Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema
Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema
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DOI：
10.1073/pnas.1121075109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Schally, Andrew V.
中科院分区：
文献类型：
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作者：
Lucas, Rudolf;Sridhar, Supriya;Schally, Andrew V.
肺炎链球菌感染患者积极应用抗生素治疗可诱导细菌毒力因子溶肺素（PLY）的释放。在肺部无菌数日后，这种成孔毒素仍可诱发患者肺通透性水肿，其特征是肺泡/毛细血管屏障功能障碍和肺泡液体清除（ALC）受损。在II型肺泡上皮细胞中，ALC主要通过Na+转运受到顶端表达的上皮钠通道（ENaC）和基底侧表达的Na+/K+- atp酶的调节。由于目前尚无治疗渗透性水肿的标准治疗方法，因此寻找新的治疗方案是当务之急。我们在人肺微血管内皮细胞（HL-MVEC）中检测了下丘脑多肽生长激素释放激素（GHRH）的活性受体剪接变体SV1以及GHRH本身的mRNA表达。因此，我们评估了GHRH激动剂JI-34对poly诱导的屏障和ALC功能障碍的影响。JI-34通过降低肌球蛋白轻链和血管内皮(VE)-钙粘蛋白的磷酸化，以camp依赖的方式减弱poly介导的HL-MVEC单层内皮细胞的高通透性。在人气道上皮H441细胞中，PLY显著损害Na+摄取，但JI-34通过增加cAMP水平将Na+摄取恢复到基础水平。经气管内灌注PLY可引起C57BL6小鼠肺泡上皮和内皮细胞的高通透性及水肿形成，而JI-34可使其钝化。这些发现表明GHRH信号通路在poly诱导的渗透性水肿中具有保护作用。
Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.