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Published on: September 24, 2020
Dexmedetomidine alleviates acute lung injury in humans by modulating the JAK1-STAT3 axis
Xianchao Ding1, Daoming Shi1, Jieru Wang1
1Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Abstract:
The clinical efficacy of dexmedetomidine (Dex) in acute lung injury (ALI) and its related molecular mechanisms in human systems are poorly defined. In the present study the modulatory functions of Dex in human ALI were investigated, together with identification of the key molecular pathways involved. Human respiratory epithelial cell lines (A549 and BEAS2b) were cultured in vitro and categorized into four experimental groups: Untreated control (Con), Dex-treated, lipopolysaccharide (LPS)-treated, and both LPS + Dex-treated (LPS + Dex) groups. In BEAS-2B cells, inflammatory cytokine levels in the culture supernatant and cell viability were measured in all groups. In A549 cells, proliferative capacity and apoptosis rates were evaluated. The mRNA levels of caspase-3 and BCL-2, BAX within the BEAS-2B cells after LPS exposure were examined using reverse transcription-quantitative PCR. The levels of Janus kinase 1 (JAK1) and signal transduction and transcription activation 3 (STAT3) proteins, along with their phosphorylated forms in A549 cells, were analyzed via western blotting. Dex substantially suppressed LPS-mediated elevation of IL-1β, IL-6 and TNF-α. LPS-associated reductions in cell viability and proliferative activity were markedly attenuated following Dex treatment. It also lowered the LPS-induced increase in apoptotic cell populations. The upregulation of caspase-3 and BAX gene expression after LPS stimulation in BEAS-2B cells was decreased by Dex treatment. The downregulation of BCL-2 gene expression after LPS stimulation in BEAS-2B cells was alleviated by Dex treatment. Moreover, Dex suppressed LPS-induced stimulation of the JAK1/STAT3 signaling cascade, as evidenced by downregulation of phosphorylated (p-)STAT3 and p-JAK1 in the A549 cells. Dex showed a protective effect against human ALI in vitro by reducing inflammatory responses, maintaining epithelial cell viability and decreasing apoptosis rate of epithelial cell. Modulation of the JAK1/STAT3 signaling cascade plays a crucial role in mediating these effects.
Insights
Dexmedetomidine (Dex) protects against acute lung injury (ALI) by reducing inflammation and apoptosis. This study investigated Dex
Area of Science:
- Pulmonology and Critical Care Medicine
- Pharmacology and Molecular Mechanisms
Background:
- The clinical efficacy and molecular mechanisms of dexmedetomidine (Dex) in acute lung injury (ALI) remain unclear.
- Understanding Dex's role in human ALI models is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the modulatory effects of dexmedetomidine (Dex) on human acute lung injury (ALI) in vitro.
- To identify the key molecular pathways, including the JAK1/STAT3 signaling cascade, involved in Dex's protective effects against ALI.
Main Methods:
- Human respiratory epithelial cell lines (A549 and BEAS2b) were treated with lipopolysaccharide (LPS) with or without Dex.
- Assessed inflammatory cytokine levels (IL-1β, IL-6, TNF-α), cell viability, proliferation, and apoptosis.
- Analyzed gene expression (caspase-3, BCL-2, BAX) and protein levels (JAK1, STAT3, p-JAK1, p-STAT3) using RT-qPCR and Western blotting.
Main Results:
- Dex significantly suppressed LPS-induced increases in inflammatory cytokines (IL-1β, IL-6, TNF-α).
- Dex treatment attenuated LPS-associated reductions in cell viability and proliferation, while lowering apoptosis rates.
- Dex inhibited the LPS-induced JAK1/STAT3 signaling pathway activation and modulated apoptosis-related gene expression.
Conclusions:
- Dexmedetomidine demonstrates a protective effect against human ALI in vitro.
- Dex reduces inflammation, preserves epithelial cell viability, and decreases apoptosis.
- The JAK1/STAT3 signaling pathway is a key mediator of Dex's protective effects in ALI.
