ASK1-p38 cascaded signal mediates pulmonary microvascular endothelial barrier injury induced by the return of PHSML in rats.

The return of post-hemorrhagic shock mesenteric lymph (PHSML) induces pulmonary vascular endothelial barrier dysfunction, which results in acute lung injury. Activation of the apoptosis signal-regulated kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38 MAPK) pathway has been shown to trigger inflammatory responses. However, whether the ASK1-p38 MAPK pathway is involved in the PHSML-induced pulmonary endothelial barrier dysfunction remains unclear. In the present study, permeability changes of pulmonary capillaries were found , and activation of the ASK1-p38 MAPK pathway was determined . PMVEC barrier dysfunction was determined by measuring TEER. Furthermore, junctional and cytoskeletal protein expressions were analyzed. The results showed that hemorrhagic shock led to a marked increase in the permeability of pulmonary capillaries , which was markedly alleviated by PHSML drainage. In cultured pulmonary microvascular endothelial cells (PMVECs), PHSML reduced the endothelial barrier function accompanied by upregulated p-ASK1 and p-p38 MAPK protein expression, impaired the cytoskeletal protein structure, and down-regulated junction protein expression. These adverse effects were eliminated by applying either Trx1 (ASK1 inhibitor) or SB203580 (p38 MAPK inhibitor). These results indicated that the ASK1-p38 MAPK pathway mediates PHSML-induced pulmonary vascular endothelial barrier dysfunction during hemorrhagic shock.