Few pharmacological interventions are able to improve the mortality rate of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). The aim of this research was to elucidate whether endoplasmic reticulum (ER) stress and c‑Jun‑N‑terminal kinase (JNK)‑mitochondria pathways serve important roles in ALI/ARDS and to determine whether the key component Sab is a potential treatment target. The current study investigated the activation of ER stress and the JNK pathway, the content of JNK located on the mitochondria during ER stress and lipopolysaccharide (LPS)‑induced ALI/ARDS by western blot analysis. The treatment effects of Tat‑SabKIM1, a selective inhibitor of JNK located on mitochondria were explored by multiple methods including histopathological evaluation, lung cell apoptosis tested by TUNEL assay, mitochondrial membrane permeability and survival analysis. The results verified that ER stress was enhanced during LPS‑induced ALI/ARDS and could induce activation of the JNK pathway and JNK‑mitochondrial localization as well as mitochondrial dysfunction and cell death. Tat‑SabKIM1 alleviated LPS injection‑induced lung injury and improved mouse survival rates by specifically inhibiting JNK localization to mitochondria and mito‑JNK signal activation without affecting cytosolic/nuclear JNK activation. The protective effect of Tat‑SabKIM1 against ALI/ARDS was partly caused by inhibition of the excessive activation of mitochondria‑mediated apoptosis and autophagy. These results showed the important role of Sab as a treatment target of ALI/ARDS and the potential treatment effect of Tat‑SabKIM1. In conclusion, abnormal activation of the JNK‑mitochondrial pathway could significantly disrupt the normal physiological function of lung cells, resulting in the occurrence of ALI/ARDS and selective inhibit of JNK located on mitochondria by Tat‑SabKIM1 had a protective effect against the mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS‑induced ALI/ARDS.

Localization of phosphorylated (p)‑JNK to the mitochondria can lead to functional mitochondrial disorder, resulting in a decrease in energy supply and membrane potential, as well as an increase in reactive oxygen species production and apoptosis. JNK is involved in the occurrence of acute lung injury (ALI), and activation of the JNK pathway is one of the crucial factors resulting in injury. The aim of the present study was to investigate whether the JNK‑mitochondria (mitoJNK) location participated in the occurrence of ALI and acute respiratory distress syndrome (ALI/ARDS). The present study examined the activation of the JNK pathway, the content of JNK located on the mitochondria and the treatment effects of a cell‑permeable peptide Tat‑SabKIM1, which can selectively inhibit the location of JNK on mitochondria. The expression levels of proteins were detected by western blot analysis. Lung injuries were evaluated by histological examination, wet‑to‑dry weight ratios, and H2O2 and malondialdehyde concentrations in the lung tissues. Lung cells apoptosis was evaluated using TUNEL assay. The results demonstrated that JNK was phosphorylated and activated during seawater inhalation‑induced ALI/ARDS, not only in the routine JNK pathway but also in the mitoJNK pathway. It was also found that Tat‑SabKIM1 could specifically inhibit JNK localization to mitochondria and the activation of mitoJNK signaling. Furthermore, Tat‑SabKIM1 could inhibit Bcl‑2‑regulated autophagy and mitochondria‑mediated apoptosis. In conclusion, mitoJNK localization disrupted the normal physiological functions of the mitochondria during ALI/ARDS, and selective inhibition of JNK and mitochondrial SH3BP5 (also known as Sab) binding with Tat‑SabKIM1 can block deterioration from ALI/ARDS.

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure and acts through angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7)/MAS receptor axis. RAS dysfunction is related to the occurrence and development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and causes a serious prognosis and even death. ALI/ARDS can be induced by various ways, one of which is viral infections, such as SARS-CoV, SARS-CoV-2, H5N1, H7N9, and EV71. This article reviews the specific mechanism on how RAS dysfunction affects ALI/ARDs caused by viral infections. SARS-CoV and SARS-CoV-2 enter the host cells by binding with ACE2. H5N1 and H7N9 avian influenza viruses reduce the ACE2 level in the body, and EV71 increases Ang II concentration. Treatment with angiotensin-converting enzyme inhibitor and angiotensin AT1 receptor blocker can alleviate ALI/ARDS symptoms. This review provides suggestions for the treatment of lung injury caused by viral infections.

Inhalation or systemic administration of lipopolysaccharide (LPS) can induce acute pulmonary inflammation and lung injury. The pulmonary vasculature is composed of pulmonary microvascular endothelial cells (PMVECs), which form a semiselective membrane for gas exchange. The miRNA miR-642a-5p has previously been reported to be up-regulated in patients with acute respiratory distress syndrome; thus, here, we examined whether this miRNA is involved in the effects of LPS on PMVECs. The levels of miR-642a-5p and mRNA encoding eukaryotic elongation factor 2 (eEF2) were detected by quantitative RT-PCR. Moesin and eEF2 protein levels were tested by western blot assay. Dual-luciferase reporter assay was used to examine the relationship between miR-642a-5p and eEF2. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell permeability was analyzed using the transendothelial electrical resistance assay. We report that miR-642a-5p levels are significantly up-regulated in LPS-stimulated PMVECs, and miR-642a-5p contributes to LPS-induced hyperpermeability and apoptosis of PMVECs. LPS treatment results in down-regulation of eEF2 in PMVECs. Overexpression of eEF2, a direct target of miR-642a-5p, inhibited the effect of LPS on PMVECs. miR-642a-5p promoted LPS-induced hyperpermeability and apoptosis by targeting eEF2. Thus, miR-642a-5p and eEF2 may serve as potential targets for acute lung injury/acute respiratory distress syndrome diagnosis or treatment.