**1. 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. The pathophysiology of the disease is characterized by a strong pulmonary inflammation with a diffuse alveolar damage and edema formation that leads to decreased pulmonary compliance, hypoxemia, and respiratory failure (reviewed in [1]). The mortality rate is still relatively high, and recovery is often associated with an increased risk of developing pulmonary fibrosis [2,3]. As of now, however, treatment options are limited to supportive care with mechanical ventilation, since pharmaceutical treatment options are still lacking [4].

MicroRNAs are small non-coding RNA sequences that regulate the gene expression of cellular processes, such as cell proliferation, differentiation, cell metabolism, or apoptosis, by forming complementary sequences to mRNAs and thereby inhibiting their translation (reviewed in [5,6]). MicroRNA-21 (miR-21) has been described to have pro-inflammatory, proliferative, and fibrotic activities in tumor development or fibrosis in a variety of different tissues and organs [7–9]. It was shown to be transcriptionally regulated via AP-1, STAT3, or NFκB signaling and interacting with a series of pathways such as PTEN/AKT, SMAD/TGFβ, PDCD4, and others (reviewed in [6,10]). In the lung, 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 [13–17]. This was also the case in patients with idiopathic pulmonary fibrosis (IPF) and in murine models of bleomycin-induced lung injury and fibrosis [12,18,19]. Previous studies have shown that the inhibition of miR-21 signaling improved lung function and oxygenation and reduced the formation of edema in ventilation-induced lung injury (VILI) or lipopolysaccharide- (LPS) induced ALI [13,17]. Other studies, however, also indicated that miR-21 could have beneficial effects on the development of ALI [20,21]. Together these studies provide evidence that miR-21 is involved in the development of ALI, however, its molecular role and the underlying mechanisms are still poorly understood.

While these previous studies have addressed the impact of miR-21 signaling in ALI by using synthetic overexpression (agomiR-21) or inhibition (antagomiR-21), in the current study miR-21 knock-out (KO) mice were used, with the advantage of a specific and permanent loss of miR-21 in the adult system. The impact of miR-21 was addressed in the acute phase of LPS-induced ALI, and we hypothesized that miR-21 KO ameliorates pulmonary inflammation and tissue damage.
