Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

Abstract

Background: Pulmonary edema is a hallmark in acute lung injury(ALI). Researchers have also revealed that dexmedetomidine (Dex) alleviate pulmonary edema following ALI, but the mechanism is unclear.The alveolar epithelial sodium channel (ENaC)-mediated alveolar fluid clearance (AFC) plays an important role in reducing pulmonary edema. In this study, we attempted to investigate the effect of Dex on ENaC in modulating AFC and its mechanism. Methods: LipopolysacchAride (LPS) was used to induce ALI in rat and alveolar epithelial cell injury in A549 cell. The rats were randomly allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002 (n = 6 per group). In vitro, cells (1×10 6 cells/cm 2 ) were subcultured in six-well plates, then cells were allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002. Results: In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC.Moreover, Dex prevented LPS-induced downregulation of α-, β- and γ-ENaC expression. In A549 cells stimulated with LPS, Dex attanuated LPS-mediated cell injury and the downregulation of α-, β- and γ-ENaC expression. Howere, all of which was blocked by PI3K inhibitor LY294002,suggesting that the protective role of Dex is PI3K dependent. Additionaly, Dex increases the expression of phosphorylated Akt and reduces the expression of Need4-2 in vivo and vitro, while the LY294002 reverses the effect of Dex, indicating that Dex activates the PI3K/Akt/Nedd4-2 signaling pathway. C onclusio ns: Dex alleviates pulmonary edema by promoting AFC, and the mechanism is partly related to up-regulation of ENaC expression via PI3K/Akt/Nedd4-2 signaling pathway.

Effects of penehyclidine hydrochloride combined with dexmedetomidine on pulmonary function in patients undergoing heart valve surgery: A Double-Blind, Randomized Trial

“…This study showed that administration of penehyclidine hydrochloride and dexmedetomidine during anesthesia for cardiac valve surgery reduced the impact of CPB, cardiac surgery and anesthesia on lung damage, increased OI, and reduced release of in ammatory factors and the occurrence and severity of PPCs, thus improving the prognosis of patients. This is consistent with the previously reported protective effects of penehyclidine hydrochloride and dexmedetomidine on lungs during cardiac surgery or other pathological conditions [11,12] . Our results showed that combination of penehyclidine hydrochloride and dexmedetomidine had a greater positive effect on the lungs than either of the two drugs alone.…”

“…In our study, the extubation time and length of ICU stay were shortened in the combination group. This supports the above results and analysis of changes in the levels of in ammatory factors, and is consistent with previous studies showing improvement of prognosis by single use of each drug [11] .…”

“…At the same time, RI increased quickly after CPB, suggesting that CPB and lung ischemia/reperfusion injury caused acute pulmonary dysfunction after CPB, which is an important cause of PPCs. However, penehyclidine hydrochloride and dexmedetomidine can reduce the decline in OI, which is consistent with metoproline reducing in ammatory mediators and improving OI in patients undergoing total arch replacement of aortic dissection [11] . Dexmedetomidine can reduce cell apoptosis, regulate immune factors, and increase OI to play a pulmonary protective role, which has also been con rmed in rat CPB experiments and human studies [28] .…”

“…However, there have been few clinical studies on the organ protective activity penehyclidine hydrochloride in adults undergoing cardiac surgery with CPB, and there is no uniform dose standard. Administration of penehyclidine hydrochloride 0.05 mg/kg before anesthesia induction reduces the incidence of ALI after aortic dissection [11] . In our study, patients underwent cardiac valve surgery that required less time and caused less trauma than aortic dissection surgery.…”

LncRNA MEG3amelioratesNiOnanoparticles‐induced pulmonary inflammatory damage via suppressing the p38 mitogen activated protein kinases pathway

“…A 2 ml of normal saline was instilled into the trachea and withdrew the BALF 30 . After centrifugation at 1200 g/min for 10 min, the BALF supernatant was stored at −80°C 31 . The cells sediment was immediately counted for total cells count and sorted cells count.…”