||Both Hypothermia and Dextromethorphan Protect Against Acute Lung Injury in Experimental Heatstroke
||Institute of Basic Medical Sciences
Acute lung injury
For human survival, one of the most important organ systems is respiratory system. Acute lung injury (ALI) is defined as a syndrome of acute and persistent lung inflammation with increased vascular permeability. The threat of heatstroke is increasing because of global climate warming that results in heat waves. ALI or Acute respiratory distress syndrome (ARDS) develops in severe heatstroke cases and the mortality rate can be more than 50%. However, there was a lack of animal studies focusing on the heatstroke-related acute lung injury. In this study, we explored potential treatments and discussed the possible mechanisms for heatstroke-related acute lung injury in the experimental model. The decreased metabolic rate during rapid cooling and the ensuing decreased expenditure of energy substrates have been an accepted explanation for hypothermic protection in heatstroke patients. However, whether there are other mechanisms for hypothermic protection in heatstroke, especially the impact on respiratory system, remains unclear. Therefore, one of our specific aims was to determine whether hypothermia (whole body cooling or selective brain cooling) could protect against heatstroke and improve survival time by attenuating acute lung inflammation and injury.
Induction of heatstroke in Sprague-Dawley rats by using temperature-controlled heating pads set at 430C was achieved after the average time of 68 minutes. The results showed that acute lung inflammation and injury, acid-base imbalance, and hypoxia that occurred during heatstroke were significantly improved by treatment with whole body cooling. Additionally, the results of another set of animal studies revealed that brain cooling caused by 4°C saline infusion via retrograde jugular vein significantly reduced the severity of heat-induced acute lung injury. The levels of glutamate in the Bronchoalveolar lavage fluid increased obviously in our experimental model of heatstroke. Recent research shows that the endogenous glutamate mediated lung damage induced by hyperoxia through N-methyl-D-aspartate receptor (NMDAR) in newborn rats. Dextromethorphan (DM) acts as a NMDAR antagonist and it also has the properties of antioxidant. So, another specific aim of this study was to test the effects of dextromethorphan on heatstroke-related acute lung injury. The results showed that inflammatory cytokines, myeloperoxidase activity, glutamate, lactate/pyruvate ratio, total protein, and LDH levels in bronchoalveolar lavage fluids (BALFs) were significantly reduced and anti-inflammatory cytokine IL-10 levels in BAL were found significantly elevated in heatstroke rats after DM treatment. DM also significantly ameliorated lung tissue damage as measured by histological examination, prolonged the survival time, and improved physiological parameters of heatstroke.
We concluded that using either hypothermia or DM therapies immediately after the onset of heatstroke is effective in protecting against heatstroke by attenuating acute lung inflammation and lung injury
Table of Contents
Chinese Abstract I
Table of Contents VIII
List of Figures XI
1.1 Acute lung injury 2
1.2 Pathophysiology of acute lung injury 3
1.3 Current treatments for acute lung injury 4
1.4 Heatstroke 5
1.5 Heatstroke related acute lung injury 7
1.6 Hypothermia for acute lung jury 8
1.7 Roles of glutamate and N-methyl-D-asparate receptor in acute lung injury 9
1.8 Research goals 10
Materials and Methods 12
2.1 Experimental Animals 13
2.2 Surgery and Physiologic Parameter Monitoring 13
2.3 Induction of Heatstroke 13
2.4 Bronchoalveolar lavage 14
2.5 Measurement of Cerebral Blood Flow and Brain Temperature 14
2.6 Measurement of Arterial Blood Gas 15
2.7 Measurement of Cytokines 15
2.8 Measurement of Glutamate and Lactate/Pyruvate ratio 15
2.9 Measurement of Nitric Oxide Metabolites 16
2.10 Measurement of Exudates volume and amounts of PMN cells 16
2.11 Determination of MPO Activity 17
2.12 Determination of Lactate dehydrogenase activity 17
2.13 Determination of BAL total protein 17
2.14 Determination of Acute Lung Damage Score 17
2.15 Assessment of Inducible Nitric Oxide Synthase in the Lung 18
2.16 Statistics 19
Attenuation of Acute Lung Inflammation and Injury by Whole Body Cooling in a Rat Heatstroke Model 20
3.1 Abstract 21
3.2 Introduction 22
3.3 Results 23
3.4 Discussion 24
Inhibition of Acute Lung Inflammation and Injury Is a Target of Brain Cooling after Heatstroke Injury 41
4.1 Abstract 42
4.2 Introduction 44
4.3 Results 45
4.4 Discussion 47
Attenuation of Acute Lung Inflammation and Injury during Experimental Heatstroke by Dextromethorphan 61
5.1 Abstract 62
5.2 Introduction 64
5.3 Results 66
5.4 Discussion 69
Conclusions and further directions 88
1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994, 149:818-824.
2. MacCallum NS, Evans TW: Epidemiology of acute lung injury. Curr Opin Crit Care 2005, 11:43-49.
3. Frutos-Vivar F, Nin N, Esteban A: Epidemiology of acute lung injury and acute respiratory distress syndrome. Curr Opin Crit Care 2004, 10:1-6.
4. Estenssoro E, Dubin A, Laffaire E, Canales H, Saenz G, Moseinco M, Pozo M, Gomez A, Baredes N, Jannello G, Osatnik J: Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 2002, 30:2450-2456.
5. Esteban A, Anzueto A, Frutos F, Alia I, Brochard L, Stewart TE, Benito S, Epstein SK, Apezteguia C, Nightingale P, et al: Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002, 287:345-355.
6. Zilberberg MD, Epstein SK: Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome. Am J Respir Crit Care Med 1998, 157:1159-1164.
7. Montgomery AB, Stager MA, Carrico CJ, Hudson LD: Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985, 132:485-489.
8. Milberg JA, Davis DR, Steinberg KP, Hudson LD: Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995, 273:306-309.
9. Chabot F, Mitchell JA, Gutteridge JM, Evans TW: Reactive oxygen species in acute lung injury. Eur Respir J 1998, 11:745-757.
10. Pugin J, Verghese G, 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, 27:304-312.
11. Parsons PE, Eisner MD, Thompson BT, Matthay MA, Ancukiewicz M, Bernard GR, Wheeler AP: Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005, 33:1-6; discussion 230-232.
12. Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, Campbell DA, Jr.: Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990, 85:1936-1943.
13. Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000, 342:1334-1349.
14. Gadek JE, Pacht ER: The interdependence of lung antioxidants and antiprotease defense in ARDS. Chest 1996, 110:273S-277S.
15. Donnelly SC, MacGregor I, Zamani A, Gordon MW, Robertson CE, Steedman DJ, Little K, Haslett C: Plasma elastase levels and the development of the adult respiratory distress syndrome. Am J Respir Crit Care Med 1995, 151:1428-1433.
16. Bachofen M, Weibel ER: Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 1982, 3:35-56.
17. Matthay MA: Conference summary: acute lung injury. Chest 1999, 116:119S-126S.
18. Prescott SM, McIntyre TM, Zimmerman G: Two of the usual suspects, platelet-activating factor and its receptor, implicated in acute lung injury. J Clin Invest 1999, 104:1019-1020.
19. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000, 342:1301-1308.
20. Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura S, Matthay MA: Alveolar fluid clearance in the resected human lung. Am J Respir Crit Care Med 1994, 150:305-310.
21. Perkins GD, Gao F, Thickett DR: In vivo and in vitro effects of salbutamol on alveolar epithelial repair in acute lung injury. Thorax 2008, 63:215-220.
22. Lewis JF, Jobe AH: Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 1993, 147:218-233.
23. Zimmerman JJ: Surfactant is a target during acute lung injury inflammation. Crit Care Med 1996, 24:916-917.
24. Rossaint R, Gerlach H, Schmidt-Ruhnke H, Pappert D, Lewandowski K, Steudel W, Falke K: Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995, 107:1107-1115.
25. Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K, Jr., Kelly KM, Smith TC, Small RJ: Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004, 291:1603-1609.
26. Davreux CJ, Soric I, Nathens AB, Watson RW, McGilvray ID, Suntres ZE, Shek PN, Rotstein OD: N-acetyl cysteine attenuates acute lung injury in the rat. Shock 1997, 8:432-438.
27. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006, 354:1671-1684.
28. Sinuff T, Cook DJ, Peterson JC, Fuller HD: Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis. J Crit Care 1999, 14:1-6.
29. Jones TS, Liang AP, Kilbourne EM, Griffin MR, Patriarca PA, Wassilak SG, Mullan RJ, Herrick RF, Donnell HD, Jr., Choi K, Thacker SB: Morbidity and mortality associated with the July 1980 heat wave in St Louis and Kansas City, Mo. JAMA 1982, 247:3327-3331.
30. Bouchama A, Knochel JP: Heat stroke. N Engl J Med 2002, 346:1978-1988.
31. Semenza JC, Rubin CH, Falter KH, Selanikio JD, Flanders WD, Howe HL, Wilhelm JL: Heat-related deaths during the July 1995 heat wave in Chicago. N Engl J Med 1996, 335:84-90.
32. Dematte JE, O'Mara K, Buescher J, Whitney CG, Forsythe S, McNamee T, Adiga RB, Ndukwu IM: Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 1998, 129:173-181.
33. Yaqub BA, Al-Harthi SS, Al-Orainey IO, Laajam MA, Obeid MT: Heat stroke at the Mekkah pilgrimage: clinical characteristics and course of 30 patients. Q J Med 1986, 59:523-530.
34. Khogali M, Weiner JS: Heat stroke: report on 18 cases. Lancet 1980, 2:276-278.
35. el-Kassimi FA, Al-Mashhadani S, Abdullah AK, Akhtar J: Adult respiratory distress syndrome and disseminated intravascular coagulation complicating heat stroke. Chest 1986, 90:571-574.
36. Eyal Z, Dunsky EH, Polliack A, Davidson JT: The acute effect of pulmonary burns on lung mechanics and gas exchange in the rabbit. Br J Anaesth 1975, 47:546-552.
37. Sprung CL: Hemodynamic alterations of heat stroke in the elderly. Chest 1979, 75:362-366.
38. Elder DE, Bolton DP, Dempster AG, Taylor BJ, Broadbent RS: Pathophysiology of overheating in a piglet model: findings compared with sudden infant death syndrome. J Paediatr Child Health 1996, 32:113-119.
39. Bouchama A, Parhar RS, el-Yazigi A, Sheth K, al-Sedairy S: Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke. J Appl Physiol 1991, 70:2640-2644.
40. Bouchama A, Hammami MM, Haq A, Jackson J, al-Sedairy S: Evidence for endothelial cell activation/injury in heatstroke. Crit Care Med 1996, 24:1173-1178.
41. Bouchama A, al-Sedairy S, Siddiqui S, Shail E, Rezeig M: Elevated pyrogenic cytokines in heatstroke. Chest 1993, 104:1498-1502.
42. Smith JE: Cooling methods used in the treatment of exertional heat illness. Br J Sports Med 2005, 39:503-507; discussion 507.
43. Varghese GM, John G, Thomas K, Abraham OC, Mathai D: Predictors of multi-organ dysfunction in heatstroke. Emerg Med J 2005, 22:185-187.
44. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, Wisniewski SR, DeKosky ST: Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997, 336:540-546.
45. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002, 346:557-563.
46. Sakuma T, Takahashi K, Ohya N, Kajikawa O, Martin TR, Albertine KH, Matthay MA: Ischemia-reperfusion lung injury in rabbits: mechanisms of injury and protection. Am J Physiol 1999, 276:L137-145.
47. Lim CM, Hong SB, Koh Y, Lee SD, Kim WS, Kim DS, Kim WD: Hypothermia attenuates vascular manifestations of ventilator-induced lung injury in rats. Lung 2003, 181:23-34.
48. Kira S, Daa T, Kashima K, Mori M, Noguchi T, Yokoyama S: Mild hypothermia reduces expression of intercellular adhesion molecule-1 (ICAM-1) and the accumulation of neutrophils after acid-induced lung injury in the rat. Acta Anaesthesiol Scand 2005, 49:351-359.
49. Fujimori S, Abe Y, Nishi M, Hamamoto A, Inoue Y, Ohnishi Y, Nishime C, Matsumoto H, Yamazaki H, Kijima H, et al: The subunits of glutamate cysteine ligase enhance cisplatin resistance in human non-small cell lung cancer xenografts in vivo. Int J Oncol 2004, 25:413-418.
50. Wang M, Luo Z, Liu S, Li L, Deng X, Huang F, Shang L, Jian C, Yue S: Glutamate mediates hyperoxia-induced newborn rat lung injury through N-methyl-D-aspartate receptors. Am J Respir Cell Mol Biol 2009, 40:260-267.
51. Shen L, Luo ZQ, Han JZ, Yue SJ, Qin XQ, Li C, Liu HJ: [Experimental study of acute lung injury induced by glutamate in vivo]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2007, 32:78-81.
52. Li G, Liu Y, Tzeng NS, Cui G, Block ML, Wilson B, Qin L, Wang T, Liu B, Liu J, Hong JS: Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol 2005, 69:233-240.
53. Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
54. Wong BY, Coulter DA, Choi DW, Prince DA: Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices. Neurosci Lett 1988, 85:261-266.
55. Hsu SF, Niu KC, Lin CL, Lin MT: Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke. Shock 2006, 26:210-220.
56. Paxinos T WL: The Rat Brain in Stereotaxic coordinates. New your: Academic Press 1982.
57. Chou YT, Lai ST, Lee CC, Lin MT: Hypothermia attenuates circulatory shock and cerebral ischemia in experimental heatstroke. Shock 2003, 19:388-393.
58. Togashi H, Mori K, Ueno K, Matsumoto M, Suda N, Saito H, Yoshioka M: Consecutive evaluation of nitric oxide production after transient cerebral ischemia in the rat hippocampus using in vivo brain microdialysis. Neurosci Lett 1998, 240:53-57.
59. Mullane KM, Kraemer R, Smith B: Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods 1985, 14:157-167.
60. Hong SB, Koh Y, Lee IC, Kim MJ, Kim WS, Kim DS, Kim WD, Lim CM: Induced hypothermia as a new approach to lung rest for the acutely injured lung. Crit Care Med 2005, 33:2049-2055.
61. Furusu A, Miyazaki M, Abe K, Tsukasaki S, Shioshita K, Sasaki O, Miyazaki K, Ozono Y, Koji T, Harada T, et al: Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int 1998, 53:1760-1768.
62. Hall DM, Buettner GR, Oberley LW, Xu L, Matthes RD, Gisolfi CV: Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia. Am J Physiol Heart Circ Physiol 2001, 280:H509-521.
63. Chen SH, Chang FM, Tsai YC, Huang KF, Lin MT: Resuscitation from experimental heatstroke by transplantation of human umbilical cord blood cells. Crit Care Med 2005, 33:1377-1383.
64. Roberts GT, Ghebeh H, Chishti MA, Al-Mohanna F, El-Sayed R, Bouchama A: Microvascular injury, thrombosis, inflammation, and apoptosis in the pathogenesis of heatstroke: a study in baboon model. Arterioscler Thromb Vasc Biol 2008, 28:1130-1136.
65. Knochel JP: Heat stroke and related heat stress disorders. Dis Mon 1989, 35:301-377.
66. Simon HB: Hyperthermia and heatstroke. Hosp Pract (Off Ed) 1994, 29:65-68, 73, 78-80.
67. Russell WMSaB, R. L: The Principles of Humane Experimental Technique. London: Methuen. 1959.
68. Chang CK, Chang CP, Chiu WT, Lin MT: Prevention and repair of circulatory shock and cerebral ischemia/injury by various agents in experimental heatstroke. Curr Med Chem 2006, 13:3145-3154.
69. Chang CK, Chang CP, Liu SY, Lin MT: Oxidative stress and ischemic injuries in heat stroke. Prog Brain Res 2007, 162:525-546.
70. Rinaldo JE, Dauber JH, Christman J, Rogers RM: Neutrophil alveolitis following endotoxemia. Enhancement by previous exposure to hyperoxia. Am Rev Respir Dis 1984, 130:1065-1071.
71. Wheeldon EB, Walker ME, Murphy DJ, Turner CR: Intratracheal aerosolization of endotoxin in the rat: a model of the adult respiratory distress syndrome (ARDS). Lab Anim 1992, 26:29-37.
72. Lu MY, Kang BH, Wan FJ, Chen CS, Huang KL: Hyperbaric oxygen attenuates lipopolysaccharide-induced acute lung injury. Intensive Care Med 2002, 28:636-641.
73. Chu SJ, Perng WC, Hung CM, Chang DM, Lin SH, Huang KL: Effects of various body temperatures after lipopolysaccharide-induced lung injury in rats. Chest 2005, 128:327-336.
74. Hall DM, Baumgardner KR, Oberley TD, Gisolfi CV: Splanchnic tissues undergo hypoxic stress during whole body hyperthermia. Am J Physiol 1999, 276:G1195-1203.
75. Shapiro Y, Alkan M, Epstein Y, Newman F, Magazanik A: Increase in rat intestinal permeability to endotoxin during hyperthermia. Eur J Appl Physiol Occup Physiol 1986, 55:410-412.
76. Doran JE: Biological effects of endotoxin. Curr Stud Hematol Blood Transfus 1992:66-99.
77. N. Butkow DM, H. Laburn: Heat stroke and endotoxaemia in rabbits. In JRS Hales (Ed), Thermal Physiology, Raven, New York 1984:511-514.
78. Bynum G BJ, Dubose D, Marsili M, Leav I, Pistole TG, Hamlet M, LeMaire M, Caleb B.: Increased survival in experimental dog heat stroke after reduction of gut flora. Aviat Space Environ Med 1979:816-819.
79. Lin MT, Liu HH, Yang YL: Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke. Am J Physiol 1997, 273:H2072-2077.
80. Shen KH, Chang CK, Lin MT, Chang CP: Interleukin-1 receptor antagonist restores homeostatic function and limits multiorgan damage in heatstroke. Eur J Appl Physiol 2008, 103:561-568.
81. Simon HB: Hyperthermia. N Engl J Med 1993, 329:483-487.
82. Hasday JD, Garrison A, Singh IS, Standiford T, Ellis GS, Rao S, He JR, Rice P, Frank M, Goldblum SE, Viscardi RM: Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity. Am J Pathol 2003, 162:2005-2017.
83. Rice P, Martin E, He JR, Frank M, DeTolla L, Hester L, O'Neill T, Manka C, Benjamin I, Nagarsekar A, et al: Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia. J Immunol 2005, 174:3676-3685.
84. Chiang CH, Wu K, Yu CP, Yan HC, Perng WC, Wu CP: Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury. Am J Respir Crit Care Med 1999, 160:1319-1323.
85. McDonald MC, Izumi M, Cuzzocrea S, Thiemermann C: A novel, potent and selective inhibitor of the activity of inducible nitric oxide synthase (GW274150) reduces the organ injury in hemorrhagic shock. J Physiol Pharmacol 2002, 53:555-569.
86. Pugin J, Ricou B, Steinberg KP, Suter PM, Martin TR: Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am J Respir Crit Care Med 1996, 153:1850-1856.
87. Xing Z, Jordana M, Kirpalani H, Driscoll KE, Schall TJ, Gauldie J: Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol 1994, 10:148-153.
88. Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 1992, 6:3051-3064.
89. Southan GJ, Szabo C: Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 1996, 51:383-394.
90. Anggard EE: Endogenous nitrates--implications for treatment and prevention. Eur Heart J 1991, 12 Suppl A:5-8.
91. Parker JO: Nitrate therapy in stable angina pectoris. N Engl J Med 1987, 316:1635-1642.
92. Dugo L, Marzocco S, Mazzon E, Di Paola R, Genovese T, Caputi AP, Cuzzocrea S: Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation. Br J Pharmacol 2004, 141:979-987.
93. Alzeer AH, Al-Arifi A, Warsy AS, Ansari Z, Zhang H, Vincent JL: Nitric oxide production is enhanced in patients with heat stroke. Intensive Care Med 1999, 25:58-62.
94. Chang CP, Lee CC, Chen SH, Lin MT: Aminoguanidine protects against intracranial hypertension and cerebral ischemic injury in experimental heatstroke. J Pharmacol Sci 2004, 95:56-64.
95. Scumpia PO, Sarcia PJ, DeMarco VG, Stevens BR, Skimming JW: Hypothermia attenuates iNOS, CAT-1, CAT-2, and nitric oxide expression in lungs of endotoxemic rats. Am J Physiol Lung Cell Mol Physiol 2002, 283:L1231-1238.
96. Said SI, Berisha HI, Pakbaz H: Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A 1996, 93:4688-4692.
97. Tang F, Yue S, Luo Z, Feng D, Wang M, Qian C, Zhen X, Duan Y: Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. Pediatr Pulmonol 2005, 40:437-444.
98. Hsiao SH, Chang CP, Chiu TH, Lin MT: Resuscitation from experimental heatstroke by brain cooling therapy. Resuscitation 2007, 73:437-445.
99. Lim CL, Mackinnon LT: The roles of exercise-induced immune system disturbances in the pathology of heat stroke : the dual pathway model of heat stroke. Sports Med 2006, 36:39-64.
100. Sharma HS, Hoopes PJ: Hyperthermia induced pathophysiology of the central nervous system. Int J Hyperthermia 2003, 19:325-354.
101. Neuronal Degeneration and Regeneration: From Basic Mechanisms to Prospects for Therapy. Proceedings of the 20th International Summer School of Brain Research. Amsterdam, the Netherlands, 25-29 August 1997. Prog Brain Res 1998, 117:1-532.
102. Seraj MA, Channa AB, al Harthi SS, Khan FM, Zafrullah A, Samarkandi AH: Are heat stroke patients fluid depleted? Importance of monitoring central venous pressure as a simple guideline for fluid therapy. Resuscitation 1991, 21:33-39.
103. Shapiro Y, Seidman DS: Field and clinical observations of exertional heat stroke patients. Med Sci Sports Exerc 1990, 22:6-14.
104. Wen YS, Huang MS, Lin MT, Lee CH: Hypothermic retrograde jugular vein flush in heatstroke rats provides brain protection by maintaining cerebral blood flow but not by hemodilution. Crit Care Med 2004, 32:1391-1395.
105. Wen YS, Huang MS, Lin MT, Lee CH: Rapid brain cooling by hypothermic retrograde jugular vein flush. J Trauma 2005, 58:577-581.
106. Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987, 7:729-738.
107. Gladstone DJ, Black SE, Hakim AM: Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002, 33:2123-2136.
108. Krieger DW, Yenari MA: Therapeutic hypothermia for acute ischemic stroke: what do laboratory studies teach us? Stroke 2004, 35:1482-1489.
109. Oberholzer A, Oberholzer C, Moldawer LL: Cytokine signaling--regulation of the immune response in normal and critically ill states. Crit Care Med 2000, 28:N3-12.
110. Persson L, Hillered L: Chemical monitoring of neurosurgical intensive care patients using intracerebral microdialysis. J Neurosurg 1992, 76:72-80.
111. Hillered L, Persson L: Neurochemical monitoring of the acutely injured human brain. Scand J Clin Lab Invest Suppl 1999, 229:9-18.
112. Lin M-T, Chang C-P: The neuropharmacological basis of heat intolerance and its treatment. Journal of Thermal Biology, 29:463-469.
113. Hsi-Hsing Y, Ching-Ping C, Juei-Tang C, Lin MT: Inhibition of acute lung inflammation and injury is a target of brain cooling after heatstroke injury. J Trauma 2010, 69:805-812.
114. Yang HH, Chang CP, Cheng JT, Lin MT: Attenuation of acute lung inflammation and injury by whole body cooling in a rat heatstroke model. J Biomed Biotechnol 2009, 2009:768086.
115. Gosselin GE, Roger RP, Harold CH : Clinical Toxicology of Commercial Products, 5th Ed: Williams and Wilkins, Baltimore; 1981.
116. Reagan-Shaw S, Nihal M, Ahmad N: Dose translation from animal to human studies revisited. FASEB J 2008, 22:659-661.
117. Sheridan BC, McIntyre RC, Meldrum DR, Fullerton DA: Pentoxifylline treatment attenuates pulmonary vasomotor dysfunction in acute lung injury. Journal of Surgical Research 1997, 71:150-154.
118. Donnelly SC, Strieter RM, Reid PT, Kunkel SL, Burdick MD, Armstrong I, Mackenzie A, Haslett C: The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Annals of Internal Medicine 1996, 125:191-196.
119. Lv T, Shen X, Shi Y, Song Y: TLR4 is essential in acute lung injury induced by unresuscitated hemorrhagic shock. Journal of Trauma-Injury Infection & Critical Care 2009, 66:124-131.
120. Kobbe P, Schmidt J, Stoffels B, Chanthaphavong RS, Bauer AJ, Pape HC: IL-10 administration attenuates pulmonary neutrophil infiltration and alters pulmonary iNOS activation following hemorrhagic shock. Inflammation Research 2009, 58:170-174.
121. Kobbe P, Stoffels B, Schmidt J, Tsukamoto T, Gutkin DW, Bauer AJ, Pape HC: IL-10 deficiency augments acute lung but not liver injury in hemorrhagic shock. Cytokine 2009, 45:26-31.
122. Bullock R, Zauner A, Woodward J, Young HF: Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke 1995, 26:2187-2189.
123. Kim K, Kim W, Rhee JE, Jo YH, Lee JH, Kim KS, Kwon WY, Suh GJ, Lee CC, Singer AJ: Induced hypothermia attenuates the acute lung injury in hemorrhagic shock. Journal of Trauma-Injury Infection & Critical Care 2010, 68:373-381.
124. Peng CK, Huang KL, Wu CP, Li MH, Lin HI, Hsu CW, Tsai SH, Chu SJ: The role of mild hypothermia in air embolism-induced acute lung injury. Anesthesia & Analgesia 2010, 110:1336-1342.
125. Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, Colgan SP: Neutrophil-derived glutamate regulates vascular endothelial barrier function. J Biol Chem 2002, 277:14801-14811.