MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

Abstract

Acute lung injury (ALI) is a critical clinical condition with a high mortality rate, characterized with excessive uncontrolled inflammation and apoptosis. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, it remains unknown the biological function and regulatory mechanisms of miRNAs in the regulation of inflammation and apoptosis in ALI. The aim of this study is to identify and evaluate the potential role of miRNAs in ALI and reveal the underlying molecular mechanisms of their effects. Here, we analyzed microRNA expression profiles in lung tissues from LPS-challenged mice using miRNA microarray. Because microRNA-27a (miR-27a) was one of the miRNAs being most significantly downregulated, which has an important role in regulation of inflammation, we investigated its function. Overexpression of miR-27a by agomir-27a improved lung injury, as evidenced by the reduced histopathological changes, lung wet/dry (W/D) ratio, lung microvascular permeability and apoptosis in the lung tissues, as well as ameliorative survival of ALI mice. This was accompanied by the alleviating of inflammation, such as the reduced total BALF cell and neutrophil counts, decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-6) interleukin-1β (IL-1β) and myeloperoxidase (MPO) activity in BAL fluid. Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor kappa-B (NF-κB) signaling pathway, was identified as a novel target of miR-27a in RAW264.7 cells. Furthermore, our results showed that LPS stimulation increased the expression of MyD88 and NF-κB p65 (p-p65), but inhibited the expression of inhibitor of nuclear factor-κB-α (IκB-α), suggesting the activation of NF-κB signaling pathway. Further investigations revealed that agomir-miR-27a reversed the promoting effect of LPS on NF-κB signaling pathway. The results here suggested that miR-27a alleviates LPS-induced ALI in mice via reducing inflammation and apoptosis through blocking TLR4/MyD88/NF-κB activation.

Clinical significance of serum levels of microRNA‑27a and its correlation with interleukin‑10 in patients with multiple organ dysfunction syndrome caused by acute paraquat poisoning

“…The present study hypothesized that miR-27a may be involved in kidney and lung injury in patients with MODS induced by paraquat poisoning. Ju et al (42) reported that miR-27a can alleviate acute lung injury in mice by inhibiting inflammation. Additionally, miR-27a was shown to inhibit pulmonary fibrosis in rats (43).…”

miR-145 plays a role in mitochondria dysfunction in alveolar epithelial cells in LPS-induced ARDS

“…The oropharynx was lifted with forceps, allowing for the direct visualization of the trachea. LPS at a dose of 0.5mg/kg (Sigma, U.S.) was injected into the trachea using an 18G catheter attached to a 1ml syringe as preciously described [28]. Control animals received equal volume of PBS.…”

“…Moreover, using rat genome database with NCBI database, seven mitochondria associated genes regulated by miR-145 were identified, including Slc1a2, Cftr, Ogt, Acs14, Camk2d, Slc8a3 and Slc25a25 (Fig.4 B-C). Plenty of evidences exhibited that LPS could induce cells inflammatory responses in various diseases, of course including ARDS [26][27][28]. Instillation of LPS intratracheal is proved to be an excellent in vivo model of lung injury and it is widely used for investigating ARDS.…”

“…MicroRNAs are small non-coding RNA that plays a crucial role in many disease processes, including malignancy and inflammatory processes. Abnormal expression miRNAs, such as miR-126-5p, miR-1246, miR-34a, miR-27a and mir-223 have been found in lung injury [28,[35][36][37][38]. MiR-145 is an important molecular marker, which has been proven to mediate cell proliferation, cell cycle, apoptosis and invasion [19].…”

Silencing of long noncoding RNA H19 alleviates pulmonary injury, inflammation and fibrosis in acute respiratory distress syndrome rats through regulating MicroRNA-423-5p

“…Numerous studies have proved the key function of miRNAs in the progresses of ALI. MiR-27a alleviates the in ammatory responses of pulmonary in LPS-induced ALI via regulating TLR4/MyD88/NF-κB pathway [15]. Overexpression of miR-125b ameliorates the in ammation and histopathology changes of pulmonary in LPS-induced ALI [16].…”