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Attenuation of Ventilation-Enhanced Epithelial-Mesenchymal Transition through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model.
Li, Li-Fu; Yu, Chung-Chieh; Huang, Chih-Yu; Wu, Huang-Pin; Chu, Chien-Ming; Liu, Ping-Chi; Liu, Yung-Yang.
Affiliation
  • Li LF; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
  • Yu CC; Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
  • Huang CY; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
  • Wu HP; Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
  • Chu CM; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
  • Liu PC; Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
  • Liu YY; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
Int J Mol Sci ; 24(6)2023 Mar 14.
Article in En | MEDLINE | ID: mdl-36982609
Mechanical ventilation (MV) used in patients with acute lung injury (ALI) induces lung inflammation and causes fibroblast proliferation and excessive collagen deposition-a process termed epithelial-mesenchymal transition (EMT). Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating EMT during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, EMT, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase EMT through the PI3K-γ pathway. C57BL/6 mice, either wild-type or PI3K-γ-deficient, were exposed to 6 or 30 mL/kg MV for 5 h after receiving 5 mg/kg AS605240 intraperitoneally 5 days after bleomycin administration. We found that, after bleomycin exposure in wild-type mice, high-tidal-volume MV induced substantial increases in inflammatory cytokine production, oxidative loads, Masson's trichrome staining level, positive staining of α-smooth muscle actin, PI3K-γ expression, and bronchial epithelial apoptosis (p < 0.05). Decreased respiratory function, antioxidants, and staining of the epithelial marker Zonula occludens-1 were also observed (p < 0.05). MV-augmented bleomycin-induced pulmonary fibrogenesis and epithelial apoptosis were attenuated in PI3K-γ-deficient mice, and we found pharmacological inhibition of PI3K-γ activity through AS605240 (p < 0.05). Our data suggest that MV augmented EMT after bleomycin-induced ALI, partially through the PI3K-γ pathway. Therapy targeting PI3K-γ may ameliorate MV-associated EMT.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphatidylinositol 3-Kinases / Acute Lung Injury Limits: Animals Language: En Journal: Int J Mol Sci Year: 2023 Document type: Article Affiliation country: Taiwan Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phosphatidylinositol 3-Kinases / Acute Lung Injury Limits: Animals Language: En Journal: Int J Mol Sci Year: 2023 Document type: Article Affiliation country: Taiwan Country of publication: Switzerland