Hydrogen-Rich Saline Inhibits Lipopolysaccharide-Induced Acute Lung Injury and Endothelial Dysfunction by Regulating Autophagy through mTOR/TFEB Signaling Pathway

Abstract

Background. Hydrogen-rich saline (HRS) has strong anti-inflammatory, antioxidative stress, and antiapoptotic properties. The study focused on the protection of HRS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models and the relationship with autophagic regulation and mTOR/TFEB signaling pathway. Material and Methods. The LPS-induced ALI rats’ model was established. Pathohistological change in lung tissue was detected by hematoxylin-eosin staining. The inflammatory cytokines were examined by enzyme-linked immunosorbent assay (ELISA). The key apoptosis proteins and autophagy-relevant proteins were analyzed by western blotting. In vitro, HPMEC models of ALI were treated with LPS. The inflammatory cytokines were detected. Apoptosis rate was determined by flow cytometry. The autophagy and mTOR/TFEB signaling pathway-related proteins were detected by western blot and immunohistochemical staining. Results. HRS attenuated LPS-induced ALI and apoptosis both in vivo and in vitro. HRS attenuated inflammatory response, inhibited apoptosis, induced and activated autophagy in LPS-induced ALI model, and downregulated mTOR/TFEB signaling pathway. The protection of HRS can be blocked by autophagy inhibitor. Moreover, mTOR activator reversed HRS protection and mTOR inhibitor enhanced HRS protection in LPS-induced model and HRS activated autophagy via mTOR/TFEB signaling pathway. Conclusion. The results confirmed the protection of HRS in LPS-induced ALI by regulating apoptosis through inhibiting the mTOR/TFEB signaling pathway.

Zisheng Shenqi Decoction Ameliorates Monosodium Urate-Mediated Gouty Arthritis in Rats via Promotion of Autophagy through the AMPK/mTOR Signaling Pathway

“…Terkeltaub [ 28 ] reported that p-AMPK significantly suppressed mononuclear phagocyte responses to urate crystals in vitro , containing NLRP3 inflammasome activation and the release of IL-1 β and chemokines. The previous work showed that hydrogen-rich saline protected lipopolysaccharide-induced acute lung injury via controlling autophagy through repression of mTOR signaling pathway activation [ 32 ]. Our experiment results suggested that ZSD activated the AMPK pathway and inhibited the mTOR pathway to facilitate autophagy.…”

Molecular hydrogen is a potential protective agent in the management of acute lung injury

“…Molecular hydrogen can prevent LPS-induced EC apoptosis by inhibiting the activity of RhoA or activating the Nrf2-mediated HO-1 pathway in in vitro experiments (Chen et al 2015a;Li et al 2020). In our study, we found that molecular hydrogen activated mTOR/transcription factor EB (TFEB)mediated autophagy and inhibited HPMEC apoptosis in LPS-induced ALI (Fu et al 2020). Through the inhibition of apoptosis, molecular hydrogen improves cell viability and suppresses the release of the cell adhesion molecules, such as vascular cell adhesion molecule-1 and ICAM-1, and pro-inflammatory cytokines, such as TNF-α, IL-1β, and HMGB1, potentially alleviating endothelial injury (Fig.…”

“…Molecular hydrogen treatment can reduce the degree of LPSinduced inflammation in lung tissues of experimental animals. It inhibits NF-κB signaling pathway-mediated inflammation and apoptosis in the lung (Xie et al 2012), reduces p38 MAPK expression and inhibits p38 MAPK activation (Liang et al 2012), inhibits the RhoA mediated pathway (Yang et al 2016), and modulates autophagy through the mTOR/TFEB signaling pathway and the PINK1/Parkin mitophagy pathway (Fu et al 2020;Chen et al 2021). Recently, molecular hydrogen was found to activate thioredoxin 1 and decrease tissue factor expression, alleviating inflammatory and coagulation cascade reactions (Li et al 2021).…”

TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

“…For example, licochalcone A, curcumin, and cobalt protoporphyrin, have been shown to alleviate liver injury (Lv et al, 2019), intestinal barrier injury (Cao et al, 2020), and septic insults in the heart (Unuma et al, 2013), induced by LPS challenge; these effects were all related to the ability of these TFEB activators to activate the ALP. Other non-conventional TFEB inducers, such as hydrogen rich saline (Fu et al, 2020) and carbon monoxide (Kim et al, 2018), have been found to confer protection against lipopolysaccharide-induced acute injury or inflammatory liver injury, respectively. Furthermore, the activation of TFEB by mTORC1 inhibitors has been shown to rescue a mouse model from lethal pancreatitis (Wang et al, 2019) and chronic ethanol-induced liver injury (Chao et al, 2018); these effects were closely associated with the onset of sepsis or during sepsis and worsened clinical outcomes.…”