欧阳彬 SICU 中山大学附属第一医院, 广州,呼吸机相关性肺损伤 （Ventilator induced lung injury, VILI) (Ventilator associated lung injury, VALI),中山大学附属第一医院,机械通气挽救了无数患者的生命,脊髓灰质炎 1952年无呼吸机时 死亡率 87%， 1953年 有呼吸机后 死亡率 15%,但机械通气同时导致了 呼吸机相关性肺损伤（VALI） 呼吸机诱导膈肌萎缩(VIDD) 呼吸机相关性肺炎(VAP) 呼吸机相关性不适（VAUE）,Inflammation Hemorrhage Edema Fibrosis Pulmonary dysfunction Systemic effects,机械通气导致了怎样的肺损伤？,1. B. Ouyang（欧阳彬), Jafari, O. Syrkina, C.A. Hales and D.A. Quinn. N-acetyl-L-cysteine inhibited TGF- production and reduced lung collagen formation in ventilator-induced lung injury. FASEB Journal. 2004 Mar: 18(4): 218.11 (A323). 2. Bin Ouyang（欧阳彬), Choi W, Hales C, Quinn D. TGF up-regulation in vitro and in vivo models of Ventilator Induced Lung Injury. ATS 2003, A622. 3. Bin Ouyang（欧阳彬）, Deborah A. Quinn, and Charles A. Hales. Stretch Induced Gene Expression in an in vitro model of Ventilator Induced Lung Injury (VILI). FASEB Journal. 2002 Mar: 16(4): 367.10 (A410). 4. Ouyang B（欧阳彬）, Choukroun G, Matyal R, Mascarenhas M, Jafari B, Bonyentre JV, Force T and Quinn DA. Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-kappaB inducing kinases. Am J Physiol Lung Cell Mol Physiol. 2003 Aug; 285(2): L464-75. 5 Jafari B, Ouyang B（欧阳彬）, Li LF, Hales CA and Quinn DA. Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like c ells. Respirology. 2004 Mar; 9(1): 43-53. 6. B. Jafari, B. Ouyang（欧阳彬), C. A. Hales and D. A. Quinn. Antioxidants inhibit stretch-induced IL-8 production through intracellular glutathione. ATS, 2002. B82. 7. Li-Fu Li, Bin Ouyang（欧阳彬）, Deborah A. Quinn. Stretch-Induced IL-8 is Dependent on c-Jun N-Terminal Kinase and Nuclear Factor-B-Inducing Kinase Pathways ATS 2003, C112. 8. Li-Fu Li, Bin Ouyang（欧阳彬）, Behrouz Jafari, Charles A. Hales, Deborah A. Quinn. Stretch Induces IL-8 Promoter Activity and IL-8 mRNA Expression in an In Vitro Model of Ventilator Induced Lung Injury (VILI). FASEB Journal. 2002 Mar: 16(4): 367.4 9. Quinn DA, Jafari B, Li LF, Mascarenhas M, Ouyang B（欧阳彬）, Syrkina O, and Hales CA. Pulmonary Epithelial Cells, Endothelial Cells and Fibroblasts Contribute to Lung Stretch- Induced Cytokine Production Found in Ventilator-Induced Lung Injury (VILI). FASEB Journal. 2003, 85.1 (A88). 10. Mascarenhas MM, Day RM, Ochoa CD, Choi WI, Yu L, Ouyang B（欧阳彬）, Garg HG, Hales CA and Quinn DA. Low molecular weight hyaluronan from stretched lung enhances interleukin-8 expression. Am J Respir Cell Mol Biol. 2004; 30 (1): 51-60.,VILI：我的体会,Ventilator,Rat Mouse Pig Sheep,1. 炎症（Inflammation）,Tidal Volume 3 ml/kg,Tidal Volume 6 ml/kg,Tidal Volume 12 ml/kg,Tidal Volume 12 ml/kg,2003, J. Am Physio. Lung,Tidal Volume 7 ml/kg for 2hrs,Tidal Volume 20 ml/kg for 2hrs,2. 出血（Hemorrhage）,3. 水肿（Edema）,Protein Leakage,Water Leakage,2003, Am J. Respir. CCM,VT 20,VT 7,4. 肺纤维化（Lung Fibrosis）,2003, ATS, Seattle,- VILI MODEL OF RATS,肺纤维化 （Lung Fibrosis）,* p 0.05 vs. Collagen(Static) p 0.05 vs. TGF-b1(Static),*,Static 0.5 hour 1 hour 4 hour,Stretch,Collagen (ug/ml),*,TG F-b1 (pg/ml),Collagen,TGF-b1,120,100,80,60,20,40,120,100,80,60,20,40,Study in Fibroblasts,2004, FASEB Journal,PaO2 (mmHg),PCO2 (mmHg),pHa,7.45 7.40 7.35 7.30 7.25,75,100,Non-MV,2 hour,2nd day,3rd day,4th day,Time of lung tissue harvested (after 2 hour MV),25,50,75,125,*,* p 0.05 vs. VT 7,VT 7,VT 20,*,*,5. 肺功能障碍（Pulmonary Dysfunction）,2002, Appl. J. Physio,6. 全身效应（Systemic Effects）,2003, Am J. Respir. CCM,- Proteinuria,Static cells,Stretched cells,Systemic Effects,2005, MJCLA,- Anti-inflammatory cytokine,TGFb1 and TGFb2 up-regulation found in rat serum of VILI,*,*,#,* p 0.05 vs Vt 7ml/kg # p 0.05 vs Control,TGFB (pg/ml),机械通气导致肺损伤的机制探讨,The Mechanism of Inflammation,Stretcher,Alveolar epithelial cells Bronchial epithelial cells Lung fibroblasts Macrophages,The Mechanism of Inflammation -Studies in lung epithelial cells,Stretch,IL-8,2003, J AM Physio.,The Mechanism of Inflammation -Studies in lung epithelial cells,Stretch,Jun K ,IL-8,2003, J AM Physio.,The Mechanism of Inflammation -Studies in lung epithelial cells,Stretch,Jun K ,IL-8,Plasma,Nuclear,mRNA, Protein,Cell membrane,NIK ,AP-1 ,NF-kB ,2003, J AM Physio.,Wild Type 6 ml/kg,Wild Type 30 ml/kg,Wild Type 30 ml/kg + JNK inhibitor,Wild Type 30 ml/kg + JNK knockout,The Mechanism of Inflammation -Studies in Jun K knockout mice,Ventilation,Jun K ,Neutrophils ,The Mechanism of Inflammation -Matrix,Ventilation,HA,Neutrophils ,2004, Am. J. Respir,The Mechanism of Inflammation -Fibroblasts,Ventilation,LMW HA ,IL-8 ,HAS 3,2004, Am. J. Respir,The Mechanism of Inflammation -Oxidant Injury,Ventilation,GSH ,IL-8 ,Oxidants ,2004, Respirology,压力伤（Barotrauma） Pneumothorax and emphysema, PIP 50 cmH2O 容量伤（Volutrauma）: Dreyfuss, 1988 (rats) , ARDS Network, 2000 剪切伤（Atelectrauma）: Atelectasis 生物伤（Biotrauma）: Cytokines (IL-8, IL-10, IL-6, TNFa, TGFb), Oxidants,Gajic et al. CCM 2