School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA.
Department of Clinical Endocrinology, Medical University of Lodz, Lodz, Poland.
Int Immunopharmacol. 2021 Dec;101(Pt B):108367. doi: 10.1016/j.intimp.2021.108367. Epub 2021 Nov 15.
The endothelial barrier regulates interstitial fluid homeostasis by transcellular and paracellular means. Dysregulation of this semipermeable barrier may lead to vascular leakage, edema, and accumulation of pro-inflammatory cytokines, inducing microvascular hyperpermeability. Investigating the molecular pathways involved in those events will most probably provide novel therapeutic possibilities in pathologies related to endothelial barrier dysfunction. Metformin (MET) is an anti-diabetic drug, opposes malignancies, inhibits cellular transformation, and promotes cardiovascular protection. In the current study, we assess the protective effects of MET in LPS-induced lung endothelial barrier dysfunction and evaluate the role of P53 in mediating the beneficial effects of MET in the vasculature. We revealed that this biguanide (MET) opposes the LPS-induced dysregulation of the lung microvasculature, since it suppressed the formation of filamentous actin stress fibers, and deactivated cofilin. To investigate whether P53 is involved in those phenomena, we employed the fluorescein isothiocyanate (FITC) - dextran permeability assay, to measure paracellular permeability. Our observations suggest that P53 inhibition increases paracellular permeability, and MET prevents those effects. Our results contribute towards the understanding of the lung endothelium and reveal the significant role of P53 in the MET-induced barrier enhancement.
内皮屏障通过细胞内和细胞旁途径调节细胞间液的动态平衡。这种半透性屏障的失调可能导致血管渗漏、水肿和促炎细胞因子的积累，从而引起微血管通透性增加。研究这些事件涉及的分子途径极有可能为与内皮屏障功能障碍相关的病理提供新的治疗可能性。二甲双胍（MET）是一种抗糖尿病药物，具有抗癌、抑制细胞转化和促进心血管保护作用。在本研究中，我们评估了 MET 在 LPS 诱导的肺内皮屏障功能障碍中的保护作用，并评估了 P53 在介导 MET 在血管中的有益作用中的作用。我们发现，这种双胍类药物（MET）可以抵抗 LPS 诱导的肺微血管失调，因为它抑制了丝状肌动蛋白应力纤维的形成，并使丝切蛋白失活。为了研究 P53 是否参与这些现象，我们采用了异硫氰酸荧光素（FITC）-葡聚糖通透性测定法来测量细胞旁通透性。我们的观察结果表明，P53 抑制增加了细胞旁通透性，而 MET 则阻止了这些效应。我们的研究结果有助于理解肺内皮，并揭示了 P53 在 MET 诱导的屏障增强中的重要作用。
