阿奇霉素对油酸致大鼠急性肺损伤的干预作用
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摘要
目的应用油酸(oleic acid, OA)静脉注射复制大鼠急性肺损伤(acute lung injury, ALI)模型,探讨肿瘤坏死因子-α(TNF-α)、γ-干扰素(IFN-γ)、白细胞介素-4(IL-4)在油酸性肺损伤中的变化规律;探讨阿奇霉素对OA致ALI大鼠的治疗作用及可能的作用机制,为临床治疗ALI提供一定的理论和实验依据。
方法应用OA静脉注射复制大鼠ALI模型。将90只SD大鼠随机分为3组:生理盐水对照组(NC组),油酸致急性肺损伤组(OA组),阿奇霉素治疗组(AZI组)。每组分别在1天、3天、7天抽取动脉血并放血迅速处死。测定动脉血氧分压(PaO2)、动脉血二氧化碳分压(PaCO2)、pH值及血浆IL-4含量,左上肺测湿/干重比(wet / dry weight,W/D值),下段行病理检查。右肺灌洗,测支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中总蛋白(total proteins,TP)、TNF–α、IFN-γ、IL-4含量,并对BALF中炎症细胞进行分类计数。
结果与NC组比较,OA组各时间点W/D值、BALF中的TNF–α、TP及炎症细胞计数显著升高(P <0.01), IFN-γ/IL-4比值、PaO2降低(P <0.01),肺组织病理见充血、水肿、出血、炎性细胞浸润等急性肺损伤表现;AZI组与OA组相比,病理学观察肺组织病变减轻, IFN-γ/IL-4比值、PaO2升高(P <0.05),W/D、TNF-α降低(P <0.05);OA组和AZI组各时间点血浆中IL-4浓度与BALF中IL-4浓度呈正相关(rOA1= 0.857;rOA3=0.841;rOA7= 0.774; r AZI1=0.797;r AZI3=0.830 ;rAZI7=0.829 ,各组P <0.01)。
结论(1)ALI病程中存在Th1/ Th2细胞因子失衡,IFN-γ分泌减少,IL-4分泌增加;(2)ALI时,测定血浆中IL-4浓度可以间接反映BALF中IL-4水平;(3)阿奇霉素可以减轻肺微血管渗漏,改善大鼠肺换气功能,降低BALF中TNF-α水平,升高IFN-γ/IL-4比值、恢复Th1优势,部分纠正OA致大鼠肺损伤中Th1/ Th2细胞因子失衡。证实阿奇霉素对ALI有一定的治疗作用。
Objective The purpose of this study was to reproduce the model of acute lung injury (ALI) in rats by injecting oleic acid (OA) into the vein, and investigate the alterations of tumour necrosis factor-α(TNF-α),interferon Gamma (IFN-γ), interleukin-4 (IL-4) after ALI induced by OA, and investigate the possible mechanisms of protective effects of azithromycin in OA induced ALI in rats.
Methods OA was used to reproduce the model of ALI in rats. 90 adult Sprague-Dawley rats were randomly divided into three groups: normal control group treated by saline injection (NC group),ALI group induced by oleic acid injection (OA group),therapy group treated by oral azithromycin (AZI group).Arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), power of hydrogen (pH) and plasma interleukin-4 level were assayed after the animals were exsanguinated and sacrificed at 1, 3 and 7 days later. The left lung was used to calculate wet / dry weight ratio(W/D)、histopathology, whereas the right lung was lavaged and determined the total proteins(TP)、TNF-α、IFN-γand IL-4 concentration in the bronchoalveolar lavage fluid(BALF), total cell counts and differential analysis in BALF were performed.
Results In the OA group, W/D、TNF-α、TP and inflammatory cell counts in the BALF were significantly increased (P <0.01), whereas the ratio of IFN-γ/ IL-4、arterial oxygen tension (PaO2) were significantly decreased(P<0.01) as compared with NC group. Obvious pathological manifestations such as hyperemia、edema、hemorrhage、neutrophil infiltration were shown . In the AZI group, the change of lung pathology was significantly relieved, the ratio of IFN-γ/ IL-4、PaO2 were increased(P <0.05), W/D、TNF-αwere significantly decreased (P <0.05)as compared with OA group. The IL-4 concentrations in the BALF were positively correlated to those in the plasma in the OA and AZI group at the same time point (rOA1= 0.857;rOA3=0.841;
方法应用OA静脉注射复制大鼠ALI模型。将90只SD大鼠随机分为3组:生理盐水对照组(NC组),油酸致急性肺损伤组(OA组),阿奇霉素治疗组(AZI组)。每组分别在1天、3天、7天抽取动脉血并放血迅速处死。测定动脉血氧分压(PaO2)、动脉血二氧化碳分压(PaCO2)、pH值及血浆IL-4含量,左上肺测湿/干重比(wet / dry weight,W/D值),下段行病理检查。右肺灌洗,测支气管肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中总蛋白(total proteins,TP)、TNF–α、IFN-γ、IL-4含量,并对BALF中炎症细胞进行分类计数。
结果与NC组比较,OA组各时间点W/D值、BALF中的TNF–α、TP及炎症细胞计数显著升高(P <0.01), IFN-γ/IL-4比值、PaO2降低(P <0.01),肺组织病理见充血、水肿、出血、炎性细胞浸润等急性肺损伤表现;AZI组与OA组相比,病理学观察肺组织病变减轻, IFN-γ/IL-4比值、PaO2升高(P <0.05),W/D、TNF-α降低(P <0.05);OA组和AZI组各时间点血浆中IL-4浓度与BALF中IL-4浓度呈正相关(rOA1= 0.857;rOA3=0.841;rOA7= 0.774; r AZI1=0.797;r AZI3=0.830 ;rAZI7=0.829 ,各组P <0.01)。
结论(1)ALI病程中存在Th1/ Th2细胞因子失衡,IFN-γ分泌减少,IL-4分泌增加;(2)ALI时,测定血浆中IL-4浓度可以间接反映BALF中IL-4水平;(3)阿奇霉素可以减轻肺微血管渗漏,改善大鼠肺换气功能,降低BALF中TNF-α水平,升高IFN-γ/IL-4比值、恢复Th1优势,部分纠正OA致大鼠肺损伤中Th1/ Th2细胞因子失衡。证实阿奇霉素对ALI有一定的治疗作用。
Objective The purpose of this study was to reproduce the model of acute lung injury (ALI) in rats by injecting oleic acid (OA) into the vein, and investigate the alterations of tumour necrosis factor-α(TNF-α),interferon Gamma (IFN-γ), interleukin-4 (IL-4) after ALI induced by OA, and investigate the possible mechanisms of protective effects of azithromycin in OA induced ALI in rats.
Methods OA was used to reproduce the model of ALI in rats. 90 adult Sprague-Dawley rats were randomly divided into three groups: normal control group treated by saline injection (NC group),ALI group induced by oleic acid injection (OA group),therapy group treated by oral azithromycin (AZI group).Arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), power of hydrogen (pH) and plasma interleukin-4 level were assayed after the animals were exsanguinated and sacrificed at 1, 3 and 7 days later. The left lung was used to calculate wet / dry weight ratio(W/D)、histopathology, whereas the right lung was lavaged and determined the total proteins(TP)、TNF-α、IFN-γand IL-4 concentration in the bronchoalveolar lavage fluid(BALF), total cell counts and differential analysis in BALF were performed.
Results In the OA group, W/D、TNF-α、TP and inflammatory cell counts in the BALF were significantly increased (P <0.01), whereas the ratio of IFN-γ/ IL-4、arterial oxygen tension (PaO2) were significantly decreased(P<0.01) as compared with NC group. Obvious pathological manifestations such as hyperemia、edema、hemorrhage、neutrophil infiltration were shown . In the AZI group, the change of lung pathology was significantly relieved, the ratio of IFN-γ/ IL-4、PaO2 were increased(P <0.05), W/D、TNF-αwere significantly decreased (P <0.05)as compared with OA group. The IL-4 concentrations in the BALF were positively correlated to those in the plasma in the OA and AZI group at the same time point (rOA1= 0.857;rOA3=0.841;
引文
1. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med, 2005 ,353(16):1685-1693.
2. 叶任高主编.内科学.第 6 版.北京:人民卫生出版社,2004:144.
3. Tamaoki J, Tagaya E, Yamawaki I, et al. Effect of erythromycin on endotoxin-induced microvascular leakage in the rat trachea and lungs. Am J Respir Crit Care Med,1995,151(5):1582-1588.
4. Azuma A, Furuta T, Enomoto T, et al. Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats. Thorax, 1998,53(1):186-189.
5. 曹慧玲 ,李艳,尹立波. 乳酸红霉素对油酸致大鼠急性肺损伤后肺纤维化的防护作用.中国现代医学杂志,2004,14(13):30-33.
6. Azuma A, Li Y, Usuki J, et al. Fourteen-Membered Ring Macrolides Inhibit Vascular Cell Adhesion Molecule-1 Messenger RNA Induction Preventing Neutrophil-Induced Lung Injury and Fibrosis in Bleomycin-Challenged Mice. Chest, 2001,120(1S): 20-22.
7. Yamasawa H, Oshikawa K, Ohno S, et al. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release. Am J Respir Cell Mol Biol, 2004,30(4): 569-575.
8. Koch CC, Esteban DJ, Chin AC, et al. Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae. Antimicrob Chemother, 2000, 46(1): 19-26.
9. 叶应妩,莫掊生,脑脊液检查,化学检查.新编临床检验法(下).第一版,山东:山东省出版社泰安分社.1986:413-414。
10. Abraham E. Neutrophils and acute lung injury. Crit Care Med ,2003,31(4 Suppl): S195–S199.
11. Beeh KM, Kornmann O, Buhl R, et al. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest, 2003,123(4):1240-1247.
12. McGuirk P, Mills KH. A regulatory role for interleukin 4 in differential inflammatory responses in the lung following infection of mice primed with Th1- or Th2-inducing pertussis vaccines. Infect Immun, 2000,68(3): 1383- 1390.
13. Kurdowska A, Noble JM, Steinberg KP, et al. Anti-IL-8 Autoantibodies in Alveolar Fluid From Patients at Risk for ARDS and With Well-defined ARDS. Chest, 1999,116(1 Suppl):9S.
14. Chow CW, Herrera Abreu MT, Suzuki T, et al. Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol, 2003, 29(4):427-431.
15. Ossovskaya VS, Bunnett NW. Protease-Activated Receptors: Contribution to Physiology and Disease. Physiol Rev, 2004, 84(2):579-621.
16. Schochett P, Mora R, Mark L, et al. Calcium-dependent degradation of surfactant protein A by activated neutrophils due to serine proteases. Exp Lung Res, 1999, 25(7):595-616.
17. Ding X, Murray PA. Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins. Am J Physiol Lung Cell Mol Physiol, 2005 ,289(5):L825-L833.
18. Watanabe J, Marathe GK, Neilsen PO, et al. Endotoxins stimulate neutrophil adhesion followed by synthesis and release of platelet-activating factor in microparticles. J Biol Chem, 2003, 278(35):33161-33168.
19. Hussain N, Wu F, Zhu L, et al. Neutrophil Apoptosis during the Development and Resolution of Oleic Acid-Induced Acute Lung Injury in the Rat. Am. J. Respir. Cell Mol. Biol, 1998 ,19(6):867-874
20. Niwa M, Hara A, Kanamori Y, et al. Nuclear factor-kappaB activates dual inhibition sites in the regulation of tumor necrosis factor-alpha-induced neutrophil apoptosis. Eur J Pharmacol, 2000 ,407(3):211-219.
21. Matute-Bello G, Liles WC, Radella F et al. Modulation of neutrophil apoptosisby granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med, 2000 ,28(1):1-7.
22. Aggarwal A, Baker CS, Evans TW, et al. G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J, 2000,15(5):895-901.
23. Inoue S, Nakao A, Kishimoto W, et al. Anti-neutrophil antibody attenuates the severity of acute lung injury in rats with experimental acute pancreatitis. Arch Surg, 1995,130(1):93-98.
24. Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther, 2004, 17(5):271-279.
25. Strieter RM, Kunkel SL, Keane MP, et al. Chemokines in lung injury: Thomas A. Neff Lecture. Chest, 1999 ,116(1 Suppl):103S-110S.
26. Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol, 2000 ,279(6):L1137-Ll145.
27. Braun C, Hamacher J, Morel DR, et al. Dichotomal role of TNF in experimental pulmonary edema reabsorption. J Immunol,2005,175(5):3402 -3408.
28. Hamacher J, Lucas R, Lijnen HR, et al. Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 2002 ,166(5):651-656.
29. Harrod KS, Jaramillo RJ. Pseudomonas aeruginosa and tumor necrosis factor-alpha attenuate Clara cell secretory protein promoter function. Am J Respir Cell Mol Biol, 2002 ,26(2):216-223.
30. Vayrynen O, Glumoff V, Hallman M. Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. Am J Physiol Lung Cell Mol Physiol , 2002 ,282(4):L803- L810.
31. Parsons PE, Matthay MA, Ware LB, et al. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury。Am J Physiol Lung Cell Mol Physiol ,2005,288(3): L426-L431.
32. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol, 2005 ,288(1):L3- L 15.
33. Park WY, Goodman RB, Steinberg KP, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 2001 ,164(10 Pt 1):1896-1903.
34. Matthys P, Vermeire K, Heremans H, et al. The protective effect of IFN-gamma in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis. J Leukoc Biol, 2000, 68 (4): 447-454.
35. Higashi K, Inagaki Y, Fujimori K, et al. Interferon-γInterferes with Transforming Growth Factor-? Signaling through Direct Interaction of YB-1 with Smad3. J Biol Chem, 2003, 278(44):43470-43479.
36. 邱慧,张德平.干扰素-r 治疗特发性肺纤维化的研究进展.国外医学呼吸系统分册,2005,25(5):376-379.
37. Kips JC, Tournoy KG, Pauwels RA . New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J, 2001,17(3):499-506.
38. Cavarra E, Carraro F, Fineschi S, et al. Early response to bleomycin is characterized by different cytokine and cytokine receptor profiles in lungs. Am J Physiol Lung Cell Mol Physiol, 2004 ,287(6):L1186- L1192.
39. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother, 2004, 54(1):21-28.
40. Wales D, Woodhead M. The anti-inflammatory effects of macrolides. Thorax, 1999, 54(Suppl 2):S58- S 62.
41. Schultz MJ, Speelman P, van der Poll T. Erythromycin inhibits Pseudomonas aeruginosa-induced tumour necrosis factor- production in human wholeblood. J Antimicrob Chemother, 2001 ,48(2):275-278.
42. Abe S, Nakamura H, Inoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2000,22(1):51-60.
43. Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin Inhibits NF- B Activation in Human Peripheral Blood Mononuclear Cells and Pulmonary Epithelial Cells. Antimicrob Agents Chemother, 2001,45(1):44-47.
44. Hiratsuka T, Mukae H, Iiboshi H, et al. Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax ,2003 ,58(5):425-430.
1. De Bosscher K, Vanden Berghe W, Haegeman G . The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev, 2003, 24(4): 488 - 522.
2. Hao H, Wendt CH, Sandhu G, et al. Dexamethasone stimulates transcription of the Na+-K+-ATPase {beta}1 gene in adult rat lung epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2003, 285(3): L593 - L601.
3. Wang G, Guo X, Floros J. Human SP-A 3'-UTR variants mediate differential gene expression in basal levels and in response to dexamethasone. Am J Physiol Lung Cell Mol Physiol, 2003, 284(5): L738 - L748.
4. Dik WA, McAnulty RJ, Versnel MA, et al. Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats. Thorax, 2003, 58(9): 765 - 771.
5. 林兆奋,景炳文,杨兴易等.气道内应用地塞米松对急性肺损伤及急性呼吸窘迫综合征的防治作用. 中华急诊医学杂志,2004,13(5): 306-309.
6. Thompson BT. Glucocorticoids and acute lung injury. Crit Care Med, 2003,31(4 Suppl):S253-S257.
7. Anzueto A . Exogenous surfactant in acute respiratory distress syndrome: more is better. Eur Respir J, 2002,19(5):787-789.
8. Bailey TC, Da Silva KA, Lewis JF, et al. Physiological and inflammatory response to instillation of an oxidized surfactant in a rat model of surfactant deficiency. J Appl Physiol, 2004,96(5): 1674 - 1680.
9. Walmrath D, Grimminger F, Pappert D,et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics. Eur Respir J, 2002, 19(5):805-810
10. Haitsma JJ, Lachmann U, Lachmann B. Exogenous surfactant as a drug delivery agent. Adv Drug Deliv Rev, 2001,47(2-3):197-207.
11. Rialp G, Betbese AJ, Perez-Marquez M ,et al. Short-term effects of inhaled nitricoxide and prone position in pulmonary and extrapulmonary acute respiratory distress syndrome. Am J Respir Crit Care Med, 2001, 164(2):243 - 249.
12. 朱友荣,龚小慧,吕勇等.肺表面活性物质和吸入一氧化氮治疗感染性急性肺损伤. 中华急诊医学杂志,2004,13(10):673-675.
13. Sood BG, Delaney-Black V, Aranda JV, et al. Aerosolized PGE1: a selective pulmonary vasodilator in neonatal hypoxemic respiratory failure results of a Phase I/II open label clinical trial. Pediatr Res, 2004, 56(4):579 - 585.
14. Wajima Zi, Shiga T, Yoshikawa T, et al. Intravenous alprostadil, an analog of prostaglandin E1, prevents thiamylal-fentanyl-induced bronchoconstriction in humans. Anesth Analg, 2003, 97(2):456 - 460.
15. Putensen C, Hormann C, Kleinsasser A, et al. Cardiopulmonary effects of aerosolized prostaglandin E1 and nitric oxide inhalation in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 1998, 157(6 Pt 1):1743 – 1747.
16. Ito K, Mizutani A, Kira S, et al. Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes. Injury, 2005,36(3):387-394.
17. Wang XL, Zhang H, Liu R, et al. Protective effect of a protease inhibitor on acute lung injury after hepatic ischemia/reperfusion in the rat .Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2003, 15(7):432-434.
18. Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther, 2004, 17(5):271-279.
19. Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med, 2004, 32(8):1695-702.
20. Kerbaul F, Van der Linden P, Pierre S, et al. Prevention of hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction by N-acetylcysteine in dogs. Anesth. Analg, 2004, 99(2):547 - 551.
21. Rhoden CR, Lawrence J, Godleski JJ, et al. N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambientparticles. Toxicol Sci, 2004,79(2):296-303.
22. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest,1997,112(1):164-172.
23. Ottonello L, Arduino N, Bertolotto M, et al. In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism. Br J Pharmacol, 2003, 140(4):736-742.
24. Yang B, Yao DF, Ohuchi M, et al. Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels . Eur Respir J, 2002, 19(5):952-958.
25. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001, 344 (10): 699 –709.
26. van der Poll T, Levi M, Nick JA, et al. Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med, 2005, 171(10):1125 - 1128.
2. 叶任高主编.内科学.第 6 版.北京:人民卫生出版社,2004:144.
3. Tamaoki J, Tagaya E, Yamawaki I, et al. Effect of erythromycin on endotoxin-induced microvascular leakage in the rat trachea and lungs. Am J Respir Crit Care Med,1995,151(5):1582-1588.
4. Azuma A, Furuta T, Enomoto T, et al. Preventive effect of erythromycin on experimental bleomycin-induced acute lung injury in rats. Thorax, 1998,53(1):186-189.
5. 曹慧玲 ,李艳,尹立波. 乳酸红霉素对油酸致大鼠急性肺损伤后肺纤维化的防护作用.中国现代医学杂志,2004,14(13):30-33.
6. Azuma A, Li Y, Usuki J, et al. Fourteen-Membered Ring Macrolides Inhibit Vascular Cell Adhesion Molecule-1 Messenger RNA Induction Preventing Neutrophil-Induced Lung Injury and Fibrosis in Bleomycin-Challenged Mice. Chest, 2001,120(1S): 20-22.
7. Yamasawa H, Oshikawa K, Ohno S, et al. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release. Am J Respir Cell Mol Biol, 2004,30(4): 569-575.
8. Koch CC, Esteban DJ, Chin AC, et al. Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae. Antimicrob Chemother, 2000, 46(1): 19-26.
9. 叶应妩,莫掊生,脑脊液检查,化学检查.新编临床检验法(下).第一版,山东:山东省出版社泰安分社.1986:413-414。
10. Abraham E. Neutrophils and acute lung injury. Crit Care Med ,2003,31(4 Suppl): S195–S199.
11. Beeh KM, Kornmann O, Buhl R, et al. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest, 2003,123(4):1240-1247.
12. McGuirk P, Mills KH. A regulatory role for interleukin 4 in differential inflammatory responses in the lung following infection of mice primed with Th1- or Th2-inducing pertussis vaccines. Infect Immun, 2000,68(3): 1383- 1390.
13. Kurdowska A, Noble JM, Steinberg KP, et al. Anti-IL-8 Autoantibodies in Alveolar Fluid From Patients at Risk for ARDS and With Well-defined ARDS. Chest, 1999,116(1 Suppl):9S.
14. Chow CW, Herrera Abreu MT, Suzuki T, et al. Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol, 2003, 29(4):427-431.
15. Ossovskaya VS, Bunnett NW. Protease-Activated Receptors: Contribution to Physiology and Disease. Physiol Rev, 2004, 84(2):579-621.
16. Schochett P, Mora R, Mark L, et al. Calcium-dependent degradation of surfactant protein A by activated neutrophils due to serine proteases. Exp Lung Res, 1999, 25(7):595-616.
17. Ding X, Murray PA. Cellular mechanisms of thromboxane A2-mediated contraction in pulmonary veins. Am J Physiol Lung Cell Mol Physiol, 2005 ,289(5):L825-L833.
18. Watanabe J, Marathe GK, Neilsen PO, et al. Endotoxins stimulate neutrophil adhesion followed by synthesis and release of platelet-activating factor in microparticles. J Biol Chem, 2003, 278(35):33161-33168.
19. Hussain N, Wu F, Zhu L, et al. Neutrophil Apoptosis during the Development and Resolution of Oleic Acid-Induced Acute Lung Injury in the Rat. Am. J. Respir. Cell Mol. Biol, 1998 ,19(6):867-874
20. Niwa M, Hara A, Kanamori Y, et al. Nuclear factor-kappaB activates dual inhibition sites in the regulation of tumor necrosis factor-alpha-induced neutrophil apoptosis. Eur J Pharmacol, 2000 ,407(3):211-219.
21. Matute-Bello G, Liles WC, Radella F et al. Modulation of neutrophil apoptosisby granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med, 2000 ,28(1):1-7.
22. Aggarwal A, Baker CS, Evans TW, et al. G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J, 2000,15(5):895-901.
23. Inoue S, Nakao A, Kishimoto W, et al. Anti-neutrophil antibody attenuates the severity of acute lung injury in rats with experimental acute pancreatitis. Arch Surg, 1995,130(1):93-98.
24. Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther, 2004, 17(5):271-279.
25. Strieter RM, Kunkel SL, Keane MP, et al. Chemokines in lung injury: Thomas A. Neff Lecture. Chest, 1999 ,116(1 Suppl):103S-110S.
26. Abraham E, Carmody A, Shenkar R, et al. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol, 2000 ,279(6):L1137-Ll145.
27. Braun C, Hamacher J, Morel DR, et al. Dichotomal role of TNF in experimental pulmonary edema reabsorption. J Immunol,2005,175(5):3402 -3408.
28. Hamacher J, Lucas R, Lijnen HR, et al. Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 2002 ,166(5):651-656.
29. Harrod KS, Jaramillo RJ. Pseudomonas aeruginosa and tumor necrosis factor-alpha attenuate Clara cell secretory protein promoter function. Am J Respir Cell Mol Biol, 2002 ,26(2):216-223.
30. Vayrynen O, Glumoff V, Hallman M. Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. Am J Physiol Lung Cell Mol Physiol , 2002 ,282(4):L803- L810.
31. Parsons PE, Matthay MA, Ware LB, et al. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury。Am J Physiol Lung Cell Mol Physiol ,2005,288(3): L426-L431.
32. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol, 2005 ,288(1):L3- L 15.
33. Park WY, Goodman RB, Steinberg KP, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 2001 ,164(10 Pt 1):1896-1903.
34. Matthys P, Vermeire K, Heremans H, et al. The protective effect of IFN-gamma in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis. J Leukoc Biol, 2000, 68 (4): 447-454.
35. Higashi K, Inagaki Y, Fujimori K, et al. Interferon-γInterferes with Transforming Growth Factor-? Signaling through Direct Interaction of YB-1 with Smad3. J Biol Chem, 2003, 278(44):43470-43479.
36. 邱慧,张德平.干扰素-r 治疗特发性肺纤维化的研究进展.国外医学呼吸系统分册,2005,25(5):376-379.
37. Kips JC, Tournoy KG, Pauwels RA . New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J, 2001,17(3):499-506.
38. Cavarra E, Carraro F, Fineschi S, et al. Early response to bleomycin is characterized by different cytokine and cytokine receptor profiles in lungs. Am J Physiol Lung Cell Mol Physiol, 2004 ,287(6):L1186- L1192.
39. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother, 2004, 54(1):21-28.
40. Wales D, Woodhead M. The anti-inflammatory effects of macrolides. Thorax, 1999, 54(Suppl 2):S58- S 62.
41. Schultz MJ, Speelman P, van der Poll T. Erythromycin inhibits Pseudomonas aeruginosa-induced tumour necrosis factor- production in human wholeblood. J Antimicrob Chemother, 2001 ,48(2):275-278.
42. Abe S, Nakamura H, Inoue S, et al. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol, 2000,22(1):51-60.
43. Ichiyama T, Nishikawa M, Yoshitomi T, et al. Clarithromycin Inhibits NF- B Activation in Human Peripheral Blood Mononuclear Cells and Pulmonary Epithelial Cells. Antimicrob Agents Chemother, 2001,45(1):44-47.
44. Hiratsuka T, Mukae H, Iiboshi H, et al. Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax ,2003 ,58(5):425-430.
1. De Bosscher K, Vanden Berghe W, Haegeman G . The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev, 2003, 24(4): 488 - 522.
2. Hao H, Wendt CH, Sandhu G, et al. Dexamethasone stimulates transcription of the Na+-K+-ATPase {beta}1 gene in adult rat lung epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2003, 285(3): L593 - L601.
3. Wang G, Guo X, Floros J. Human SP-A 3'-UTR variants mediate differential gene expression in basal levels and in response to dexamethasone. Am J Physiol Lung Cell Mol Physiol, 2003, 284(5): L738 - L748.
4. Dik WA, McAnulty RJ, Versnel MA, et al. Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats. Thorax, 2003, 58(9): 765 - 771.
5. 林兆奋,景炳文,杨兴易等.气道内应用地塞米松对急性肺损伤及急性呼吸窘迫综合征的防治作用. 中华急诊医学杂志,2004,13(5): 306-309.
6. Thompson BT. Glucocorticoids and acute lung injury. Crit Care Med, 2003,31(4 Suppl):S253-S257.
7. Anzueto A . Exogenous surfactant in acute respiratory distress syndrome: more is better. Eur Respir J, 2002,19(5):787-789.
8. Bailey TC, Da Silva KA, Lewis JF, et al. Physiological and inflammatory response to instillation of an oxidized surfactant in a rat model of surfactant deficiency. J Appl Physiol, 2004,96(5): 1674 - 1680.
9. Walmrath D, Grimminger F, Pappert D,et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics. Eur Respir J, 2002, 19(5):805-810
10. Haitsma JJ, Lachmann U, Lachmann B. Exogenous surfactant as a drug delivery agent. Adv Drug Deliv Rev, 2001,47(2-3):197-207.
11. Rialp G, Betbese AJ, Perez-Marquez M ,et al. Short-term effects of inhaled nitricoxide and prone position in pulmonary and extrapulmonary acute respiratory distress syndrome. Am J Respir Crit Care Med, 2001, 164(2):243 - 249.
12. 朱友荣,龚小慧,吕勇等.肺表面活性物质和吸入一氧化氮治疗感染性急性肺损伤. 中华急诊医学杂志,2004,13(10):673-675.
13. Sood BG, Delaney-Black V, Aranda JV, et al. Aerosolized PGE1: a selective pulmonary vasodilator in neonatal hypoxemic respiratory failure results of a Phase I/II open label clinical trial. Pediatr Res, 2004, 56(4):579 - 585.
14. Wajima Zi, Shiga T, Yoshikawa T, et al. Intravenous alprostadil, an analog of prostaglandin E1, prevents thiamylal-fentanyl-induced bronchoconstriction in humans. Anesth Analg, 2003, 97(2):456 - 460.
15. Putensen C, Hormann C, Kleinsasser A, et al. Cardiopulmonary effects of aerosolized prostaglandin E1 and nitric oxide inhalation in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med, 1998, 157(6 Pt 1):1743 – 1747.
16. Ito K, Mizutani A, Kira S, et al. Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes. Injury, 2005,36(3):387-394.
17. Wang XL, Zhang H, Liu R, et al. Protective effect of a protease inhibitor on acute lung injury after hepatic ischemia/reperfusion in the rat .Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2003, 15(7):432-434.
18. Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther, 2004, 17(5):271-279.
19. Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med, 2004, 32(8):1695-702.
20. Kerbaul F, Van der Linden P, Pierre S, et al. Prevention of hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction by N-acetylcysteine in dogs. Anesth. Analg, 2004, 99(2):547 - 551.
21. Rhoden CR, Lawrence J, Godleski JJ, et al. N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambientparticles. Toxicol Sci, 2004,79(2):296-303.
22. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest,1997,112(1):164-172.
23. Ottonello L, Arduino N, Bertolotto M, et al. In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism. Br J Pharmacol, 2003, 140(4):736-742.
24. Yang B, Yao DF, Ohuchi M, et al. Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels . Eur Respir J, 2002, 19(5):952-958.
25. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001, 344 (10): 699 –709.
26. van der Poll T, Levi M, Nick JA, et al. Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med, 2005, 171(10):1125 - 1128.