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Sulfonylurea receptor 1 deficiency alleviates acute lung injury by activating PARP1 in epithelial cells

ABSTRACT: Acute lung injury (ALI) is a critical disease with high mortality, yet its mechanisms remain incompletely elucidated. In this study we investigated sulfonylurea receptor 1 (SUR1), the regulatory subunit of ATP-sensitive potassium (KATP) channels, in the progression of ALI. We observed elevated SUR1 protein levels in the bronchial alveolar lavage fluid (BALF) of patients with sepsis-associated ALI, as well as in BALF and lung tissues of ALI mouse models. Genetic deletion of SUR1, but not Kir6.2 (the pore-forming subunit of KATP channels), significantly alleviated ALI induced by cecal ligation and puncture (CLP) or by lipopolysaccharide (LPS) intratracheal instillation. Mechanistically, SUR1 interacted with poly (ADP-ribose) polymerase 1 (PARP1), impairing DNA damage repair and promoting apoptosis and NF-κB (nuclear factor kappa B) activation in bronchial epithelial cells. Notably, glibenclamide, a clinically approved SUR1 inhibitor, significantly alleviated ALI, at least in part, by disrupting the SUR1–PARP1 interaction. Our findings identify SUR1 as a new therapeutic target and highlighting the potential repurposing of glibenclamide as a therapeutic drug in ALI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345117 | GEO | 2026/08/26

REPOSITORIES: GEO

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Project description:The SARS-CoV-2 spike protein mediates attachment of the virus to host cell receptor and fusion between the virus and cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection and constitutes the viral component of mRNA based COVID-19 vaccines. Therefore, in this work we assessed the effect of exposure (24 hours) of 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n=6/experimental group). Corresponding sham exposed samples served as control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes. Exposure of S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p< 0.01). Pathway analysis revealed enriched terms as specific as COVID-19, interferon (IFN) signaling, influenza, Corona virus, anti-viral response in the bro-ALI. Secreted levels of Interleukin (IL) 4 and IL12 were significantly (p<0.05; non-parametric) increased whereas IL6 decreased in the bro-ALI. In case of alv-ALI, enriched terms involving p53, APRIL, tight junction, integrin kinase, IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p<0.05; non-parametric) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and tumor necrosis factor alpha were detected in alv-ALI. Altered levels of these cytokines are also associated with lung fibrotic response. Taken together, we observed a typical anti-viral response in the bronchial model whereas a pro-fibrotic response in the alveolar model. Therefore the bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of variants of concern at different lung regions.

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Sulfonylurea receptor 1 deficiency alleviates acute lung injury by activating PARP1 in epithelial cells

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