Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, PR China.
Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China.
Int Immunopharmacol. 2019 Jul;72:176-185. doi: 10.1016/j.intimp.2019.04.008. Epub 2019 Apr 12.
Eph receptor tyrosine kinases have a wide range of biological functions and have gradually been recognized increasingly as key regulators of inflammation and injury diseases. Although previous studies suggested that EphA2 receptor may be involved in the regulation of inflammation and vascular permeability in injured lung, the detailed effects of EphA2 on LPS-induced acute lung injury (ALI) are still inadequate and the underlying mechanism remains poorly understood. In this study, we detected the effects of EphA2 antagonism on inflammation, pulmonary vascular permeability and oxidative stress in LPS-induced ALI and investigate the potential mechanism. Our results showed that EphA2 antagonism markedly inhibited the cytokines release and inflammatory cells infiltration in BALF, prevented the LPS-induced elevations of MPO activity and MDA level in lung tissues. Our study also found that EphA2 antagonism significantly decreased the wet/dry ratios, reduced the Evans blue albumin extravasation in lung tissues and obviously alleviated the LPS-induced increment of pulmonary vascular permeability. Mechanistically, EphA2 antagonism significantly increased the activation of Nrf2 along with its target antioxidant enzyme HO-1 and inhibited the expressions of TLR4/MyD88 in lung tissues and A549 alveolar epithelial cells. Furthermore, EphA2 antagonism dramatically inhibited the LPS-evoked activations of RhoA/ROCK in lung tissues. In conclusion, our data indicate that EphA2 receptor plays an essential role in LPS-induced ALI and EphA2 antagonism has protective effects against LPS-induced ALI via Nrf2/HO-1, TLR4/MyD88 and RhoA/ROCK pathways. These results suggest that antagonism of EphA2 may be an effective therapeutic strategy for the treatment of ALI.
Eph 受体酪氨酸激酶具有广泛的生物学功能，逐渐被认为是炎症和损伤性疾病的关键调节因子。虽然先前的研究表明 EphA2 受体可能参与调节受损肺中的炎症和血管通透性，但 EphA2 对 LPS 诱导的急性肺损伤 (ALI) 的详细影响仍不充分，其潜在机制仍知之甚少。在这项研究中，我们检测了 EphA2 拮抗作用对 LPS 诱导的 ALI 中炎症、肺血管通透性和氧化应激的影响，并探讨了潜在的机制。我们的结果表明，EphA2 拮抗作用显著抑制了 BALF 中的细胞因子释放和炎症细胞浸润，阻止了 LPS 诱导的肺组织 MPO 活性和 MDA 水平升高。我们的研究还发现，EphA2 拮抗作用显著降低了肺湿/干重比，减少了肺组织中 Evans 蓝白蛋白渗出，并明显减轻了 LPS 诱导的肺血管通透性增加。在机制上，EphA2 拮抗作用显著增加了 Nrf2 的激活及其靶抗氧化酶 HO-1 的表达，并抑制了 TLR4/MyD88 在肺组织和 A549 肺泡上皮细胞中的表达。此外，EphA2 拮抗作用显著抑制了肺组织中 RhoA/ROCK 的 LPS 激活。总之，我们的数据表明 EphA2 受体在 LPS 诱导的 ALI 中起重要作用，EphA2 拮抗作用通过 Nrf2/HO-1、TLR4/MyD88 和 RhoA/ROCK 通路对 LPS 诱导的 ALI 具有保护作用。这些结果表明，EphA2 拮抗作用可能是治疗 ALI 的有效治疗策略。
