MiR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury.

Johanna Christine Jansing,Christina Brandenberger,Thomas Thum,Jan Fiedler,Janika Viereck,Christian Mühlfeld,Andreas Pich

doi:10.3390/ijms21030822

Johanna Christine Jansing, Christina Brandenberger + Show 5 more

Open Access

https://doi.org/10.3390/ijms21030822

Copy DOI

Abstract

Acute lung injury (ALI) is characterized by enhanced permeability of the air–blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (n = 10 per group). The control mice received saline alone (n = 7 per group). After 24 h, lung function was measured. The lungs were then excised for proteomics, cytokine, and stereological analysis to address inflammatory signaling and structural damage. LPS exposure induced ALI in both strains, however, only WT mice showed increased tissue resistance and septal thickening upon LPS treatment. Septal alterations due to LPS exposure in WT mice consisted of an increase in extracellular matrix (ECM), including collagen fibrils, elastic fibers, and amorphous ECM. Proteomics analysis revealed that the inflammatory response was dampened in miR-21 KO mice with reduced platelet and neutrophil activation compared with WT mice. The WT mice showed more functional and structural changes and inflammatory signaling in ALI than miR-21 KO mice, confirming the hypothesis that miR-21 KO reduces the development of pathological changes in ALI.

Highlights

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) results from severe alveolar injury with increased permeability of the alveolar–capillary barrier, which is most often caused by pneumonia or sepsis
Vaporidi and colleagues showed that mice pretreated with anti-miR-21 before the induction of ventilation-induced lung injury (VILI) had better oxygenation and lower BALF protein concentrations in comparison to mice that were not pretreated with anti-miR-21, suggesting that the downregulation of miR-21 ameliorated the development of VILI [17]
Qi and colleagues showed that miR-21 supported the inhibition of ENaC-γ, an epithelial sodium channel that is essential for the removal of edematous fluid in ALI, through PTEN/AKT signaling, and downregulation of miR-21 reversed this effect [13]

Summary

Introduction

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) results from severe alveolar injury with increased permeability of the alveolar–capillary barrier, which is most often caused by pneumonia or sepsis. MiR-21 was found to be upregulated and involved in the development of ALI and pulmonary fibrosis [11,12]. Patients with ARDS showed increased levels of miR-21 in the blood serum [13] and miR-21 was upregulated in different murine models of ALI [13,14,15,16,17]. This was the case in patients with idiopathic pulmonary fibrosis (IPF) and in murine models of bleomycin-induced lung injury and fibrosis [12,18,19]. Together these studies provide evidence that miR-21 is involved in the development of ALI, its molecular role and the underlying mechanisms are still poorly understood

Methods

Results

Conclusion