呼吸器是一重要的維生工具，然而較長的通氣時間與較高的通氣容積卻會引發肺部的二度傷害，增加感染的機率而造成患者的死亡率上升。介白素-6（IL-6）為一多效性的細胞激素，可調控發炎與抗發炎反應，其在呼吸器所引發之肺部損傷的角色仍有爭議。因此，為了探討呼吸器引發肺部損傷的機轉，以及，將WT、IL6-/-、IL6-/- → WT嵌合小鼠以及IKK△mye小鼠以呼吸器連接六小時後進行分析。此外，藉由給予IL-6抗體進一步了解IL-6在呼吸器所引發肺部損傷中所扮演的角色。實驗結果顯示，呼吸器的通氣刺激會造成肺部微血管通透性及組織嗜中性白血球浸潤程度的增加，而肺部組織與支氣管肺泡沖提液中也有較多的發炎性細胞激素生成。然而給予IL-6抗體的小鼠、IL6-/-、IL6-/- → WT嵌合小鼠以及IKK△mye小鼠皆可減緩肺部發炎以及損傷的情形，因此，介白素-6-核因子-κB訊息傳遞路徑促進的發炎反應與呼吸器引發之肺部損傷有關。此外，呼吸器的通氣刺激會損害肺泡巨噬細胞的抗菌能力，因而增加發展成呼吸器相關肺炎的危險性。

Although mechanical ventilator is a life-saving intervention, longer ventilation time and excessive tidal volume contribute to lung injury and increased incidence of infection which is associated with higher mortality. IL-6, a pleiotropic cytokine, participates in both pro- and anti-inflammatory responses. Till now, opinions of the role of IL-6 are widely divided. To study the pathogenesis mechanism of ventilator-induced lung injury (VILI), C57BL/6 mice (WT), IL-6 knockout mice (IL6-/-), chimera (IL6-/- → WT) and deletion of IκB kinase in the myeloid (IKK△mye) mice were placed on ventilator for 6 hr. WT mice were also given the IL-6-blocking antibody just before ventilation to evaluate the role of IL-6 signaling in VILI. The results revealed that the pulmonary capillary permeability, neutrophil sequestration, macrophage drifting and protein concentration in bronchoalveolar lavage fluid, and the proinflammatory cytokine levels were significantly increased in ventilated WT mice but not in those pretreated with IL-6-blocking antibody as well as IL6-/-, IKK△mye, and IL6-/- → WT chimera mice, suggesting that NF-κB–IL-6 signaling could induce inflammation which contributes to the VILI. Furthermore, the antibacterial ability of alveolar macrophages was impaired by ventilation that subsequently increased the danger of developing to ventilator-associated pneumonia.

Acknowledgement……………………………....…….i
Abstract in Chinese……………………......................ii
Abstract in English…………………...........................iii
Introduction………………............................................1
Materials and Methods…………………………........6
Results…………………………………………....….16
Discussion………………………..............................22
Figures…………………………….............................28
Tables……………………………………………......45
References…………………………….....................47

1. Budweiser S, Jorres RA, Pfeifer M. 2008. Treatment of respiratory failure in COPD. Int J Chron Obstruct Pulmon Dis 3: 605-18
2. Dhanireddy S, Altemeier WA, Matute-Bello G, O'Mahony DS, Glenny RW, Martin TR, Liles WC. 2006. Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia. Lab Invest 86: 790-9
3. Damarla M, Hasan E, Boueiz A, Le A, Pae HH, Montouchet C, Kolb T, Simms T, Myers A, Kayyali US, Gaestel M, Peng X, Reddy SP, Damico R, Hassoun PM. 2009. Mitogen activated protein kinase activated protein kinase 2 regulates actin polymerization and vascular leak in ventilator associated lung injury. PLoS One 4: e4600
4. Frank JA, Pittet JF, Wray C, Matthay MA. 2008. Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade. Thorax 63: 147-53
5. Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C. 1999. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med 159: 1249-56
6. Cannizzaro V, Hantos Z, Sly PD, Zosky GR. 2011. Linking lung function and inflammatory responses in ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300: L112-20
7. Halbertsma FJ, Vaneker M, Scheffer GJ, van der Hoeven JG. 2005. Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature. Neth J Med 63: 382-92
8. Dolinay T, Wu W, Kaminski N, Ifedigbo E, Kaynar AM, Szilasi M, Watkins SC, Ryter SW, Hoetzel A, Choi AM. 2008. Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury. PLoS One 3: e1601
9. Wolters PJ, Wray C, Sutherland RE, Kim SS, Koff J, Mao Y, Frank JA. 2009. Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury. J Immunol 182: 8056-62
10. Wilson MR, O'Dea KP, Zhang D, Shearman AD, van Rooijen N, Takata M. 2009. Role of lung-marginated monocytes in an in vivo mouse model of ventilator-induced lung injury. Am J Respir Crit Care Med 179: 914-22
11. Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M. 2006. Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Altern Med Rev 11: 128-50
12. Jones SA. 2005. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175: 3463-8
13. Jones SA, Rose-John S. 2002. The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex. Biochim Biophys Acta 1592: 251-63
14. Nishimoto N, Kishimoto T. 2004. Inhibition of IL-6 for the treatment of inflammatory diseases. Curr Opin Pharmacol 4: 386-91
15. Hennigan S, Kavanaugh A. 2008. Interleukin-6 inhibitors in the treatment of rheumatoid arthritis. Ther Clin Risk Manag 4: 767-75
16. Barton BE. 1997. IL-6: insights into novel biological activities. Clin Immunol Immunopathol 85: 16-20
17. Ward NS, Waxman AB, Homer RJ, Mantell LL, Einarsson O, Du Y, Elias JA. 2000. Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 22: 535-42
18. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK. 1998. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101: 311-20
19. Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. 1994. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83: 113-8
20. Aderka D, Le JM, Vilcek J. 1989. IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells, and in mice. J Immunol 143: 3517-23
21. McLoughlin RM, Witowski J, Robson RL, Wilkinson TS, Hurst SM, Williams AS, Williams JD, Rose-John S, Jones SA, Topley N. 2003. Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J Clin Invest 112: 598-607
22. Frank JA, Parsons PE, Matthay MA. 2006. Pathogenetic significance of biological markers of ventilator-associated lung injury in experimental and clinical studies. Chest 130: 1906-14
23. Ramirez P, Ferrer M, Gimeno R, Tormo S, Valencia M, Piner R, Menendez R, Torres A. 2009. Systemic inflammatory response and increased risk for ventilator-associated pneumonia: a preliminary study. Crit Care Med 37: 1691-5
24. Libermann TA, Baltimore D. 1990. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 10: 2327-34
25. Hegeman MA, Hennus MP, Heijnen CJ, Specht PA, Lachmann B, Jansen NJ, van Vught AJ, Cobelens PM. 2009. Ventilator-induced endothelial activation and inflammation in the lung and distal organs. Crit Care 13: R182
26. Srivastava SK, Ramana KV. 2009. Focus on molecules: nuclear factor-kappaB. Exp Eye Res 88: 2-3
27. Liu YY, Liao SK, Huang CC, Tsai YH, Quinn DA, Li LF. 2009. Role for nuclear factor-kappaB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation. Transl Res 154: 228-40
28. Held HD, Boettcher S, Hamann L, Uhlig S. 2001. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. Am J Respir Crit Care Med 163: 711-6
29. Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST, Kollef MH. 2008. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest 134: 281-7
30. Hunter JD. 2006. Ventilator associated pneumonia. Postgrad Med J 82: 172-8
31. Joseph NM, Sistla S, Dutta TK, Badhe AS, Parija SC. 2010. Ventilator-associated pneumonia: a review. Eur J Intern Med 21: 360-8
32. Matute-Bello G, Lee JS, Frevert CW, Liles WC, Sutlief S, Ballman K, Wong V, Selk A, Martin TR. 2004. Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J Immunol Methods 292: 25-34
33. Patterson CE, Rhoades RA, Garcia JG. 1992. Evans blue dye as a marker of albumin clearance in cultured endothelial monolayer and isolated lung. J Appl Physiol 72: 865-73
34. Renckens R, van Westerloo DJ, Roelofs JJ, Pater JM, Schultz MJ, Florquin S, van der Poll T. 2008. Acute phase response impairs host defense against Pseudomonas aeruginosa pneumonia in mice. Crit Care Med 36: 580-7
35. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. 1998. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338: 347-54
36. Oeckler RA, Hubmayr RD. 2007. Ventilator-associated lung injury: a search for better therapeutic targets. Eur Respir J 30: 1216-26
37. Liang B, Song Z, Wu B, Gardner D, Shealy D, Song XY, Wooley PH. 2009. Evaluation of anti-IL-6 monoclonal antibody therapy using murine type II collagen-induced arthritis. J Inflamm (Lond) 6: 10
38. Hsu LC, Enzler T, Seita J, Timmer AM, Lee CY, Lai TY, Yu GY, Lai LC, Temkin V, Sinzig U, Aung T, Nizet V, Weissman IL, Karin M. 2011. IL-1beta-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKbeta. Nat Immunol 12: 144-50
39. Palmer LB. 2009. Ventilator-associated infection. Curr Opin Pulm Med 15: 230-5
40. Silva RC, Landgraf MA, Hiyane MI, Pacheco-Silva A, Camara NO, Landgraf RG. 2010. Leukotrienes produced in allergic lung inflammation activate alveolar macrophages. Cell Physiol Biochem 26: 319-26