Abstract
BackgroundPulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this.MethodsOur ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 μM) with or without GW9662 (10 μM). The expressions of αENaC and SGK1 were determined 24 h later.ResultsA mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1β levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662.ConclusionsRosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.
Highlights
Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS)
Rosiglitazone decreased the inflammatory mediators in the bronchoalveolar lavage fluid LPS caused inflammatory cascades in the lung, which promoted the production of a series of pro-inflammatory mediators, including TNF-α and IL-1β
Rosiglitazone decreased the levels of TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF) to a certain extent, but this decrease was prevented by GW9662 (p < 0.05; Fig. 2a and b)
Summary
Pulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. We investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). Acute respiratory distress syndrome (ARDS) is a severe illness that is characterized by diffuse alveolar damage, increased lung permeability and pulmonary edema [1]. Pulmonary edema is induced when inflammation causes damage to alveolar epithelial and endothelial cells, and results in alveolar fluid buildup and stubborn hypoxemia. Epithelial sodium channel (ENaC) is a multimeric protein that plays a critical role in the process of alveolar fluid clearance (AFC). Its α subunit is necessary to form functional ENaC, while the β and γ subunits promote the channel’s activity [4–6]
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