Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model

• Published in: International journal of molecular sciences 2024-06, Vol.25 (12), p.6370
• Main Authors: Li, Li-Fu, Yu, Chung-Chieh, Huang, Chih-Yu, Wu, Huang-Pin, Chu, Chien-Ming, Liu, Ping-Chi, Liu, Yung-Yang
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute respiratory distress syndrome; Animals; apoptosis; Apoptosis - drug effects; Bleomycin; Bleomycin - adverse effects; Class Ib Phosphatidylinositol 3-Kinase - genetics; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Collagen; Cytokines; Diaphragm (Anatomy); Diaphragm - metabolism; Diaphragm - pathology; diaphragm fibrosis; Disease Models, Animal; Fibroblasts; Fibrosis; Growth factors; Kinases; Lipids; Male; Mice; Mice, Inbred C57BL; Oxidative stress; phosphoinositide 3-kinase-γ; Protein expression; Proteins; Quinoxalines; Respiration, Artificial - adverse effects; Thiazolidinediones; Transforming Growth Factor beta1 - metabolism; ventilator-induced diaphragm dysfunction; Ventilators; Weaning
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25126370

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-β1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis ( < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed ( < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity ( < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.