Involvement of claudin-5 in H₂S-induced acute lung injury

Abstract

Acute exposure to hydrogen sulfide (H 2 S) can cause fatal acute lung injury (ALI). However, the mechanisms of H 2 S-induced ALI are still not fully understood. This study aims to investigate the role of the tight junction protein claudin-5 in H 2 S-induced ALI. In our study, Sprague-Dawley (SD) rats were exposed to H 2 S to establish the ALI model, and in parallel, human pulmonary microvascular endothelial cells (HPMECs) were incubated with NaHS (a H 2 S donor) to establish a cell model. Lung immunohistochemistry and electron microscopy assays were used to identify H 2 S-induced ALI, and the expression of claudin-5, p-AKT/t-AKT and p-FoxO1/t-FoxO1 was detected. Our results show that H 2 S promoted the formation of ALI by morphological investigation and decreased claudin-5 expression. Dexamethasone (Dex) could partly attenuate NaHS-mediated claudin-5 downregulation, and the protective effects of Dex could be partially blocked by LY294002, a PI3K/AKT/FoxO1 pathway antagonist. Moreover, as a consequence of the altered phosphorylation of AKT and FoxO1, a change in claudin-5 with the same trend was observed. Therefore, the tight junction protein claudin-5 might be considered a therapeutic target for the treatment of ALI induced by H 2 S and other hazardous gases.

Countermeasures against Pulmonary Threat Agents

“…Potential therapies include chemosensory transient receptor potential A1 (TRPA1) antagonists (Conklin 2016), antioxidants (Hochman, Collaco et al 2014), and targeting claudin 5 (CLDN5) to preserve endothelial barrier integrity (Jang, Concel et al 2011). Investigators show increased perivascular edema and reduced CLDN5 expression in acrolein-sensitive mice (Jang, Concel et al 2011), and CLDN5 is being studied in other models of chemically induced ALI/ARDS (Geng, Ma et al 2018, Geng, Yu et al 2020.…”

Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury

“…Lung injury caused by chemicals and particulate matter: Cadmium-, hydrogen sulfide-, phosgene-NaHS-, diethylenetriamine (NO donor)-, oleic acid-, arsenic trioxide-, particulate matter (PM)2.5-, thrombin-, nocodazole (inducer of microtubule disassembly)-, alcohol-, and ozoneinduced injury in mice and rats, and primary human lung microvascular endothelial cells, A549 cells, human bronchial epithelial (HBEC)-2 and HBEC-3 cells, BEAS-2B cells, primary type II epithelial cells, human bronchial epithelial 16HBE cells, human pulmonary artery endothelial cells, bovine pulmonary arterial endothelial cells, and primary normal human bronchial epithelial cells [44,[225][226][227][228][229][230][231][232][233][234][235] Decrease in ZO-1 and occludin and dysregulation of E-cadherin and N-cadherin Allergic asthma: Aspergillus fumigatus and co-infection with Streptococcus pneumoniae-, and Ovalbumin (OVA)-LPS-induced allergic asthma in mice, and TGF-β-challenged mouse MLE-12 cells [236,237] Decrease in claudin-1, claudin-4, claudin-5, and claudin-10b, ZO-1, ZO-2, occludin, and tricellulin; increase in claudin-2 and claudin-7, and soluble E-cadherin; no change in occludin, claudin-1, claudin-7, and claudin-18, ZO-1, E-cadherin, and β-catenin; disrupted distribution and structure of ZO-1, occludin, and β-catenin Infections: CLP/sepsis-, RSV-, VP1 capsid protein of enterovirus (EV71)-, and influenza-induced lung injury models in mice, primary human lung microvascular endothelial cells, human bronchial epithelial cells from healthy asthmatic patients, and mouse tracheal epithelial cells, lung tissues from HIV-1 seropositive patients with interstitial pneumonitis or bronchopneumonia, and ex vivo perfused human lungs [55, 238-241, 242, 243] Decrease in ZO-1, ZO-2, occludin, claudin-5 and claudin-18, E-cadherin, and VE-cadherin; increased expression of VE-cadherin and ZO-1, and association of ZO-1, α-catenin, VASP, and VE-cadherin; no effect on claudin-1 and -4; increased expression and localization of VE-cadherin; and altered distribution of ZO-1, VE-cadherin, and β-catenin…”

Respiratory effects of hydrogen sulfide poisoning: dysfunction, damage, and diseases

“…Mechanistically, certain strides have been made towards understanding the effects of acute H2S poisoning in the lungs. Claudin-5, a key tight junction protein in the vascular endothelium, was decreased in an H2S-induced ALI model of Sprague-Dawley rats [118].…”