Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Int Immunopharmacol. 2020 Jun;83:106369. doi: 10.1016/j.intimp.2020.106369. Epub 2020 Mar 9.
Acute lung injury (ALI) is linked with considerable morbidity and mortality. ALI can be caused by various agents, one of them being sepsis. ALI is characterized by injury to vascular endothelium and alveolar epithelium that results in edema, pulmonary immune cells infiltration and hypoxemia. Neutrophils and T cells particularly play a huge role in amplification of pulmonary inflammation through release of multiple inflammatory mediators. Recent reports suggest a strong involvement of Th17 cells and oxidative stress in initiation/amplification of pulmonary inflammation during ALI. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. Therefore, our study explored the role of ITK on airway inflammation (total/neutrophilic cell counts, myeloperoxidase activity, E-cadherin expression, histopathological analyses) and effect of its inhibition on various inflammatory/anti-inflammatory pathways during ALI [phosphorylated-ITK (p-ITK), NFATc1, IL-17A, STAT3, Foxp3, IL-10, iNOS, nitrotyrosine, lipid peroxides). ALI was associated with increased total/neutrophilic cell counts and myeloperoxidase activity, and decreased E-cadherin expression in airway epithelial cells (AECs) which was concurrent with upregulation of p-ITK, NFATc1, IL-17A, STAT3 in CD4+ T cells and iNOS/nitrotyrosine in AECs. Treatment with ITK inhibitor reversed ALI-induced changes in airway inflammation and Th17 cells/oxidative stress. Treatment with ITK inhibitor further expanded Treg cells in mice with ALI. In short, our study proposes that ITK signaling plays a significant role in sepsis-induced ALI through upregulation of Th17 cells and oxidative stress. Further, findings provide evidence that ITK blockade could be a potential treatment strategy to attenuate airway inflammation associated with ALI.
急性肺损伤 (ALI) 与较高的发病率和死亡率相关。ALI 可由多种因素引起，其中之一是败血症。ALI 的特征是血管内皮和肺泡上皮损伤，导致水肿、肺免疫细胞浸润和低氧血症。中性粒细胞和 T 细胞通过释放多种炎症介质，在肺炎症的放大中起着巨大的作用。最近的报告表明，在 ALI 中，Th17 细胞和氧化应激在肺炎症的启动/放大中起重要作用。白细胞介素 2 诱导的 T 细胞激酶 (ITK) 通过控制几种转录因子在 Th17 细胞的发育中起关键作用。因此，我们的研究探讨了 ITK 在气道炎症（总/中性粒细胞计数、髓过氧化物酶活性、E-钙黏蛋白表达、组织病理学分析）中的作用及其对 ALI 期间各种炎症/抗炎途径的抑制作用[磷酸化-ITK (p-ITK)、NFATc1、IL-17A、STAT3、Foxp3、IL-10、iNOS、硝基酪氨酸、脂质过氧化物]。ALI 与气道上皮细胞 (AEC) 中的总/中性粒细胞计数和髓过氧化物酶活性增加以及 E-钙黏蛋白表达减少有关，同时 CD4+T 细胞中的 p-ITK、NFATc1、IL-17A 和 STAT3 以及 AEC 中的 iNOS/硝基酪氨酸表达上调。用 ITK 抑制剂治疗可逆转 ALI 诱导的气道炎症和 Th17 细胞/氧化应激变化。用 ITK 抑制剂治疗进一步增加了 ALI 小鼠中的 Treg 细胞。总之，我们的研究表明，ITK 信号通过上调 Th17 细胞和氧化应激在败血症引起的 ALI 中起重要作用。此外，研究结果为 ITK 阻断可能是减轻与 ALI 相关的气道炎症的潜在治疗策略提供了证据。
