microRNAs mediate oleic acid-induced acute lung injury in rats using an alternative injury mechanism

Abstract

Intravenous (IV) infusion of oleic acid (OA) distributes OA microemboli in the pulmonary capillaries, which results in severe vascular congestion, hemorrhage vascular congestion, interstitial edema, intravascular coagulation and bleeding. The immune response to acute lung injury (ALI) is known to be associated with rapid and widespread changes in microRNA (miRNA) expression in the lung. The present study of a model of rat lung injury aimed to investigate how the lung miRNA profile changes to mediate ALI. For the induction of ALI, OA (200 µl/kg) suspended in 20% ethyl alcohol was injected through the tail vein for 20 min. Lung tissue samples were acquired at 3, 6 and 24 h, and miRNA microarray and quantitative polymerase chain reaction were performed using these samples. The activation of phosphatase and tensin homolog (PTEN), protein kinase B (Akt), extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) were analyzed by western blot analysis. There were 75 miRNAs that demonstrated >1.5‑fold changes in expression levels. miR-101a was highly upregulated at 3 h. miR-21 was upregulated in the OA group throughout the 24 h following OA challenge. miR-1 was the most downregulated miRNA at 24 h. In order to examine the expression levels of PTEN and Akt as targets of miR-21, western blot analysis was performed. At 3 h, the levels of PTEN were attenuated in the OA group as compared with those in the control group; however, p-Akt/Akt levels were increased at 3 h for the OA group. PTEN and p-Akt/Akt were significantly higher in the OA group at 3 h and were rapidly decreased at 6 h. The immunohistochemical stain of α-smooth muscle actin in the bronchial and alveolar wall increased 24 h after OA‑induced ALI. These results indicated that the profile of miRNAs dynamically changed throughout the OA-induced ALI process, and mitogen-activated protein kinase activation, PTEN/Akt pathway alteration and smooth muscle actin activation were observed in this ALI model.

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

“…Lee et al reported that miR-21 was also upregulated throughout the 24 h following OA challenge, with a time-course analysis of miRNA expression in rat OA-induced ALI. 47 These in vitro and in vivo results suggest the importance of miR-21 in ALI. Coincidently, we also found an increase in miR-21 serum concentrations in ARDS patients.…”

“…Consistent with previous studies that upregulated miR-21 depressed PTEN mRNA and protein expression in ventilator-induced and OA-stimulated rat ALI model. 47,49 In addition, PTEN contains miR-21-binging site within 3′ UTR. 45 Hence, we provide evidence linking LPS-mediated upregulation of miR-21 with downregulation of PTEN mRNA and protein in alveolar epithelia.…”

MicroRNA Regulation of Acute Lung Injury and Acute Respiratory Distress Syndrome

“…In addition, a few miRNA studies also reported either up/or down‐regulated miRNAs expression (Table ) consistent with ALI (Guo et al, ; Huang et al, ; Lee et al, ; Tan et al, ; Li et al, ; Otsuki et al, ; Rao et al, ), but the functional role of those miRNAs has not been studied either in vivo and/or in vitro conditions. Overall, these studies suggest the regulatory roles of miRNAs in controlling inflammatory target gene expression in ALI/ARDS and that a small change in miRNA expression could result in marked phenotypic consequences.…”

MicroRNAs in mucosal inflammation

“…Additionally, it was found that pulmonary miRNA expression varies depending on the specific mechanism of lung injury. MiRNA expression patterns have been analyzed in lung injury caused by mechanical ventilation [77–79], by administration of oleic acid [80], induced by pathogens including endotoxin exposure [81–84] or induced by radiation or hyperoxia [85, 86]. In vitro studies using cyclic mechanical stretch modeling mucosal injury showed changes in epithelial miRNAs expression [87].…”