应，主要由髓性白血病细胞分化蛋白（MCL-1）介导。我们的研究表明，LMMHA诱导支气管肺泡灌洗液中的炎症因子水平显着增加，PI 3K / AKT1途径的激活，其上调抗凋亡蛋白MCL-1的表达并抑制Caspase-3的活化，从而抑制中性粒细胞凋亡以引发肺炎。这些发现揭示了一种新的无菌炎症的分子机制，为治疗肺病提供了新的潜在目标。

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