Effects of Ad-FLIP on Expressionof FLIP inRatsLung and Its ProtectiveEffect in Acute Lung Injury_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Wenya ¹ , QU Shuoyao ¹ , OUYANG Haifeng ¹ , HUANG Yun ^1,2 , WU Shuo ¹ , WU Changgui. ¹

Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi′an, Shanxi, 70032, ChinaCorresponding Author: WU Chang-gui, E-mail: changgui@ fmmu. edu. cn;

Corresponding author：

Keywords：

Acute lung injury; Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein; Adenoviruses

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Objective To investigate the expression of FLIP in the lung of rats and the protective effect in development of acute lung injury( ALI) with the adenovirus vector carrying FLIP gene( Ad-FLIP)inhaled. Methods Forty-eight rats were randomly divided into four groups, with 12 rats in each gruop. In treatment group, ALI rats model was eatablished by LPS intraperitoneal injection and then inhaled Ad-FLIP vector. In prevention group, the animals were infected with Ad-FLIP vector before ALI model was
established. Two control groups of treatment and prevention received Ad-EGFP vectors respectively.Pathological changes of lung were observed under light microscope. Wet/dry weight ( W/D) of lung lobes and lung permeability index( LPI) were also measured. The mRNA and protein expressions of FLIP in lung
were investigated by RT-PCR and immunohistochemistry, respectively. Results Lung histopathological changes were alleviated, the index of W/D and LPI were significantly lower, the expressions of FILP mRNA and protein in the lung were elevated both in the treatment group and prevention group compared to the
control groups ( all P lt;0. 01) . Conclusion Ad-FLIP transfection can up-regulate the expression of FLIP in lung of rats, and might protect respiratory membrane and lessen pulmonary edema to prevent the development of ALI.

Citation： WANG Wenya,QU Shuoyao,OUYANG Haifeng,HUANG Yun,WU Shuo,WU Changgui.. Effects of Ad-FLIP on Expressionof FLIP inRatsLung and Its ProtectiveEffect in Acute Lung Injury. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(2): 158-162. doi: Copy

1.	Esper AM, Martin GS. Evolution of treatments for patients with acute lung injury. Expert Opin Investig Drugs, 2005 , 14: 633 -645.
2.	de Souza PM, Lindsay MA. Apoptosis as a therapeutic target for the treatment of lung disease. Curr Opin Pharmacol, 2005 , 5: 232-237 .
3.	Li X, Shu R, Filippatos G, et al. Apoptosis in lung injury and remodeling. J Appl Physiol. 2004, 97: 1535-1542.
4.	Nastiuk KL, Yoo K, Lo K, et al. FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res, 2008, 6 :231 -242.
5.	屈朔瑶, 欧阳海峰, 遆新宇, 等. FLIP 腺病毒表达载体的构建及其在大鼠肺血管内皮细胞中的表达. 第四军医大学报, 2009 ,30: 1746-1748.
6.	薛昀, 吴新民, 张生锁, 等. 内毒素预处理对大鼠急性肺损伤的影响. 中国危重病急救医学, 2004, 16 : 361-363.
7.	Derks CM, Jacoboritz-Derks D. Embolic pneumopathy induced by oleic acid. A systematic morphologic. Am J Pathol, 1977 , 87: 143 -158 .
8.	Ware LB, Kaner RJ, Crystal RG, et al. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J, 2005 , 26 : 101-105.
9.	Newton CJ, Xie YX, Burgoyne CH, et al. Fluvastatin induces apoptosis of vascular endothelial cells: blockade by glucocorticoids.Cardiovasc Surg, 2003, 11: 52-60 .
10.	Maniatis NA, Kotanidou A, Catravas JD, et al. Endothelial pathomechanisms in acute lung injury. Vascul Pharmacol, 2008, 49 :119-133.
11.	Gropper MA, Wiener-Kronish J. The epithelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care,2008, 14: 11 -15 .
12.	Kuwano K. Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol, 2007, 4 : 419-429 .
13.	Macredmond R, Singhera GK, Dorscheid DR. Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injurg. Eur Respir J, 2009, 33: 1403-1414.
14.	Srinivasula SM, Ahmad M, Ottilie S, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/ TNFR1 -induced apoptosis. J Biol Chem, 1997, 272: 18542-18545.
15.	Boatright KM, Deis C, Denault JB, et al. Activation of caspases-8 and-10 by FLIP ( L) . BiochemJ, 2004, 382: 651 -657.
16.	Erwert RD, Winn RK, Harlan JM, et al. Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis. J BiolChem, 2002, 277: 40567 -40574.
17.	Cudrici C, Niculescu F, Jensen T, et al. C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. J Immunol, 2006 ,176: 3173-3180.

1. Esper AM, Martin GS. Evolution of treatments for patients with acute lung injury. Expert Opin Investig Drugs, 2005 , 14: 633 -645.
2. de Souza PM, Lindsay MA. Apoptosis as a therapeutic target for the treatment of lung disease. Curr Opin Pharmacol, 2005 , 5: 232-237 .
3. Li X, Shu R, Filippatos G, et al. Apoptosis in lung injury and remodeling. J Appl Physiol. 2004, 97: 1535-1542.
4. Nastiuk KL, Yoo K, Lo K, et al. FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res, 2008, 6 :231 -242.
5. 屈朔瑶, 欧阳海峰, 遆新宇, 等. FLIP 腺病毒表达载体的构建及其在大鼠肺血管内皮细胞中的表达. 第四军医大学报, 2009 ,30: 1746-1748.
6. 薛昀, 吴新民, 张生锁, 等. 内毒素预处理对大鼠急性肺损伤的影响. 中国危重病急救医学, 2004, 16 : 361-363.
7. Derks CM, Jacoboritz-Derks D. Embolic pneumopathy induced by oleic acid. A systematic morphologic. Am J Pathol, 1977 , 87: 143 -158 .
8. Ware LB, Kaner RJ, Crystal RG, et al. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J, 2005 , 26 : 101-105.
9. Newton CJ, Xie YX, Burgoyne CH, et al. Fluvastatin induces apoptosis of vascular endothelial cells: blockade by glucocorticoids.Cardiovasc Surg, 2003, 11: 52-60 .
10. Maniatis NA, Kotanidou A, Catravas JD, et al. Endothelial pathomechanisms in acute lung injury. Vascul Pharmacol, 2008, 49 :119-133.
11. Gropper MA, Wiener-Kronish J. The epithelium in acute lung injury/acute respiratory distress syndrome. Curr Opin Crit Care,2008, 14: 11 -15 .
12. Kuwano K. Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol, 2007, 4 : 419-429 .
13. Macredmond R, Singhera GK, Dorscheid DR. Erythropoietin inhibits respiratory epithelial cell apoptosis in a model of acute lung injurg. Eur Respir J, 2009, 33: 1403-1414.
14. Srinivasula SM, Ahmad M, Ottilie S, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/ TNFR1 -induced apoptosis. J Biol Chem, 1997, 272: 18542-18545.
15. Boatright KM, Deis C, Denault JB, et al. Activation of caspases-8 and-10 by FLIP ( L) . BiochemJ, 2004, 382: 651 -657.
16. Erwert RD, Winn RK, Harlan JM, et al. Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis. J BiolChem, 2002, 277: 40567 -40574.
17. Cudrici C, Niculescu F, Jensen T, et al. C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. J Immunol, 2006 ,176: 3173-3180.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of Ad-FLIP on Expressionof FLIP inRatsLung and Its ProtectiveEffect in Acute Lung Injury

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