(A). (cytokine and chemokines) TNF- IL-1 IL-1ra IL-6 IL-10 IL-

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1 1 1,2 1,2 1,2 (A). (cytokine and chemokines) TNF- IL-1 IL-1ra IL-6 IL-10 IL- 8 (B). Arachadonic acid PLA2 LTB4 (C). protein C PAI-1 Thrombomodulin IL-1 IL-6 IL-10 IL-8 PAI-1 ARDS protein C IL-1 IL-8 PLA2 LTB4 protein C PAI-1 (A). pulmonary edema protein rate of protein clearance (B). ET-1 VWF (C). Surfactant protein A Surfactant protein D KL-6 (D). Neutrophil elastase MMPs Nitrate and Nitrite TGF- (E). PCP VWF Surfactant D KL-6 TGF- PCP ET-1 VWF Surfactant A KL-6 MMP-9 Nitrite TGF- ALI

2 5 1-3 ALI Acute Respiratory Distress Syndrome ARDS inactivation ARDS 50-60% 10,11 12 ARDS TNF- Selectins ARDS 12,13 ARDS The interaction of epithelium, endothelium, inflammatory cell and cytokines in ARDS ARDS The role of coagulation and ARDS Proinflammatory IL-1 TNF- IL-6 profibrotic TGF- CTGF connective tissue growth factor PDGF II 114

3 antifibrinolytic RNA Factor VII-activating protease-- FSAP procoagulant state fibrin degradation products recruitment Thrombin factor Xa TF-factor VIIa PAR-1 14 Biomarkers in ARDS ARDS biomarker BAL I. Broncho-alveolar lavage fluid ALI ARDS , II. Markers of endothelial cell dysfunction -1 ET ,21 von Willebrand 65% ARDSNET III. Markers of epithelial cell dysfunction transdifferentiate 5-10% 4 SP-A, -B, -C, and -D SP-A and SP-D

4 pulmonary epithelial mucin KL-6, muc-1 KL-6 23,24 IV. Inflammatory cell-derived mediators 19 Neutrophil elastase NE 25 Matrix metalloproteases metalloendopeptidases MMP-9 26 Reactive oxygen species superoxide hydrogen peroxide hydroxyl radicals 27 byproducts nitrate/ nitrite hydrostatic edema 19 TGF- 28 V. Markers of fibroblasts and of collagen synthesis alveoli-capillary unit remoldering Pro-collagen peptide III PCP III PCP III 29 VI. Early release cytokines and chemokines Cytokines/chemokines TNF- TNF- TNF decoy TNF- 30,31 IL-1 IL-1 IL-1 IL-1ra 32 IL-1 /IL-1ra 31,33,34 IL-6 35 IL-10 T sensitization 700 ARDSnet low tidal volume ventilation trial IL-6 IL Chemokines G- recruitment CXC chemokines ELR motif glutamylleucylarginine 116

5 VII. A2 Phospholipase A2 and leukotrienes Phospholipase A2 PLA2 arachidonic acid LTB4 LTC4 LTD4 LTE4 LTB4 LTB4 14 pmol/ml 37 VIII. Markers of coagulation cascade - 38,39-1 Plasminogen activator inhibitor-1 PAI-1 17 Protein C thrombomodulin protein C 40 Further applications of biomarkers in ARDS 1 ARDS ARDS 2 ARDS 3 ARDS ARDS 01. Cohen J. The immunopathogenesis of sepsis. Nature 2002;420: Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29:S109-S Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med 2000;26: S64-S Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions,mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: Weinacker AB, Vaszar LT. Acute respiratory distress syndrome: physiology and new management strategies. Annu Rev Med 2001;52: Tasaka S, Hasegawa N, Ishizaka A. Pharmacology of acute lung injury. Pulm Pharmacol Ther 2002;15:

6 07. Bhatia M, Brady M, Shokuhi S, et al. Inflammatory mediators in acute pancreatitis. J Pathol 2000;190: Bhatia M, Neoptolemos JP, Slavin J. Inflammatory mediators as therapeutic targets in acute pancreatitis. Curr Opin Invest Drugs 2001;2: Bhatia M. Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome. Curr Drug Targets -- Infl Allergy 2002;1: Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342: Schwarz MA, Paediatr Respir Rev02001 Mar;2(1): Donnelly SC, Haslett C, Dransfield I, Robertson CE, Carter DC, Ross JA, Grant IS, Tedder TF. Role of selectins in development of adult respiratory distress syndrome. Lancet 1994;344: Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P.Thromb Haemost 2008;99: Pittet JF, Mackersie RC, Martin TR, Matthay MA. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997;155: Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 1999;142: Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol, Lung Cell Mol Physiol 2003;285:L Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III procollagen peptide in the adult respiratory distress syndrome.ann Intern Med 1995;122: Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in adult respiratory distress syndrome. Am J Respir Crit Care Med 1994;150: Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger RD, Stewart DJ. Endothelin-1 in acute lung injury and the adult respiratory distress syndrome. Am Rev Respir Dis 1993;148: Sanai L, Haynes WG, Mackenzie A, Grant IS, Webb DJ. Endothelin production in sepsis and the adult respiratory distress syndrome. Intensive Care Med 1996; 22: Eisner MD, Parsons P, Matthay MA, Ware L, Greene K. Acute respiratory distress syndrome network. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003;58: Ishizaka A, Matsuda T, Albertine KH, Koh H, Tasaka S, Hasegawa N, et al. Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2004;286:L Sato H, Callister MEJ, Mumby S, Quinlan GJ,Welsh KI, dubois RM, et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J 2004;23: Moraes TJ, Chow C-W, Downey GP. Proteases and lung injury. Crit Care Med 2003;31:S Pugin J, Verghese GM, Widmer MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 1999; 27: Chabot F, Mitchell JA, Gutteridge JMC, Evans TW. Reactive oxygen species in acute lung injury. Eur Respir J 1998;11: Madtes DK, Rubenfeld GD, Klima LD, Milberg JA, Steinberg KP, Martin TR, et al. Elevated transforming growth factor \ levels in bronchoalveolar lavage fluid of patientswith acute respiratory distress syndrome. AmJ Respir Crit Care Med 1998;158: Chesnutt AN, Matthay MA, Tibayan FA, Clark JG. Early detection of type III procollagen peptide in acute lung injury. Am J Respir Crit Care Med 1997;156: Hyers TM, Tricomi SM, Dettenmeier PA, Fowler AA. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1991;144: Park WY, Goodman RB, Steinberg KP, Ruzinski JT, Radella F, Park DR, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164: Suter PM, Suter SM, Girardin E, Roux-Lombard P, Grau GE, Dayer JM. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin- 1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am Rev Respir Dis 1992;145: Goodman R, Pugin J, Lee JS, Matthay MA. Cytokinemediated inflammation in acute lung injury. Cytokine Growth Factor Rev 2003;14: Goodman RB, Strieter RM, Martin DP, Steinberg KP, Milberg JA, Maunder RJ, et al. Inflammatory cytokines in patients with persistence of the acute respiratory 118

7 distress syndrome. Am J Respir Crit Care Med 1996; 154: Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998;101: Parsons PE, Eisner MD, Thompson T, Matthay MA, Ancukiewica M, Bernard GR, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; Amat M, Barcons M, Mancebo J, Mateo J, Oliver A, Mayoral J-F, et al. Evaluation of leukotriene B4, peptide leukotrienes, and interleukin-8 plasma concentrations in patients at risk of acute respiratory distress syndrome with acute respiratory distress syndrome: mortality prognostic study. Crit Care Med 2000;28: Snow RL, Davies P, Pontoppidan H, Zapol WM, Reid L. Pulmonary vascular remodeling in adult respiratory distress syndrome. Am Rev Respir Dis 1982;126: Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002;346: Ware LB, Fang Z, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285:L

8 BIOMARKERS IN ACUTE LUNG INJURY Chien-Yu Huang 1, Kuang-Yao Yang 1,2, Yu-Chin Lee 1,2, Reury-Perng Perng 1,2 Abstract Acute lung injury(ali) and acute respiratory distress syndrome (ARDS) are lifethreatening disorders that could be resulted from various conditions that directly or indirectly injure the lung. Because these patients develop severe and progressive pulmonary gas exchange impairments and pulmonary mechanical dysfunction which cause high morbidity and mortality (>40%), numerous biomarkers for ALI have been researched. These biomarkers can be used not only to differentiate other diseases which mimic ALI, evaluate the severity of ALI, but also predict the mortality. Update biomarkers include early release cytokines and chemokines (TNF-, IL-1, IL-1ra, IL-6, IL-10 and IL-8), phospholipase A2 and leukotrienes, inflammatory cell-derived mediators (neutrophil elastase, MMPs, Nitrate and Nitrite, TGF- ), markers of coagulation pathway (protein C, PAI-1, Thrombomodulin), markers of endothelial cell dysfunction (ET-1, VWF), markers of broncho-alveolar lavage fluid (pulmonary edema protein, rate of protein clearance), markers of epithelial cell dysfunction (surfactant protein A, surfactant protein D, KL-6), markers of fibroblasts and of collagen synthesis (PCP III). Of these biomarkers, VWF, surfactant D, KL-6, TGF- and PCP III are related to the prognosis and mortality of ALI. Besides, ET-1, VWF, surfactant A, KL-6, MMP-9, Nitrite, TGF- are predictable for ALI development. In addition, IL- 1, IL-8, PLA2, LTB4, protein C, PAI-1 can also be used to differentiate ALI and cardiogenic pulmlonary edema. In conclusion, biomarkers will serve as prognostic measures of ALI and deserve further exploration in the future. Key words: Acute lung injury, Biomarker, Cytokine, BAL fluid Correspondence: Dr. Kuang-Yao Yang Department of Chest, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan Phone: ext 3090; Fax: ; School of Medicine, National Yang-Ming University 2 120