Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Gaseous Therapeutics in Acute Lung Injury

Stefan W. Ryter, Augustine M. K. Choi

10.1002/cphy.c090003

Source: Volume 1, Issue 1, January 2011

Published online: November 2010

Full Article on Wiley Online Library



Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain major causes of morbidity and mortality in critical care medicine despite advances in therapeutic modalities. ALI can be associated with sepsis, trauma, pharmaceutical or xenobiotic exposures, high oxygen therapy (hyperoxia), and mechanical ventilation. Of the small gas molecules (NO, CO, H2S) that arise in human beings from endogenous enzymatic activities, the physiological significance of NO is well established, whereas that of CO or H2S remains controversial. Recent studies have explored the potential efficacy of inhalation therapies using these small gas molecules in animal models of ALI. NO has vasoregulatory and redox‐active properties and can function as a selective pulmonary vasodilator. Inhaled NO (iNO) has shown promise as a therapy in animal models of ALI including endotoxin challenge, ischemia/reperfusion (I/R) injury, and lung transplantation. CO, another diatomic gas, can exert cellular tissue protection through antiapoptotic, anti‐inflammatory, and antiproliferative effects. CO has shown therapeutic potential in animal models of endotoxin challenge, oxidative lung injury, I/R injury, pulmonary fibrosis, ventilator‐induced lung injury, and lung transplantation. H2S, a third potential therapeutic gas, can induce hypometabolic states in mice and can confer both pro‐ and anti‐inflammatory effects in rodent models of ALI and sepsis. Clinical studies have shown variable results for the efficacy of iNO in lung transplantation and failure for this therapy to improve mortality in ARDS patients. No clinical studies have been conducted with H2S. The clinical efficacy of CO remains unclear and awaits further controlled clinical studies in transplantation and sepsis. © 2011 American Physiological Society. Compr Physiol 1:105‐121, 2011.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Endogenous production of gaseous signaling molecules. (A) Nitric oxide is synthesized from l‐arginine by the action of nitric oxide synthase enzymes. (B) Carbon monoxide is generated from the oxidative catabolism of heme by the action of heme oxygenase enzymes. (C) H2S is synthesized from l‐cysteine. Simplified reaction catalyzed by cystathionine‐γ‐lyase is shown.
Figure 2. Figure 2.

Rationale for therapeutic application of carbon monoxide (CO). CO can provide tissue protection dependent largely on antiapoptotic, anti‐inflammatory, and antiproliferative properties. Additional systemic effects that can promote tissue protection include inhibition of microvascular leakage and inhibition of thrombosis. The molecular mechanisms for these effects are not entirely clear, but several candidate biochemical targets/pathways have been described. Finally, the therapeutic application of low‐concentration CO may have limitations, including inhibition of alveolar fluid clearance, unclear neurotoxicity, carboxyhemoglobinemia, and systemic/extrapulmonary effects.


Figure 1.

Endogenous production of gaseous signaling molecules. (A) Nitric oxide is synthesized from l‐arginine by the action of nitric oxide synthase enzymes. (B) Carbon monoxide is generated from the oxidative catabolism of heme by the action of heme oxygenase enzymes. (C) H2S is synthesized from l‐cysteine. Simplified reaction catalyzed by cystathionine‐γ‐lyase is shown.



Figure 2.

Rationale for therapeutic application of carbon monoxide (CO). CO can provide tissue protection dependent largely on antiapoptotic, anti‐inflammatory, and antiproliferative properties. Additional systemic effects that can promote tissue protection include inhibition of microvascular leakage and inhibition of thrombosis. The molecular mechanisms for these effects are not entirely clear, but several candidate biochemical targets/pathways have been described. Finally, the therapeutic application of low‐concentration CO may have limitations, including inhibition of alveolar fluid clearance, unclear neurotoxicity, carboxyhemoglobinemia, and systemic/extrapulmonary effects.

References
 1. Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuro‐modulator. J Neurosci 16: 1066‐1071, 1996.
 2. Albina JE, Cui S, Mateo RB, Reichner JS. Nitric oxide‐mediated apoptosis in murine peritoneal macrophages. J Immunol 150: 5080‐5085, 1993.
 3. Albina JE, Reichner JS. Nitric oxide in inflammation and immunity. New Horiz 3: 46‐64, 1995.
 4. Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M, Moore PK. Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 149: 625‐634, 2006.
 5. Althaus M, Fronius M, Buchackert Y, Vadasz I, Clauss WG, Seeger W, Motterlini R, Morty RE. Carbon monoxide rapidly impairs alveolar fluid clearance by inhibiting epithelial sodium channels. Am J Respir Cell Mol Biol 41: 639‐650.
 6. Barbotin‐Larrieu F, Mazmanian M, Baudet B, Détruit H, Chapelier A, Libert JM, Dartevelle P, Hervé P. Prevention of ischemia‐reperfusion lung injury by inhaled nitric oxide in neonatal piglets. J Appl Physiol 80: 782‐788, 1996.
 7. Bathoorn E, Slebos DJ, Postma DS, Koeter GH, van Oosterhout AJ, van Der Toorn M, Boezen HM, Kerstjens HA. Anti‐inflammatory effects of inhaled carbon monoxide in patients with COPD: A pilot study. Eur Respir J 30: 1131‐1137, 2007.
 8. Bauer PM, Buga GM, Ignarro LJ. Role of p42/p44 mitogen‐activated‐protein kinase and p21waf1/cip1 in the regulation of vascular smooth muscle cell proliferation by nitric oxide. Proc Natl Acad Sci U S A 98: 12802‐12807, 2001.
 9. Bilban M, Bach FH, Otterbein SL, Ifedigbo E, d'Avila JC, Esterbauer H, Chin BY, Usheva A, Robson SC, Wagner O, Otterbein LE. Carbon monoxide orchestrates a protective response through PPARgamma. Immunity 24: 601‐610, 2006.
 10. Billiar TR. Nitric oxide. Novel biology with clinical relevance. Ann Surg 221: 339‐349, 1995.
 11. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation‐like state in mice. Science 308: 518, 2005
 12. Blackstone E, Roth MB. Suspended animation‐like state protects mice from lethal hypoxia. Shock 27: 370‐372, 2007.
 13. Bloch KD, Ichinose F, Roberts JD, Zapol WM. Inhaled NO as a therapeutic agent. Cardiovasc Res 75: 339‐348, 2007.
 14. Bloomfield GL, Holloway S, Ridings PC, Fisher BJ, Blocher CR, Sholley M, Bunch T, Sugerman HJ, Fowler AA. Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis‐induced acute lung injury. Crit Care Med 25: 584‐593, 1997.
 15. Botha P, Jeyakanthan M, Rao JN, Fisher AJ, Prabhu M, Dark JH, Clark SC. Inhaled nitric oxide for modulation of ischemia‐reperfusion injury in lung transplantation. J Heart Lung Transplant 26: 1199‐1205, 2007.
 16. Bouton C, Demple B. Nitric oxide‐inducible expression of heme oxygenase‐1 in human cells. Translation‐independent stabilization of the mRNA and evidence for direct action of nitric oxide. J Biol Chem 275: 32688‐32693, 2000.
 17. Bredt DS, Snyder SH. Nitric oxide: A physiologic messenger molecule. Annu Rev Biochem 63: 175‐195, 1994.
 18. Broccard AF, Feihl F, Vannay C, Markert M, Hotchkiss J, Schaller MD. Effects of L‐NAME and inhaled nitric oxide on ventilator‐induced lung injury in isolated, perfused rabbit lungs. Crit Care Med 32: 1872‐1878, 2004.
 19. Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, Soares MP. Heme oxygenase‐1‐derived carbon monoxide requires the activation of transcription factor NF‐kappa B to protect endothelial cells from tumor necrosis factor‐alpha‐mediated apoptosis. J Biol Chem 277: 17950‐17961, 2002.
 20. Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP. Carbon monoxide generated by heme oxygenase‐1 suppresses endothelial cell apoptosis. J Exp Med 192: 1015‐1026, 2000.
 21. Camhi SL, Alam J, Otterbein L, Sylvester SL, Choi AM. Induction of heme oxygenase‐1 gene expression by lipopolysaccharide is mediated by AP‐1 activation. Am J Respir Cell Mol Biol 13: 387‐398, 1995.
 22. Capellier G, Maupoil V, Boillot A, Kantelip JP, Rochette L, Regnard J, Barale F. L‐NAME aggravates pulmonary oxygen toxicity in rats. Eur Respir J 9: 2531‐2536, 1996.
 23. Ceneviva GD, Tzeng E, Hoyt DG, Yee E, Gallagher A, Engelhardt JF, Kim YM, Billiar TR, Watkins SA, Pitt BR. Nitric oxide inhibits lipopolysaccharide‐induced apoptosis in pulmonary artery endothelial cells. Am J Physiol 275: L717‐L728, 1998.
 24. Choi BM, Pae HO, Jang SI, Kim YM, Chung HT. Nitric oxide as a pro‐apoptotic as well as anti‐apoptotic modulator. J Biochem Mol Biol 35: 116‐126, 2002.
 25. Choi J, Hoffman LA, Rodway GW, Sethi JM. Markers of lung disease in exhaled breath: Nitric oxide. Biol Res Nurs 7: 241‐255, 2006.
 26. Clayton CE, Carraway MS, Suliman HB, Thalmann ED, Thalmann KN, Schmechel DE, Piantadosi CA. Inhaled carbon monoxide and hyperoxic lung injury in rats. Am J Physiol Lung Cell Mol Physiol 281: L949‐L957, 2001.
 27. Coburn RF, Blakemore WS, Forster RE. Endogenous carbon monoxide production in man. J Clin Invest 42: 1172‐1178, 1963.
 28. Coburn RF, Williams WJ, Kahn SB. Endogenous carbon monoxide production in patients with hemolytic anemia. J Clin Invest 45: 460‐468, 1966.
 29. Crapo JD. Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48: 721‐731, 1986.
 30. Crapo JD, Barry BE, Foscue HA, Shelburne J. Structural and biochemical changes in rat lungs occurring during exposures to lethal and adaptive doses of oxygen. Am Rev Respir Dis 122: 123‐143, 1980.
 31. Cui S, Reichner JS, Mateo RB, Albina JE. Activated murine macrophages induce apoptosis in tumor cells through nitric oxide‐dependent or ‐independent mechanisms. Cancer Res 54: 2462‐2467, 1994.
 32. Date H, Triantafillou AN, Trulock EP. Inhaled nitric oxide reduces human allograft dysfunction. J Thorac Cardiovasc Surg 111: 913‐919, 1996.
 33. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC. Placebo and inhaled nitric oxide mortality the same in ARDS clinical trial. Crit Care Med 26: 619, 1998.
 34. Deplancke B, Gaskins HR. Hydrogen sulfide induces serum‐independent cell cycle entry in nontransformed rat intestinal epithelial cells. FASEB J 17: 1310‐1312, 2003.
 35. Dolinay T, Szilasi M, Liu M, Choi AM. Inhaled carbon monoxide confers anti‐inflammatory effects against ventilator‐induced lung injury. Am J Respir Crit Care Med 170: 613‐620, 2004.
 36. Dolinay T, Wu W, Kaminski N, Ifedigbo E, Kaynar AM, Szilasi M, Watkins SC, Ryter SW, Hoetzel A, Choi AM. Mitogen‐activated protein kinases regulate susceptibility to ventilator‐induced lung injury. PLoS ONE 3: e1601, 2008.
 37. Durante W, Johnson FK, Johnson RA. Role of carbon monoxide in cardiovascular function. J Cell Mol Med 10: 672‐686, 2006.
 38. Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C, Kimura H, Chow CW, Lefer DJ. Hydrogen sulfide attenuates myocardial ischemia reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci U S A 104: 15560‐15565, 2007.
 39. Esechie A, Kiss L, Olah G, Horváth EM, Hawkins H, Szabo C, Traber DL. Protective effect of hydrogen sulfide in a murine model of acute lung injury induced by combined burn and smoke inhalation. Clin Sci (Lond) 115: 91‐97, 2008.
 40. Fang L, Li H, Tang C, Geng B, Qi Y, Liu X. Hydrogen sulfide attenuates the pathogenesis of pulmonary fibrosis induced by bleomycin in rats. Can J Physiol Pharmacol 87: 531‐538, 2009.
 41. Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, Orlandi S, Zanardo R, Renga B, Di Sante M, Morelli A, Cirino G, Wallace JL. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti‐inflammatory nonsteroidal drugs. Gastroenterology 129: 1210‐1224, 2005.
 42. Freedman, B. Environmental Ecology: The Ecological Effects of Pollution, Disturbance, and other Stresses. New York: Academic Press, 1995, p. 11‐19.
 43. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83: 2038‐2047, 1991.
 44. Fu Z, Liu X, Geng B, Fang L, Tang C. Hydrogen sulfide protects rat lung from ischemia‐reperfusion injury. Life Sci 82: 1196‐1202, 2008.
 45. Fujita T, Toda K, Karimova A, Yan SF, Naka Y, Yet SF, Pinsky DJ. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nat Med 7: 598‐604, 2001.
 46. Furchgott RF, Jothianandan D. Endothelium‐dependent and independent vasodilation involving cyclic GMP: Relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels 28: 52‐61, 1991.
 47. Garat C, Jayr C, Eddahibi S, Laffon M, Meignan M, Adnot S. Effects of inhaled nitric oxide or inhibition of endogenous nitric oxide formation on hyperoxic lung injury. Am J Respir Crit Care Med 155: 1957‐1964, 1997.
 48. Garg UC, Hassid A. Nitric oxide‐generating vasodilators and 8‐bromo‐cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774‐1777, 1989.
 49. Ghosh S, Wilson MR, Choudhury S, Yamamoto H, Goddard ME, Falusi B, Marczin N, Takata M. Effects of inhaled carbon monoxide on acute lung injury in mice. Am J Physiol Lung Cell Mol Physiol 288: L1003‐L1009, 2005.
 50. Gorman D, Drewry A, Huang YL, Sames C. The clinical toxicology of carbon monoxide. Toxicology 187: 25‐38, 2003.
 51. Gow AJ. The biological chemistry of nitric oxide as it pertains to the extrapulmonary effects of inhaled nitric oxide. Proc Am Thorac Soc 3: 150‐152, 2006.
 52. Gow AJ, Stamler JS. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 391: 169‐173, 1998.
 53. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 353: 2683‐2695, 2005.
 54. Gross SS, Lane P. Physiological reactions of nitric oxide and hemoglobin: A radical rethink. Proc Natl Acad Sci U S A 96: 9967‐9969, 1999.
 55. Haggard HW, Charlton TJ. The fate of sulfides in the blood. J Biol Chem 49: 519‐529, 1921.
 56. Hartsfield CL. Cross talk between carbon monoxide and nitric oxide. Antioxid Redox Signal 4: 301‐307, 2002.
 57. Hartsfield CL, Alam J, Cook JL, Choi AM. Regulation of heme oxygenase‐1 gene expression in vascular smooth muscle cells by nitric oxide. Am J Physiol 273: L980‐L988, 2007.
 58. Hashiba T, Suzuki M, Nagashima Y, Suzuki S, Inoue S, Tsuburai T, Matsuse T, Ishigatubo Y. Adenovirus‐mediated transfer of heme oxygenase‐1 cDNA attenuates severe lung injury induced by the influenza virus in mice. Gene Ther 8: 1499‐1507, 2001.
 59. Hickey MJ, Sihota E, Amrani A, Santamaria P, Zbytnuik LD, Ng ES, Ho W, Sharkey KA, Kubes P. Inducible nitric oxide synthase (iNOS) in endotoxemia: Chimeric mice reveal different cellular sources in various tissues. FASEB J 16: 1141‐1143, 2002.
 60. Hillman ND, Meliones JN, Black DR, Craig DM, Cheifetz IM, Smith PK. In acute lung injury, inhaled nitric oxide improves ventilation‐perfusion matching, pulmonary vascular mechanics, and transpulmonary vascular efficiency. J Thorac Cardiovasc Surg 110: 593‐599, 1995.
 61. Hoetzel A, Dolinay T, Schmidt R, Choi AM, Ryter SW. Carbon monoxide in sepsis. Antioxid Redox Signal 9: 2013‐2026, 2007.
 62. Hoetzel A, Dolinay T, Vallbracht S, Zhang Y, Kim HP, Ifedigbo E, Alber S, Kaynar AM, Schmidt R, Ryter SW, Choi AM. Carbon monoxide protects against ventilator‐induced lung injury via PPAR‐gamma and inhibition of Egr‐1. Am J Respir Crit Care Med 177: 1223‐1232, 2008.
 63. Hoetzel A, Schmidt R, Vallbracht S, Goebel U, Dolinay T, Kim HP, Ifedigbo E, Ryter SW, Choi AM. Carbon monoxide prevents ventilator induced lung injury via caveolin‐1. Crit Care Med 37: 1708‐1715, 2009
 64. Horowitz S, Davis JM. Lung injury when development is interrupted by premature birth. In: McDonald JM, editor. Lung Growth and Development. New York: Marcel Dekker, 577‐610, 1997.
 65. Horvath I, MacNee W, Kelly FJ, Dekhuijzen PN, Phillips M, Doring G, Choi AM, Yamaya M, Bach FH, Willis D, Donnelly LE, Chung KF, Barnes PJ. “Haemoxygenase‐1 induction and exhaled markers of oxidative stress in lung diseases,” summary of the ERS Research Seminar in Budapest, Hungary, September, 1999. Eur Respir J 18: 420‐430, 2001.
 66. Howlett CE, Hutchison JS, Veinot JP, Chiu A, Merchant P, Fliss H. Inhaled nitric oxide protects against hyperoxia‐induced apoptosis in rat lungs. Am J Physiol 277: L596‐L605, 1999.
 67. Huang XL, Zhou XH, Wei P, Xian XH, Ling YL. The role of hydrogen sulfide in acute lung injury during endotoxic shock and its relationship with nitric oxide and carbon monoxide. Zhonghua Yi Xue Za Zhi 88: 2240‐2245, 2008.
 68. Ignarro LJ. Physiology and pathophysiology of nitric oxide. Kidney Int 55: S2‐S5, 1996.
 69. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium‐derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84: 9265‐9269, 1987.
 70. Ignarro LJ. Byrns RE, Buga GM, Wood KS. Endothelium‐derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 61: 866‐879, 1987.
 71. Ingbar DH. Mechanisms of repair and remodeling following acute lung injury. Clin Chest Med 21: 589‐616, 2000.
 72. Ingi T, Cheng J, Ronnett GV. Carbon monoxide: An endogenous modulator of the nitric oxide‐cyclic GMP signaling system. Neuron 16: 835‐842, 1996.
 73. Inoue S, Suzuki M, Nagashima Y, Suzuki S, Hashiba T, Tsuburai T, Ikehara K, Matsuse T, Ishigatsubo Y. Transfer of heme oxygenase 1 cDNA by a replication‐deficient adenovirus enhances interleukin 10 production from alveolar macrophages that attenuates lipopolysaccharide‐induced acute lung injury in mice. Hum Gene Ther 12: 967‐979, 2001.
 74. Ishii I, Akahoshi N, Yu XN, Kobayashi Y, Namekata K, Komaki G, Kimura H. Murine cystathionine γ‐lyase: Complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression. Biochem J 381: 113‐123, 2004.
 75. Jacobs BR, Brilli RJ, Ballard ET, Passerini DJ, Smith DJ. Aerosolized soluble nitric oxide donor improves oxygenation and pulmonary hypertension in acute lung injury. Am J Respir Crit Care Med 158: 1536‐1542, 1998.
 76. Jaffrey SR, Snyder SH. Nitric oxide: A neural messenger. Ann Rev Cell Dev Biol 11: 417‐440, 1995.
 77. Kaestle SM, Reich CA, Yin N, Habazettl H, Weimann J, Kuebler WM. Nitric oxide‐dependent inhibition of alveolar fluid clearance in hydrostatic lung edema. Am J Physiol Lung Cell Mol Physiol 293: L859‐L869, 2007.
 78. Kang JL, Park W, Pack IS, Lee HS, Kim MJ, Lim CM, Koh Y. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor‐kappa B and inflammation. J Appl Physiol 92: 795‐801, 2002.
 79. Kavanagh BP, Mouchawar A, Goldsmith J, Pearl RG. Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant‐induced acute lung injury. J Appl Physiol 76: 1324‐3329; 1994.
 80. Keyse SM, Tyrrell RM. Heme oxygenase is the major 32‐kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci U S A 86: 99‐103, 1989.
 81. Kharitonov SA, Barnes PJ. Exhaled biomarkers. Chest 130: 1541‐1546; 2006.
 82. Kim HP, Wang X, Nakao A, Kim SI, Murase N, Choi ME, Ryter SW, Choi AMK. Caveolin‐1 expression by means of p38β mitogen activated protein kinase mediates the antiproliferative effect of carbon monoxide. Proc Natl Acad Sci U S A 102: 11319‐11324, 2005.
 83. Kim HP, Ryter SW, Choi AMK. CO as a cellular signaling molecule. Ann Rev Pharm Tox 46: 411‐449, 2006.
 84. Kim HP, Wang X, Zhang J, Suh GY, Benjamin I, Ryter SW, Choi AM. Heat shock factor‐1 mediates the cytoprotective effect of carbon monoxide. J Immunol 175: 2622‐2629, 2005.
 85. Kim KM, Kim PK, Kwon YG, Bai SK, Nam WD, Kim YM. Regulation of apoptosis by nitrosative stress. J Biochem Mol Biol 35: 127‐133, 2002.
 86. Kim YM, Kim TH, Chung HT, Talanian RV, Yin XM, Billiar TR. Nitric oxide prevents tumor necrosis factor alpha‐induced rat hepatocyte apoptosis by the interruption of mitochondrial apoptotic signaling through S‐nitrosylation of caspase‐8. Hepatology 32: 770‐778, 2000.
 87. Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase‐3‐like activity via two distinct mechanisms, J Biol Chem 272: 31138‐31148, 1997.
 88. Kim‐Shapiro DB, Schechter AN, Gladwin MT. Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 26: 697‐705, 2006.
 89. Kimura H. Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26: 13‐19, 2002.
 90. Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J 18: 1165‐1167, 2004.
 91. Kitamura Y, Hashimoto S, Mizuta N, Kobayashi A, Kooguchi K, Fujiwara I, Nakajima H. Fas/FasL‐dependent apoptosis of alveolar cells after lipopolysaccharide‐induced lung injury in mice. Am J Respir Crit Care Med 163: 762‐769, 2001.
 92. Knight LD, Presnell SE. Death by sewer gas: Case report of a double fatality and review of the literature. Am J Forensic Med Pathol 26: 181‐185, 2005
 93. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 298: 249‐258, 1994.
 94. Kobayashi A, Hashimoto S, Kooguchi K, Kitamura Y, Onodera H, Urata Y, Ashihara T. Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis. Chest 113: 1632‐1639, 1998.
 95. Kohmoto J, Nakao A, Kaizu T, Tsung A, Ikeda A, Tomiyama K, Billiar TR, Choi AM, Murase N, McCurry KR. Low‐dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery 140: 179‐185; 2006.
 96. Kohmoto J, Nakao A, Sugimoto R, Wang Y, Zhan J, Ueda H, McCurry KR. Carbon monoxide‐saturated preservation solution protects lung grafts from ischemia‐reperfusion injury. J Thorac Cardiovasc Surg 136: 1067‐1075, 2008.
 97. Kolls J, Xie J, LeBlanc R, Malinski T, Nelson S, Summer W, Greenberg SS. Rapid induction of messenger RNA for nitric oxide synthase II in rat neutrophils in vivo by endotoxin and its suppression by prednisolone. Proc Soc Exp Biol Med 205: 220‐229, 1994.
 98. Koppenol WH, Traynham JG. Say NO to nitric oxide: Nomenclature for nitrogen and oxygen containing compounds. Methods Enzymol 268: 3‐7, 1996.
 99. Lee PJ, Alam J, Sylvester SL, Inamdar N, Otterbein L, Choi AM. Regulation of heme oxygenase‐1 expression in vivo and in vitro in hyperoxic lung injury. Am J Respir Cell Mol Biol 14: 556‐568, 1996.
 100. Lee PJ, Choi AMK. Pathways of cell signaling in hyperoxia. Free Radic Biol Med 35: 341‐350, 2003.
 101. Lee TS, Chau LY. Heme oxygenase‐1 mediates the anti‐inflammatory effect of interleukin‐10 in mice. Nat Med 8: 240‐246, 2002.
 102. Li L, Bhatia M, Moore PK. Hydrogen sulphide—A novel mediator of inflammation? Curr Opin Pharmacol 6: 125‐129, 2006.
 103. Li L, Bhatia M, Zhu YZ, Zhu YC, Ramnath RD, Wang ZJ, Anuar FB, Whiteman M, Salto‐Tellez M, Moore PK. Hydrogen sulfide is a novel mediator of lipopolysaccharide‐induced inflammation in the mouse. FASEB J 19: 1196‐1198, 2005.
 104. Li L, Moore PK. Putative biological roles of hydrogen sulfide in health and disease: A breath of not so fresh air? Trends Pharmacol Sci 29: 84‐90, 2008.
 105. Li T, Zhao B, Wang C, Wang H, Liu Z, Li W, Jin H, Tang C, Du J. Regulatory effects of hydrogen sulfide on IL‐6, IL‐8 and IL‐10 levels in the plasma and pulmonary tissue of rats with acute lung injury. Exp Biol Med (Maywood) 233: 1081‐1087, 2008.
 106. Liu Q, Gross SS. Binding sites of nitric oxide synthases. Methods Enzymol 268, 311‐324, 1996.
 107. Lopez A, Prior MG, Reiffenstein RJ, Goodwin LR. Peracute toxic effects of inhaled hydrogen sulfide and injected sodium hydrosulfide on the lungs of rats. Fundam Appl Toxicol 12: 367‐373, 1989.
 108. Łowicka E, Bełtowski J. Hydrogen sulfide (H2S)—The third gas of interest for pharmacologists. Pharmacol Rep 59: 4‐24, 2007.
 109. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: Results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med 25: 911‐919, 1999.
 110. Maclean KN, Kraus JP. Hydrogen sulfide production and metabolism in mammalian tissues. In: Wang R, editor. NO, CO, and H2S in Biology and Medicine. Totowa, NJ: Humana Press, 2004, p. 275‐292.
 111. Maines MD. The heme oxygenase system: A regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37: 517‐554, 1997.
 112. Maines MD, Trakshel GM, Kutty RK. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem 261: 411‐419, 1986.
 113. Mancardi D, Penna C, Merlino A, Del Soldato P, Wink DA, Pagliaro P. Physiological and pharmacological features of the novel gasotransmitter: Hydrogen sulfide. Biochim Biophys Acta 1787: 864‐872, 2009.
 114. Mayr FB, Spiel A, Leitner J, Marsik C, Germann P, Ullrich R, Wagner O, Jilma B. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med 171: 354‐360, 2006.
 115. Mazzola S, Forni M, Albertini M, Bacci ML, Zannoni A, Gentilini F, Lavitrano M, Bach FH, Otterbein LE, Clement MG. Carbon monoxide pretreatment prevents respiratory derangement and ameliorates hyperacute endotoxic shock in pigs. FASEB J 19: 2045‐2047, 2005.
 116. McElroy MC, Wiener‐Kronish JP, Miyazaki H, Sawa T, Modelska K, Dobbs LG, Pittet JF. Nitric oxide attenuates lung endothelial injury caused by sublethal hyperoxia in rats. Am J Physiol 272: L631‐L6318, 1997.
 117. McMahon TJ, Doctor A. Extrapulmonary effects of inhaled nitric oxide: Role of reversible S‐nitrosylation of erythrocytic hemoglobin. Proc Am Thorac Soc 3: 153‐160, 2006.
 118. Meade MO, Granton JT, Matte‐Martyn A, McRae K, Weaver B, Cripps P, Keshavjee SH; Toronto Lung Transplant Program. A randomized trial of inhaled nitric oxide to prevent ischemia‐reperfusion injury after lung transplantation. Am J Respir Crit Care Med 167: 1483‐1489, 2003.
 119. Mehta S. The effects of nitric oxide in acute lung injury. Vascul Pharmacol 43: 390‐403, 2005.
 120. Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, Elstad MR, Campbell EJ, Troyer BE, Whatley RE, Liou TG, Samuelson WM, Carveth HJ, Hinson DM, Morris SE, Davis BL, Day RW. Inhaled nitric oxide versus conventional therapy: Effect on oxygenation in ARDS. Am J Respir Crit Care Med 157: 1372‐1380, 1998.
 121. Mishra S, Fujita T, Lama VN, Nam D, Liao H, Okada M, Minamoto K, Yoshikawa Y, Harada H, Pinsky DJ. Carbon monoxide rescues ischemic lungs by interrupting MAPK‐driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci U S A 13: 5191‐5196, 2006.
 122. Moncada S. Nitric oxide and cell respiration: Physiology and pathology. Verh K Acad Geneeskd Belg 62: 171‐181, 2000.
 123. Moncada S, Higgs EA. Endogenous nitric oxide: Physiology, pathology and clinical relevance. Eur J Clin Invest 21: 361‐374, 1991.
 124. Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell‐derived carbon monoxide. J Clin Invest 96: 2676‐2682, 1995.
 125. Morita T, Mitsialis SA, Koike H, Liu Y, Kourembanas S. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem 272: 32804‐32809, 1997.
 126. Morse D, Choi AM. Inhaled CO in the treatment of acute lung injury. Am J Physiol Lung Cell Mol Physiol 294: L642‐L643, 2008.
 127. Morse D, Pischke SE, Zhou Z, Davis RJ, Flavell RA, Loop T, Otterbein SL, Otterbein LE, Choi AM. Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP‐1. J Biol Chem 278: 36993‐36998, 2003.
 128. Motterlini R, Mann BE, Foresti R. Therapeutic applications of carbon monoxide‐releasing molecules. Expert Opin Investig Drugs 14: 1305‐1318, 2005.
 129. Mudd SH, Finkelstein JD, Irreverre F, Laster L. Transsulfuration in mammals: Microassays and tissue distribution of three enzymes in the pathway. J Biol Chem 240: 4382‐4392, 1965.
 130. Mumby S, Upton RL, Chen Y, Stanford SJ, Quinlan GJ, Nicholson AG, Gutteridge JM, Lamb NJ, Evans TW. Lung heme oxygenase‐1 is elevated in acute respiratory distress syndrome. Crit Care Med 32: 1130‐1135, 2004.
 131. Murad F. The nitric oxide‐cyclic GMP signal transduction system for intracellular and intercellular communication. Recent Prog Horm Res 49: 239‐248, 1994.
 132. Nakahira K, Kim HP, Geng XH, Nakao A, Wang X, Murase N, Drain PF, Wang X, Sasidhar M, Nabel EG, Takahashi T, Lukacs NW, Ryter SW, Morita K, Choi AM. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS‐induced trafficking of TLRs to lipid rafts. J Exp Med 203: 2377‐2389, 2006.
 133. Nakao A, Toyokawa H, Abe M, Kiyomoto T, Nakahira K, Choi AM, Nalesnik MA, Thomson AW, Murase N. Heart allograft protection with low‐dose carbon monoxide inhalation: Effects on inflammatory mediators and alloreactive T‐cell responses. Transplantation 81: 220‐230, 2006.
 134. Nemzek JA, Fry C, Abatan O. Low‐dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration. Am J Physiol Lung Cell Mol Physiol 294: L644‐L653, 2008.
 135. Ochoa JB, Udekwu AO, Billiar TR, Curran RD, Cerra FB, Simmons RL, Peitzman AB. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 214: 621‐626, 1991.
 136. Oh GS, Pae HO, Lee BS, Kim BN, Kim JM, Kim HR, Jeon SB, Jeon WK, Chae HJ, Chung HT. Hydrogen sulfide inhibits nitric oxide production and nuclear factor‐kappaB via heme oxygenase‐1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Free Radic Biol Med 41: 106‐119, 2006.
 137. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti‐inflammatory effects involving the mitogen‐activated protein kinase pathway. Nat Med 6: 422‐428, 2000.
 138. Otterbein LE, Kolls JK, Mantell LL, Cook JL, Alam J, Choi AM. Exogenous administration of heme oxygenase‐1 by gene transfer provides protection against hyperoxic lung injury. J Clin Invest 103: 1047‐1054, 1999.
 139. Otterbein LE, Mantell LL, Choi AM. Carbon monoxide provides protection against hyperoxic lung injury. Am J Physiol 276: L688‐L694, 1999.
 140. Otterbein LE, Otterbein SL, Ifedigbo E, Liu F, Morse DE, Fearns C, Ulevitch RJ, Knicklebein R, Flavell RA, Choi AM. MKK3 mitogen activated protein kinase pathway mediates carbon monoxide‐induced protection against oxidant induced lung injury. Am J Pathol 163: 2555‐2563, 2003.
 141. Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, Tyagi S, Akamatsu Y, Flavell RJ, Billiar TR, Tzeng E, Bach FH, Choi AM, Soares MP. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 9: 183‐190, 2003.
 142. Peng X, Abdulnour RE, Sammani S, Ma SF, Han EJ, Hasan EJ, Tuder R, Garcia JG, Hassoun PM. Inducible nitric oxide synthase contributes to ventilator‐induced lung injury. Am J Respir Crit Care Med 172: 470‐479, 2005.
 143. Petrache I, Otterbein LE, Alam J, Wiegand GW, Choi AM. Heme oxygenase‐1 inhibits TNF‐alpha‐induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol 278: L312‐L319, 2000.
 144. Raveendran M, Wang J, Senthil D, Wang J, Utama B, Shen Y, Dudley D, Zhang Y, Wang XL. Endogenous nitric oxide activation protects against cigarette smoking induced apoptosis in endothelial cells. FEBS Lett 579: 733‐740, 2005.
 145. Rayhrer CS, Edmisten TD, Cephas GA, Tribble CG, Kron IL, Young JS. Nitric oxide potentiates acute lung injury in an isolated rabbit lung model. Ann Thorac Surg 65: 935‐938; 1998.
 146. Reiffenstein RJ, Hulbert WC, Roth SH. Toxicology of hydrogen sulfide. Annu Rev Pharmacol Toxicol 32: 109‐134, 1992.
 147. Ricciardolo FL, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 84: 731‐765, 2004.
 148. Rossaint R, Falke K, Lopez F, Slama K, Pison U, Zapol W. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328: 399‐405, 1993.
 149. Rudkowski JC, Barreiro E, Harfouche R, Goldberg P, Kishta O, D'Orleans‐Juste P, Labonte J, Lesur O, Hussain SN. Roles of iNOS and nNOS in sepsis‐induced pulmonary apoptosis. Am J Physiol Lung Cell Mol Physiol 286: L793‐L800, 2004.
 150. Ryter SW, Alam J, Choi AM. Heme oxygenase‐1/carbon monoxide: From basic science to therapeutic applications. Physiol Rev 86: 583‐650, 2006.
 151. Ryter SW, Choi AM. Therapeutic applications of carbon monoxide in lung disease. Curr Opin Pharmacol 6: 257‐262, 2006.
 152. Ryter SW, Kim HP, Nakahira K, Zuckerbraun BS, Morse D, Choi AM. Protective functions of heme oxygenase‐1 and carbon monoxide in the respiratory system. Antioxid Redox Signal 9: 2157‐2173, 2007.
 153. Ryter SW, Morse D, Choi AM. Carbon monoxide: To boldly go where NO has gone before. Sci STKE 230: RE6, 2004.
 154. Ryter SW, Otterbein LE. Carbon monoxide in biology and medicine. Bioessays 26: 270‐280, 2004.
 155. Ryter SW, Sethi JM. Exhaled carbon monoxide as a biomarker of inflammatory lung disease J Breath Res 1: 026004, 2007. doi:10.1088/1752‐7155/1/2/026004.
 156. Sarady JK, Otterbein SL, Liu F, Otterbein LE, Choi AM. Carbon monoxide modulates endotoxin‐induced production of granulocyte macrophage colony‐stimulating factor in macrophages. Am J Respir Cell Mol Biol 27: 739‐745, 2002.
 157. Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, Motterlini R. Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol 145: 800‐810, 2005.
 158. Shah NS, Nakayama DK, Jacob TD, Nishio I, Imai T, Billiar TR, Exler R, Yousem SA, Motoyama EK, Peitzman AB. Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome. Arch Surg 129: 158‐164, 1994.
 159. Shah NS, Nakayama DK, Jacob TD, Nishio I, Imai T, Billiar TR, Exler R, Yousem SA, Motoyama EK, Peitzman AB. Efficacy of inhaled nitric oxide in oleic acid‐induced acute lung injury. Crit Care Med 25: 153‐158, 1997.
 160. Shen YH, Wang XL, Wilcken DE. Nitric oxide induces and inhibits apoptosis through different pathways. FEBS Lett 433: 125‐131, 1998.
 161. Sjostrand T. Endogenous production of carbon monoxide in man under normal and pathophysiological conditions. Scand J Clin Lab Invest 1: 201‐214, 1949.
 162. Sjostrand T. Endogenous formation of carbon monoxide; the CO concentration in the inspired and expired air of hospital patients. Acta Physiol Scand 22: 137‐141, 1951.
 163. Sjostrand T. Formation of carbon monoxide in connexion with haemoglobin catabolism. Nature 168: 1118‐1119, 1951.
 164. Slutsky AS. Lung injury caused by mechanical ventilation. Chest 116: 9S‐15S, 1999.
 165. Smith RP. Toxic Responses of the blood. In: Klaasen CD, Amdur MO, Doull J, editors. Casarett and Doull's Toxicology, the Basic Science of Poisons (3rd ed). New York: Macmillan, 1986, p. 223‐244.
 166. Sodha NR, Clements RT, Feng J, Liu Y, Bianchi C, Horvath EM, Szabo C, Sellke FW. The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia‐reperfusion injury. Eur J Cardiothorac Surg 33: 906‐913, 2008.
 167. Sodha NR, Clements RT, Feng J, Liu Y, Bianchi C, Horvath EM, Szabo C, Stahl GL, Sellke FW. Hydrogen sulfide therapy attenuates the inflammatory response in a porcine model of myocardial ischemia/reperfusion injury. J Thorac Cardiovasc Surg 138: 977‐984, 2009.
 168. Song R, Kubo M, Morse D, Zhou Z, Zhang X, Dauber JH, Fabisiak J, Alber SM, Watkins SC, Zuckerbraun BS, Otterbein LE, Ning W, Oury TD, Lee PJ, McCurry KR, Choi AM. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti‐inflammatory and anti‐apoptotic effects. Am J Pathol 163: 231‐242, 2003.
 169. Song R, Mahidhara RS, Liu F, Ning W, Otterbein LE, Choi AM. Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen‐activated protein kinase pathway. Am J Respir Cell Mol Biol 27: 603‐610, 2002.
 170. Song R, Zhou Z, Kim PK, Shapiro RA, Liu F, Ferran C, Choi AM, Otterbein LE. Carbon monoxide promotes Fas/CD95‐induced apoptosis in Jurkat cells. J Biol Chem 279: 44327‐4434 2004.
 171. Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox‐activated forms. Science 258: 1898‐1902, 1992.
 172. Steinberg KP, Hudson LD. Acute lung injury and acute respiratory distress syndrome: The clinical syndrome. Clin Chest Med 21: 402‐417, 2000.
 173. Steinhorn H. Nitric oxide and beyond: New insights and therapies for pulmonary hypertension. J Perinatol 28: S67‐S71, 2008.
 174. Stone JR, Marletta MA. Soluble guanylate cyclase from bovine lung: Activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. Biochemistry 33: 5636‐5640, 1994.
 175. Szabó C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6: 917‐935, 2007.
 176. Taille C, El‐Benna J, Lanone S, Boczkowski J, Motterlini R. Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J Biol Chem 280: 25350‐25360, 2005.
 177. Takenaka K, Nishimura Y, Nishiuma T, Sakashita A, Yamashita T, Kobayashi K, Satouchi M, Ishida T, Kawashima S, Yokoyama M. Ventilator‐induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 290: L1078‐L1086, 2006.
 178. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A 61: 748‐755, 1968.
 179. Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem 244: 6388‐6394, 1969.
 180. Thom SR, Fisher D, Xu YA, Notarfrancesco K, Ischiropoulos H. Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide. Proc Natl Acad Sci U S A 97: 1305‐1310, 2000.
 181. Thomas DD, Ridnour LA, Isenberg JS, Flores‐Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA. The chemical biology of nitric oxide: Implications in cellular signaling. Free Radic Biol Med 45: 18‐31, 2008.
 182. Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G. Inhaled nitric oxide in acute respiratory distress syndrome: A pilot randomized controlled study. Am J Respir Crit Care Med 157: 1483‐1488, 1998.
 183. Troncy E, Francoeur M, Blaise G. Inhaled nitric oxide: Clinical applications, indications, and toxicology. Can J Anaesth 44: 973‐988, 1997.
 184. Tsubochi H, Suzuki S, Kubo H, Ueno T, Yoshimura T, Suzuki T, Sasano H, Kondo T. Early changes in alveolar fluid clearance by nitric oxide after endotoxin instillation in rats. Am J Respir Crit Care Med 167: 205‐210, 2003.
 185. Tsuburai T, Suzuki M, Nagashima Y, Suzuki S, Inoue S, Hasiba T, Ueda A, Ikehara K, Matsuse T, Ishigatsubo Y. Adenovirus‐mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin‐induced pulmonary fibrosis via a Fas‐Fas ligand‐independent pathway. Hum Gene Ther 13: 1945‐1960, 2002.
 186. Volpato GP, Searles R, Yu B, Scherrer‐Crosbie M, Bloch KD, Ichinose F, Zapol WM. Inhaled hydrogen sulfide: A rapidly reversible inhibitor of cardiac and metabolic function in the mouse. Anesthesiology 108: 659‐668, 2008.
 187. Von Burg R. Carbon monoxide. J Appl Toxicol 19: 379‐386, 1999.
 188. Vreman HJ, Wong RJ, Stevenson DK. Carbon monoxide in breath, blood, and other tissues. In: Penney DG, editor. Carbon Monoxide Poisoning (1st ed.). Boca Raton, FL: CRC Press LLC, 2000. p. 19‐60.
 189. Wang R. Resurgence of carbon monoxide: An endogenous gaseous vasorelaxing factor. Can J Physiol Pharmacol 76: 1‐15, 1998.
 190. Wang R. Two's company, three's a crowd: Can H2S be the third endogenous gaseous transmitter? FASEB J 16: 1792‐1798, 2002.
 191. Wang R. The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal 5: 493‐501, 2003.
 192. Wang X, Wang Y, Kim HP, Nakahira K, Ryter SW, Choi AM. Carbon monoxide protects against hyperoxia‐induced endothelial cell apoptosis by inhibiting reactive oxygen species formation. J Biol Chem 282: 1718‐1726, 2007.
 193. Wang XM, Kim HP, Nakahira K, Ryter SW, Choi AM. The heme oxygenase‐1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin‐1. J Immunol 182: 3809‐3818, 2009.
 194. Wang Y, Marsden PA. Nitric oxide synthases: Biochemical and molecular regulation. Curr Opin Nephrol Hypertens 4: 12‐22, 1995.
 195. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 342: 1334‐1349, 2000.
 196. Weinberger B, Laskin DL, Heck DE, Laskin JD. The toxicology of inhaled nitric oxide. Toxicol Sci 59: 5‐16, 2001.
 197. Whiteman M, Li L, Kostetski I, Chu SH, Siau JL, Bhatia M, Moore PK. Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 343: 303‐310, 2006.
 198. Wink DA, Mitchell JB. Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25: 434‐456, 1998.
 199. Wolff DG. The formation of carbon monoxide during peroxidation of microsomal lipids. Biochem Biophys Res Commun 73: 850‐857, 1976.
 200. Xia ZY, Wang XY, Chen X, Xia Z. Effect of NO donor sodium nitroprusside on lipopolysaccharide induced acute lung injury in rats. Injury 38: 53‐59, 2007.
 201. Yamagishi H, Yamashita C, Okada M. Preventive influence of inhaled nitric oxide on lung ischemia‐reperfusion injury. Surg Today 29: 897‐901, 1999.
 202. Yang G, Sun X, Wang R. Hydrogen sulfide‐induced apoptosis of human aorta smooth muscle cells via the activation of mitogen‐activated protein kinases and caspase‐3. FASEB J 18: 1782‐1784, 2004.
 203. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine gamma‐lyase. Science 322: 587‐590, 2008.
 204. Yee EL, Pitt BR, Billiar TR, Kim YM. Effect of nitric oxide on heme metabolism in pulmonary artery endothelial cells. Am J Physiol 271: L512‐L518, 1996.
 205. Yerebakan C, Ugurlucan M, Bayraktar S, Bethea BT, Conte JV. Effects of inhaled nitric oxide following lung transplantation. J Card Surg 24: 269‐274, 2009.
 206. Young JS, Rayhrer CS, Edmisten TD, Cephas GA, Tribble CG, Kron IL. Sodium nitroprusside mitigates oleic acid‐induced acute lung injury. Ann Thorac Surg 69: 224‐227, 2000
 207. Zakhary R, Poss KD, Jaffrey SR, Ferris CD, Tonegawa S, Synder SH. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide. Proc Natl Acad Sci U S A 94: 14848‐14853, 1997.
 208. Zhang H, Zhi L, Moochhala SM, Moore PK, Bhatia M. Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture‐induced sepsis in mice by upregulating the production of cytokines and chemokines via NF‐kappaB. Am J Physiol Lung Cell Mol Physiol 292: L960‐L971, 2007.
 209. Zhang H, Zhi L, Moochhala SM, Moore PK, Bhatia M. Endogenous hydrogen sulfide regulates leukocyte trafficking in cecal ligation and puncture‐induced sepsis. J Leukoc Biol 82: 894‐905, 2007.
 210. Zhang H, Zhi L, Moore PK, Bhatia M. Role of hydrogen sulfide in cecal ligation and puncture‐induced sepsis in the mouse. Am J Physiol Lung Cell Mol Physiol 290: L1193‐L1201, 2006.
 211. Zhang X, Shan P, Alam J, Davis RJ, Flavell RA, Lee PJ. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl‐2 family proteins via the p38alpha mitogen‐activated protein kinase pathway during ischemia‐reperfusion lung injury. J Biol Chem 278: 22061‐22070, 2003.
 212. Zhang X, Shan P, Alam J, Fu XY, Lee PJ. Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3‐kinase/Akt and p38 kinase‐dependent STAT3 pathway during anoxia‐reoxygenation injury. J Biol Chem 280: 8714‐8721, 2005.
 213. Zhang X, Shan P, Jiang G, Zhang SS, Otterbein LE, Fu XY, Lee PJ. Endothelial STAT3 is essential for the protective effects of HO‐1 in oxidant‐induced lung injury. FASEB J 20: 2156‐2158, 2006.
 214. Zhang X, Shan P, Otterbein LE, Alam J, Flavell RA, Davis RJ, Choi AM, Lee PJ. Carbon monoxide inhibition of apoptosis during ischemia‐reperfusion lung injury is dependent on the p38 mitogen‐activated protein kinase and involves caspase‐3. J Biol Chem 278: 1248‐1258, 2003.
 215. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J 20: 6008‐6016, 2001.
 216. Zhou Z, Song R, Fattman CL, Greenhill S, Alber S, Oury TD, Choi AM, Morse D. Carbon monoxide suppresses bleomycin‐induced lung fibrosis. Am J Pathol 166: 27‐37, 2005.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Gaseous Therapeutics in Acute Lung Injury
 

How to Cite

Stefan W. Ryter, Augustine M. K. Choi. Gaseous Therapeutics in Acute Lung Injury. Compr Physiol 2010, 1: 105-121. doi: 10.1002/cphy.c090003