ArticleJournal of inflammation (London, England)2026
Hypoxia synergizes cGAS-STING activation and AKT1 phosphorylation to drive pulmonary inflammation in one-lung ventilation: therapeutic attenuation by RU.521 and MK2206.
Article in Journal of inflammation (London, England), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundTo explore the mechanisms involved in hypoxia-induced acute lung injury (ALI) and oxidative stress during one-lung ventilation (OLV) in order to find pharmacological interventions that can attenuate OLV injury.
methodsAn OLV model was established in Sprague-Dawley (SD) rats. Lung tissue damage was assessed via histological staining and by quantifying inflammatory factors (TNF-α, IL-6, IL-1β) using qPCR. High-throughput transcriptome sequencing of left lung tissues from the OLV group and the two-lung ventilation (TLV) group screened for differentially expressed genes (DEGs) in pathways and biological functions associated with lung injury. Furthermore, a hypoxia reoxygenation (H/R) model was established using the mouse lung epithelial cell line (MLE-12) for further mechanism mapping and validation in vitro.
resultsTranscriptomic analysis revealed upregulated gene signatures linked to DNA damage, mitochondrial membrane permeabilization, oxidative stress, and innate immune activation. KEGG enrichment identified innate immune pathways, specifically cytosolic DNA sensing. Subsequent in vivo and in vitro studies confirmed cGAS-STING pathway activation, characterized by increased expression and enhanced phosphorylation of downstream components. Genetic knockdown of cGAS or AKT1 (a kinase required for downstream phosphorylation of key cGAS-STING downstream effectors) suppressed cGAS-STING pathway signaling.
conclusionThis study highlights that innate immunity contributes to lung tissue damage during OLV. Hypoxia-induced DNA damage activates the cytoplasmic DNA-sensing cGAS-STING pathway. Subsequently, AKT1 modulates the downstream phosphorylation of TBK1, IRF3, and NF-κB, thereby promoting DNA damage-associated inflammation in alveolar epithelial cells. Pharmacologically, both the cGAS inhibitor RU.521 and AKT1 inhibitor MK2206 attenuated cGAS-STING-mediated inflammation and mitigated hypoxia-induced oxidative stress in alveolar epithelia. CLINICAL TRIAL NUMBER: Not applicable.
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