PDF(Pubmed)
Abstract：
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 (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 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 (p < 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.
摘要：
机械通气(MV),用于急性肺损伤（ALI）患者，诱导膈肌纤维萎缩和收缩不活动，称为呼吸机诱发的膈肌功能障碍。磷酸肌醇3-激酶-γ（PI3K-γ）在调节ALI修复期的纤维形成中至关重要；然而，调节MV之间相互作用的机制，肌纤维纤维化，和PI3K-γ仍不清楚。我们假设有或没有博来霉素治疗的MV会通过PI3K-γ途径增加膈肌纤维化。气管内单次推注0.075单位博来霉素后五天，在腹膜内接受5mg/kg的AS605240后，将C57BL/6小鼠暴露于6或10mL/kg的MV中8小时。在野生型小鼠中,博来霉素暴露后的MV10mL/kg促使膈肌原纤维组织的破坏显着增加，转化生长因子-β1，氧化负荷，马森三色染色，细胞外胶原蛋白水平，α-平滑肌肌动蛋白阳性染色，PI3K-γ表达,和肌核凋亡（p<0.05）。还观察到膈肌收缩力和过氧化物酶体增殖物激活受体-γ共激活因子-1α水平降低(p<0.05)。在PI3K-γ缺陷小鼠中，通过AS605240诱导的PI3K-γ活性抑制，MV增强的博来霉素诱导的膈肌纤维化和肌核凋亡减弱（p<0.05）。博来霉素诱导的ALI后MV增强的膈肌纤维化部分由PI3K-γ介导。针对PI3K-γ的治疗可以改善MV相关的膈肌纤维化。
