Rosiglitazone promotes ENaC-mediated alveolar fluid clearance in acute lung injury through the PPARŒ≥/SGK1 signaling pathway
Authors: Jing He
Di Qi
Yan Zhao
Dao-Xin Wang
Xu-Mao Tang
Wang Deng
Xin-Yu Deng
Journal: Cellular & Molecular Biology Letters (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Acute lung injury; Alveolar epithelial sodium channel; Alveolar fluid clearance; Peroxisome proliferator-activated receptor Œ≥; Serum and glucocorticoid induced kinase-1.
Affiliations: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010 China.

Abstract:  Background: 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. The peroxisome proliferator-activated receptor Œ≥ (PPARŒ≥) 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 PPARŒ≥ 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. Methods: Our 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-Œ± and IL-1Œ≤ in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of Œ±ENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 ŒºM) with or without GW9662 (10 ŒºM). The expressions of Œ±ENaC and SGK1 were determined 24 h later. Results: A mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-Œ± and IL-1Œ≤ levels in the BALF, enhancing AFC, and promoting the expressions of Œ±ENaC and SGK1 in ALI mice, which were abolished by the specific PPARŒ≥ blocker GW9662. In vitro, rosiglitazone increased the expressions of Œ±ENaC and SGK1. This increase was prevented by GW9662. Conclusions: Rosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARŒ≥/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI. 

Retracted: No

PubPeer comments:
 (a) In Definition 3, the authors claimed that $Delta$ is a mapping $$Delta: [0,g] to Stimes [-0.5, 0.5)$$ **It is clear that $Delta$ is a mapping of one argument.** However, in Example 1, the authors in eq.(6) used the term $$Delta(s_2, -0.4)$$ which implies **that $Delta$ is a mapping of two arguments.** It is inconsistent with Definition 3. Besides, the calculations demonstrated in Example 1 are very confusing. (b) In Step 4 of Section 5.1, the authors presented a programming problem and claimed that the optimal solution is $$(0.15, 0.15, 0.375, 0.325)$$ It can be calculated that the corresponding objective value is $$2.03times 0.15 + 3.5times 0.15 + 2.67times 0.375 + 3.97times 0.325 = 3.121$$ Consider another solution $$(0.15, 0.15, 0.25, 0.45)$$ with its corresponding objective value $$2.03times 0.15 + 3.5times 0.15 + 2.67times 0.25 + 3.97times 0.45 = 3.2835$$ Since $$3.2835 3.121$$ **it is obvious that the reported optimal solution is not optimal** although it is produced by Matlab as claimed by the authors.     ,