Lionetti Vincenzo, Lisi Alberto, Patrucco Enrico, De Giuli Paolo, Milazzo Maria Giovanna, Ceci Simone, Wymann Matthias, Lena Annalisa, Gremigni Vittorio, Fanelli Vito, Hirsch Emilio, Ranieri V Marco
Dipartimento di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista-Molinette, Università di Torino, Torino, Italy.
Crit Care Med. 2006 Jan;34(1):134-41. doi: 10.1097/01.ccm.0000190909.70601.2c.
G protein-coupled receptors may up-regulate the inflammatory response elicited by ventilator-induced lung injury but also regulate cell survival via protein kinase B (Akt) and extracellular signal regulated kinases 1/2 (ERK1/2). The G protein-sensitive phosphoinositide-3-kinase gamma (PI3Kgamma) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3Kgamma on ventilator-induced lung injury.
Prospective, randomized, experimental study.
University animal research laboratory.
Wild-type (PI3Kgamma), knock-out (PI3Kgamma ), and kinase-dead (PI3Kgamma) mice.
Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3Kgamma, PI3Kgamma, and PI3Kgamma mice.
Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). Inflammatory cytokines and IkBalpha phosphorylation with high stretch did not differ among PI3Kgamma, PI3Kgamma, and PI3Kgamma. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p < .01) in PI3Kgamma and PI3Kgamma than in PI3Kgamma. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3Kgamma mice whereas PI3Kgamma mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01).
Silencing PI3Kgamma seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.
G蛋白偶联受体可能上调呼吸机诱导的肺损伤引发的炎症反应，但也可通过蛋白激酶B（Akt）和细胞外信号调节激酶1/2（ERK1/2）调节细胞存活。G蛋白敏感的磷酸肌醇-3-激酶γ（PI3Kγ）调节多种细胞功能，包括炎症和细胞存活。我们探讨了PI3Kγ在呼吸机诱导的肺损伤中的作用。
前瞻性、随机、实验性研究。
大学动物研究实验室。
野生型（PI3Kγ）、基因敲除型（PI3Kγ）和激酶失活型（PI3Kγ）小鼠。
在PI3Kγ、PI3Kγ和PI3Kγ小鼠的急性肺损伤（肺灌洗）离体、非灌注模型中研究三种通气策略（无拉伸、低拉伸、高拉伸）。
与PI3Kγ和PI3Kγ相比，PI3Kγ中高拉伸导致的肺顺应性降低、透明膜形成和上皮脱落更为明显（p < 0.01）。PI3Kγ、PI3Kγ和PI3Kγ之间，高拉伸时炎症细胞因子和IkBα磷酸化无差异。高拉伸时，PI3Kγ和PI3Kγ的凋亡指数（末端脱氧核苷酸转移酶介导的生物素-dUTP缺口末端标记）和半胱天冬酶-3（免疫组织化学）高于PI3Kγ（p < 0.01）。电子显微镜显示，高拉伸导致PI3Kγ小鼠肺泡细胞发生凋亡改变，而PI3Kγ小鼠表现为坏死。高拉伸时，PI3Kγ中Akt和ERK1/2的磷酸化比PI3Kγ和PI3Kγ更明显（p < 0.01）。
沉默PI3Kγ似乎可减轻呼吸机诱导的肺损伤的功能和形态学后果，这并非通过抑制细胞因子释放，而是通过增强肺细胞凋亡实现。
