Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Genetic and Environmental Influences on Gas Exchange

Reuben Howden, Steven R. Kleeberger

10.1002/cphy.c110060

Source: Volume 2, Issue 4, October 2012

Published online: October 2012

Full Article on Wiley Online Library



Abstract

Gas exchange is a critical process required for sufficient tissue perfusion. The environment, genetics, or a combination of the two can affect this process. Various strategies have evolved to overcome the specific gas exchange challenges in different environments and it is clear that some genes are pivotal to the development of gas exchanging organs (e.g. Bmp4). Lower partial pressure of oxygen (hypoxia), reducing the partial pressure gradient, makes gas exchange more challenging and therefore the height to which gas exchangers can travel above sea level is limited. However, some human populations (e.g. Tibetans) and other animals (e.g. Bar‐headed goose) have adapted well to profoundly hypoxic conditions, suggesting genetic factors are important. Gas exchange can also be affected by air pollution, including particulate matter and ozone among others, and exposure can lead to cardiopulmonary responses depending on individual susceptibility or preexisting disease, both of which have genetic and environmental components. Diseases that affect gas exchange include, but are not limited to, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and bronchopulmonary dysplasia. Moreover, different species successfully exchange gases in their specific environment, for example animals that fly or burrow. Under these conditions, common genetic mechanisms, and their interaction with environment, help to maintain, or are detrimental to, gas exchange. Published 2012. Compr Physiol 2:2595‐2614, 2012.

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.

A model of the interactions between Bmp4, Shh, and Fgf10 during lung bud morphogenesis. Reproduced/adapted, with permission, from Weaver et al. (2000) 263.
Figure 2. Figure 2.

Principal candidate gene products that affect gas exchange and their common role under multiple environmental conditions. Blue arrows indicate genes that are involved in improving or maintaining lung gas exchange. Red arrows indicate genes whose actions are detrimental to gas exchange.


Figure 1.

A model of the interactions between Bmp4, Shh, and Fgf10 during lung bud morphogenesis. Reproduced/adapted, with permission, from Weaver et al. (2000) 263.



Figure 2.

Principal candidate gene products that affect gas exchange and their common role under multiple environmental conditions. Blue arrows indicate genes that are involved in improving or maintaining lung gas exchange. Red arrows indicate genes whose actions are detrimental to gas exchange.

References
 1. Alexeeff SE, Litonjua AA, Wright RO, Baccarelli A, Suh H, Sparrow D, Vokonas PS, Schwartz J. Ozone exposure, antioxidant genes, and lung function in an elderly cohort: VA normative aging study. Occup Environ Med 65: 736‐742, 2008.
 2. Anundi I, Lahteenmaki T, Rundgren M, Moldeus P, Lindros KO. Zonation of acetaminophen metabolism and cytochrome P450 2E1‐mediated toxicity studied in isolated periportal and perivenous hepatocytes. Biochem Pharmacol 45: 1251‐1259, 1993.
 3. ARDSnetwork. 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 342: 1301‐1308, 2000.
 4. Ashenden MJ, Gore CJ, Dobson GP, Hahn AG. “Live high, train low” does not change the total haemoglobin mass of male endurance athletes sleeping at a simulated altitude of 3000 m for 23 nights. Eur J Appl Physiol Occup Physiol 80: 479‐484, 1999.
 5. Ashenden MJ, Gore CJ, Martin DT, Dobson GP, Hahn AG. Effects of a 12‐day “live high, train low” camp on reticulocyte production and haemoglobin mass in elite female road cyclists. Eur J Appl Physiol Occup Physiol 80: 472‐478, 1999.
 6. Austin ED, Loyd JE, Phillips JA, 3rd. Genetics of pulmonary arterial hypertension. Semin Respir Crit Care Med 30: 386‐398, 2009.
 7. Avivi A, Resnick MB, Nevo E, Joel A, Levy AP. Adaptive hypoxic tolerance in the subterranean mole rat Spalax ehrenbergi: The role of vascular endothelial growth factor. FEBS Lett 452: 133‐140, 1999.
 8. Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 179: 572‐578, 2009.
 9. Bai J, Meng Z. Effects of sulfur dioxide on apoptosis‐related gene expressions in lungs from rats. Regul Toxicol Pharmacol 43: 272‐279, 2005.
 10. Bakke PS, Zhu G, Gulsvik A, Kong X, Agusti AG, Calverley PM, Donner CF, Levy RD, Make BJ, Pare PD, Rennard SI, Vestbo J, Wouters EF, Anderson W, Lomas DA, Silverman EK, Pillai SG. Candidate genes for chronic obstructive pulmonary disease in two large data sets. Eur Respir J. 37: 255‐263, 2011.
 11. Balla G, Vercellotti GM, Muller‐Eberhard U, Eaton J, Jacob HS. Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species. Lab Invest 64: 648‐655, 1991.
 12. Ballester E, Reyes A, Roca J, Guitart R, Wagner PD, Rodriguez‐Roisin R. Ventilation‐perfusion mismatching in acute severe asthma: Effects of salbutamol and 100% oxygen. Thorax 44: 258‐267, 1989.
 13. Bancalari E, del Moral T. Bronchopulmonary dysplasia and surfactant. Biol Neonate 80(Suppl 1): 7‐13, 2001.
 14. Barnes PJ. Against the Dutch hypothesis: Asthma and chronic obstructive pulmonary disease are distinct diseases. Am J Respir Crit Care Med 174: 240‐243; discussion 243‐244, 2006a.
 15. Barnes PJ. Rebuttal by Dr Barnes. Am J Respir Crit Care Med 174: 244, 2006b.
 16. Bauer AK, Malkinson AM, Kleeberger SR. Susceptibility to neoplastic and non‐neoplastic pulmonary diseases in mice: Genetic similarities. Am J Physiol Lung Cell Mol Physiol 287: L685‐703, 2004.
 17. Bauer I, Pannen BH. Bench‐to‐bedside review: Carbon monoxide‐from mitochondrial poisoning to therapeutic use. Crit Care 13: 220, 2009.
 18. Beall CM. Two routes to functional adaptation: Tibetan and Andean high‐altitude natives. Proc Natl Acad Sci U S A 104(Suppl 1): 8655‐8660, 2007.
 19. Bell ML, Samet JM, Dominici F. Time‐series studies of particulate matter. Annu Rev Public Health 25: 247‐280, 2004.
 20. Bellusci S, Furuta Y, Rush MG, Henderson R, Winnier G, Hogan BL. Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development 124: 53‐63, 1997.
 21. Bergamaschi E, De Palma G, Mozzoni P, Vanni S, Vettori MV, Broeckaert F, Bernard A, Mutti A. Polymorphism of quinone‐metabolizing enzymes and susceptibility to ozone‐induced acute effects. Am J Respir Crit Care Med 163: 1426‐1431, 2001.
 22. Bhandari A, Panitch HB. Pulmonary outcomes in bronchopulmonary dysplasia. Semin Perinatol 30: 219‐226, 2006.
 23. Bhandari V, Bizzarro MJ, Shetty A, Zhong X, Page GP, Zhang H, Ment LR, Gruen JR. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 117: 1901‐1906, 2006.
 24. Bhandari V, Gruen JR. The genetics of bronchopulmonary dysplasia. Semin Perinatol 30: 185‐191, 2006.
 25. Bilolikar H, Nam AR, Rosenthal M, Davies JC, Henderson DC, Balfour‐Lynn IM. Tumour necrosis factor gene polymorphisms and childhood wheezing. Eur Respir J 26: 637‐646, 2005.
 26. Blessing WW, Seaman B. 5‐hydroxytryptamine(2A) receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats. Neuroscience 117: 939‐948, 2003.
 27. Boezen HM, Vonk JM, van der Zee SC, Gerritsen J, Hoek G, Brunekreef B, Schouten JP, Postma DS. Susceptibility to air pollution in elderly males and females. Eur Respir J 25: 1018‐1024, 2005.
 28. Breton CV, Salam MT, Vora H, Gauderman WJ, Gilliland FD. Genetic variation in the glutathione synthesis pathway, air pollution, and children's lung function growth. Am J Respir Crit Care Med 183: 243‐248, 2011.
 29. Brogger J, Steen VM, Eiken HG, Gulsvik A, Bakke P. Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1. Eur Respir J 27: 682‐688, 2006.
 30. Brown KR, England KM, Goss KL, Snyder JM, Acarregui MJ. VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281: L1001‐L1010, 2001.
 31. Brunekreef B, Holgate ST. Air pollution and health. Lancet 360: 1233‐1242, 2002.
 32. Bryant CE, Spring DR, Gangloff M, Gay NJ. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol 8: 8‐14, 2010.
 33. Carroll SB. Endless forms: The evolution of gene regulation and morphological diversity. Cell 101: 577‐580, 2000.
 34. Castro‐Giner F, Kunzli N, Jacquemin B, Forsberg B, de Cid R, Sunyer J, Jarvis D, Briggs D, Vienneau D, Norback D, Gonzalez JR, Guerra S, Janson C, Anto JM, Wjst M, Heinrich J, Estivill X, Kogevinas M. Traffic‐related air pollution, oxidative stress genes, and asthma (ECHRS). Environ Health Perspect 117: 1919‐1924, 2009.
 35. Cerny L, Torday JS, Rehan VK. Prevention and treatment of bronchopulmonary dysplasia: Contemporary status and future outlook. Lung 186: 75‐89, 2008.
 36. Chahine T, Baccarelli A, Litonjua A, Wright RO, Suh H, Gold DR, Sparrow D, Vokonas P, Schwartz J. Particulate air pollution, oxidative stress genes, and heart rate variability in an elderly cohort. Environ Health Perspect 115: 1617‐1622, 2007.
 37. Chang H, Shyu KG, Wang BW, Kuan P. Regulation of hypoxia‐inducible factor‐1alpha by cyclical mechanical stretch in rat vascular smooth muscle cells. Clin Sci (Lond) 105: 447‐456, 2003.
 38. Chen C, Arjomandi M, Tager IB, Holland N, Balmes JR. Effects of antioxidant enzyme polymorphisms on ozone‐induced lung function changes. Eur Respir J 30: 677‐683, 2007.
 39. Chen Y, Horne SL, Rennie DC, Dosman JA. Segregation analysis of two lung function indices in a random sample of young families: The Humboldt Family Study. Genet Epidemiol 13: 35‐47, 1996.
 40. Cho HY, Jedlicka AE, Reddy SP, Kensler TW, Yamamoto M, Zhang LY, Kleeberger SR. Role of NRF2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 26: 175‐182., 2002.
 41. Cho HY, Jedlicka AE, Reddy SP, Zhang LY, Kensler TW, Kleeberger SR. Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am J Respir Cell Mol Biol 26: 42‐51., 2002.
 42. Cho HY, Kleeberger SR. Genetic mechanisms of susceptibility to oxidative lung injury in mice. Free Radic Biol Med 42: 433‐445, 2007.
 43. Cho HY, Morgan DL, Bauer AK, Kleeberger SR. Signal transduction pathways of tumor necrosis factor‐mediated lung injury induced by ozone in mice. Am J Respir Crit Care Med 175: 829‐839, 2007.
 44. Cho HY, Reddy SP, Debiase A, Yamamoto M, Kleeberger SR. Gene expression profiling of NRF2‐mediated protection against oxidative injury. Free Radic Biol Med 38: 325‐343, 2005.
 45. Cho HY, Zhang LY, Kleeberger SR. Ozone‐induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor‐alpha receptors. Am J Physiol Lung Cell Mol Physiol 280: L537‐546., 2001.
 46. Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 8: 76‐87, 2006.
 47. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F. Toll‐like receptor‐4 mediates lipopolysaccharide‐induced signal transduction. J Biol Chem 274: 10689‐10692, 1999.
 48. Christou H, Yoshida A, Arthur V, Morita T, Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia‐induced pulmonary hypertension. Am J Respir Cell Mol Biol 18: 768‐776, 1998.
 49. Ciencewicki J, Trivedi S, Kleeberger SR. Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol 122: 456‐468; quiz 469‐470, 2008.
 50. Cobb N, Etzel RA. Unintentional carbon monoxide‐related deaths in the United States, 1979 through 1988. Jama 266: 659‐663, 1991.
 51. Cote TR, Stroup DF, Dwyer DM, Horan JM, Peterson DE. Chronic obstructive pulmonary disease mortality. A role for altitude. Chest 103: 1194‐1197, 1993.
 52. Coultas DB, Hanis CL, Howard CA, Skipper BJ, Samet JM. Heritability of ventilatory function in smoking and nonsmoking New Mexico Hispanics. Am Rev Respir Dis 144: 770‐775, 1991.
 53. Curjuric I, Imboden M, Schindler C, Downs SH, Hersberger M, Liu SL, Matyas G, Russi EW, Schwartz J, Thun GA, Postma DS, Rochat T, Probst‐Hensch NM. HMOX1 and GST variants modify attenuation of FEF25‐75% decline due to PM10 reduction. Eur Respir J 35: 505‐514, 2010.
 54. D'Amato G, Liccardi G, D'Amato M, Cazzola M. Outdoor air pollution, climatic changes and allergic bronchial asthma. Eur Respir J 20: 763‐776, 2002.
 55. Daniels CB, Orgeig S. Pulmonary surfactant: The key to the evolution of air breathing. News Physiol Sci 18: 151‐157, 2003.
 56. Dantzker DR, Bower JS. Pulmonary vascular tone improves VA/Q matching in obliterative pulmonary hypertension. J Appl Physiol 51: 607‐613, 1981.
 57. Deakins KM. Bronchopulmonary dysplasia. Respir Care 54: 1252‐1262, 2009.
 58. De Caestecker M, Meyrick B. Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Respir Res 2: 193‐197, 2001.
 59. Demayo F, Minoo P, Plopper CG, Schuger L, Shannon J, Torday JS. Mesenchymal‐epithelial interactions in lung development and repair: Are modeling and remodeling the same process? Am J Physiol Lung Cell Mol Physiol 283: L510‐L517, 2002.
 60. DeMeo DL, Celedon JC, Lange C, Reilly JJ, Chapman HA, Sylvia JS, Speizer FE, Weiss ST, Silverman EK. Genome‐wide linkage of forced mid‐expiratory flow in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170: 1294‐1301, 2004.
 61. Desai TJ, Cardoso WV. Growth factors in lung development and disease: Friends or foe? Respir Res 3: 2, 2002.
 62. Dockery DW, Pope CA, 3rd, Xu X, Spengler JD, Ware JH, Fay ME, Ferris BG, Jr., Speizer FE. An association between air pollution and mortality in six U.S. cities. N Engl J Med 329: 1753‐1759, 1993.
 63. Dockery DW, Schwartz J, Spengler JD. Air pollution and daily mortality: Associations with particulates and acid aerosols. Environ Res 59: 362‐373, 1992.
 64. Dominici F, Peng RD, Bell ML, Pham L, McDermott A, Zeger SL, Samet JM. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. Jama 295: 1127‐1134, 2006.
 65. Douglas NJ, Calverley PM, Leggett RJ, Brash HM, Flenley DC, Brezinova V. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1: 1‐4, 1979.
 66. Downs SH, Schindler C, Liu LJ, Keidel D, Bayer‐Oglesby L, Brutsche MH, Gerbase MW, Keller R, Kunzli N, Leuenberger P, Probst‐Hensch NM, Tschopp JM, Zellweger JP, Rochat T, Schwartz J, Ackermann‐Liebrich U. Reduced exposure to PM10 and attenuated age‐related decline in lung function. N Engl J Med 357: 2338‐2347, 2007.
 67. Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 11: 686‐705, 1951.
 68. Dreyfuss D, Saumon G. Ventilator‐induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 157: 294‐323, 1998.
 69. Durr RA, Dubaybo BA, Thet LA. Repair of chronic hyperoxic lung injury: Changes in lung ultrastructure and matrix. Exp Mol Pathol 47: 219‐240, 1987.
 70. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5‐hydroxytryptamine transporter gene. J Clin Invest 105: 1555‐1562, 2000.
 71. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108: 1141‐1150, 2001.
 72. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, Wrage LA, Poole K. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116: 1353‐1360, 2005.
 73. Elias JA, Kang MJ, Crothers K, Homer R, Lee CG. State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: Insights from transgenic mice. Proc Am Thorac Soc 3: 494‐498, 2006.
 74. Fagenholz PJ, Gutman JA, Murray AF, Noble VE, Wu A, Zeimer G, Harris NS. Arterial thrombosis at high altitude resulting in loss of limb. High Alt Med Biol 8: 340‐347, 2007.
 75. Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia‐induced erythropoietin production. Blood 79: 1987‐1994, 1992.
 76. Fishman AP, Mc CJ, Himmelstein A, Cournand A. Effects of acute anoxia on the circulation and respiration in patients with chronic pulmonary disease studied during the steady state. J Clin Invest 31: 770‐781, 1952.
 77. Fletcher CM. The prevention of chronic bronchitis [proceedings]. Br J Dis Chest 73: 48‐50, 1979.
 78. Floros J, Hoover RR. Genetics of the hydrophilic surfactant proteins A and D. Biochim Biophys Acta 1408: 312‐322, 1998.
 79. Foster DJ, Moe OW, Hsia CC. Upregulation of erythropoietin receptor during postnatal and postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 287: L1107‐1115, 2004.
 80. Frank NR, Yoder RE, Brain JD, Yokoyama E. SO2 (35S labeled) absorption by the nose and mouth under conditions of varying concentration and flow. Arch Environ Health 18: 315‐322, 1969.
 81. Friedmann B, Frese F, Menold E, Bartsch P. Individual variation in the reduction of heart rate and performance at lactate thresholds in acute normobaric hypoxia. Int J Sports Med 26: 531‐536, 2005.
 82. 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.
 83. Givelber RJ, Couropmitree NN, Gottlieb DJ, Evans JC, Levy D, Myers RH, O'Connor GT. Segregation analysis of pulmonary function among families in the Framingham Study. Am J Respir Crit Care Med 157: 1445‐1451, 1998.
 84. Golden JA, Nadel JA, Boushey HA. Bronchial hyperirritability in healthy subjects after exposure to ozone. Am Rev Respir Dis 118: 287‐294, 1978.
 85. Gore CJ, Rodriguez FA, Truijens MJ, Townsend NE, Stray‐Gundersen J, Levine BD. Increased serum erythropoietin but not red cell production after 4 wk of intermittent hypobaric hypoxia (4,000‐5,500 m). J Appl Physiol 101: 1386‐1393, 2006.
 86. Goss AM, Tian Y, Tsukiyama T, Cohen ED, Zhou D, Lu MM, Yamaguchi TP, Morrisey EE. Wnt2/2b and beta‐catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev Cell 17: 290‐298, 2009.
 87. Gracey AY, Cossins AR. Application of microarray technology in environmental and comparative physiology. Annu Rev Physiol 65: 231‐259, 2003.
 88. Grigg J. Particulate matter exposure in children: Relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 6: 564‐569, 2009.
 89. Ha EH, Hong YC, Lee BE, Woo BH, Schwartz J, Christiani DC. Is air pollution a risk factor for low birth weight in Seoul? Epidemiology 12: 643‐648, 2001.
 90. Ha EH, Lee JT, Kim H, Hong YC, Lee BE, Park HS, Christiani DC. Infant susceptibility of mortality to air pollution in Seoul, South Korea. Pediatrics 111: 284‐290, 2003.
 91. Haataja R, Ramet M, Marttila R, Hallman M. Surfactant proteins A and B as interactive genetic determinants of neonatal respiratory distress syndrome. Hum Mol Genet 9: 2751‐2760, 2000.
 92. Hampel R, Schneider A, Bruske I, Zareba W, Cyrys J, Ruckerl R, Breitner S, Korb H, Sunyer J, Wichmann HE, Peters A. Altered cardiac repolarization in association with air pollution and air temperature among myocardial infarction survivors. Environ Health Perspect 118: 1755‐1761, 2010.
 93. Hampson NB, Weaver LK. Carbon monoxide poisoning: A new incidence for an old disease. Undersea Hyperb Med 34: 163‐168, 2007.
 94. Han RN, Liu J, Tanswell AK, Post M. Expression of basic fibroblast growth factor and receptor: Immunolocalization studies in developing rat fetal lung. Pediatr Res 31: 435‐440, 1992.
 95. Harding R, Pinkerton KE, Plopper CG. The Lung: Development, Aging, and Environment. San Diego, CA: Acadmeic Press, 2003.
 96. Hattis D, Russ A, Goble R, Banati P, Chu M. Human interindividual variability in susceptibility to airborne particles. Risk Anal 21: 585‐599, 2001.
 97. Hayashi Y, Kohno T, Ohwada H. Morphological effects of nitrogen dioxide on the rat lung. Environ Health Perspect 73: 135‐145, 1987.
 98. Hazucha MJ, Ginsberg JF, McDonnell WF, Haak ED, Jr., Pimmel RL, Salaam SA, House DE, Bromberg PA. Effects of 0.1 ppm nitrogen dioxide on airways of normal and asthmatic subjects. J Appl Physiol 54: 730‐739, 1983.
 99. Hellwig‐Burgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W. Interleukin‐1beta and tumor necrosis factor‐alpha stimulate DNA binding of hypoxia‐inducible factor‐1. Blood 94: 1561‐1567, 1999.
 100. Hersh CP, Demeo DL, Lange C, Litonjua AA, Reilly JJ, Kwiatkowski D, Laird N, Sylvia JS, Sparrow D, Speizer FE, Weiss ST, Silverman EK. Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 33: 71‐78, 2005.
 101. Hollingsworth JW, Kleeberger SR, Foster WM. Ozone and pulmonary innate immunity. Proc Am Thorac Soc 4: 240‐246, 2007.
 102. Holroyd KJ, Eleff SM, Zhang LY, Jakab GJ, Kleeberger SR. Genetic modeling of susceptibility to nitrogen dioxide‐induced lung injury in mice. Am J Physiol 273: L595‐602, 1997.
 103. Hoover RR, Floros J. Organization of the human SP‐A and SP‐D loci at 10q22‐q23. Physical and radiation hybrid mapping reveal gene order and orientation. Am J Respir Cell Mol Biol 18: 353‐362, 1998.
 104. Huang SL, Su CH, Chang SC. Tumor necrosis factor‐alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 156: 1436‐1439, 1997.
 105. Hudak BB, Zhang LY, Kleeberger SR. Inter‐strain variation in susceptibility to hyperoxic injury of murine airways. Pharmacogenetics 3: 135‐143, 1993.
 106. Imboden M, Schwartz J, Schindler C, Curjuric I, Berger W, Liu SL, Russi EW, Ackermann‐Liebrich U, Rochat T, Probst‐Hensch NM. Decreased PM10 exposure attenuates age‐related lung function decline: Genetic variants in p53, p21, and CCND1 modify this effect. Environ Health Perspect 117: 1420‐1427, 2009.
 107. Islam T, Berhane K, McConnell R, Gauderman WJ, Avol E, Peters JM, Gilliland FD. Glutathione‐S‐transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children. Thorax 64: 197‐202, 2009.
 108. Islam T, McConnell R, Gauderman WJ, Avol E, Peters JM, Gilliland FD. Ozone, oxidant defense genes, and risk of asthma during adolescence. Am J Respir Crit Care Med 177: 388‐395, 2008.
 109. Jansen KL, Larson TV, Koenig JQ, Mar TF, Fields C, Stewart J, Lippmann M. Associations between health effects and particulate matter and black carbon in subjects with respiratory disease. Environ Health Perspect 113: 1741‐1746, 2005.
 110. Janssen YM, Van Houten B, Borm PJ, Mossman BT. Cell and tissue responses to oxidative damage. Lab Invest 69: 261‐274, 1993.
 111. Jelkmann W, Metzen E. Erythropoietin in the control of red cell production. Ann Anat 178: 391‐403, 1996.
 112. Jelkmann W, Pagel H, Wolff M, Fandrey J. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci 50: 301‐308, 1992.
 113. Jerrett M, Burnett RT, Brook J, Kanaroglou P, Giovis C, Finkelstein N, Hutchison B. Do socioeconomic characteristics modify the short term association between air pollution and mortality? Evidence from a zonal time series in Hamilton, Canada. J Epidemiol Community Health 58: 31‐40, 2004.
 114. Jerrett M, Burnett RT, Pope CA, Ito K, Thurston G, Krewski D, Shi Y, Calle E, Thun M. Long‐Term Ozone Exposure and Mortality. N Engl J Med 360: 1085‐1095, 2009.
 115. Jiang L, He B, Zhao MW, Ning LD, Li XY, Yao WZ. Association of gene polymorphisms of tumour necrosis factor‐alpha and interleukin‐13 with chronic obstructive pulmonary disease in Han nationality in Beijing. Chin Med J (Engl) 118: 541‐547, 2005.
 116. Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL. An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev 17: 2362‐2367, 2003.
 117. Johansson J, Curstedt T, Robertson B. The proteins of the surfactant system. Eur Respir J 7: 372‐391, 1994.
 118. Joost O, Wilk JB, Cupples LA, Harmon M, Shearman AM, Baldwin CT, O'Connor GT, Myers RH, Gottlieb DJ. Genetic loci influencing lung function: A genome‐wide scan in the Framingham Study. Am J Respir Crit Care Med 165: 795‐799, 2002.
 119. Jorres R, Magnussen H. Effect of 0.25 ppm nitrogen dioxide on the airway response to methacholine in asymptomatic asthmatic patients. Lung 169: 77‐85, 1991.
 120. Kabir Z, Connolly GN, Koh HK, Clancy L. Chronic obstructive pulmonary disease hospitalization rates in Massachusetts: A trend analysis. Qjm 103: 163‐168, 2010.
 121. Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste JC, Gehring U, Koppelman GH. Toll‐like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic‐related air pollution on childhood asthma. Thorax 65: 690‐697, 2010.
 122. Kim CS, Kang TC. Comparative measurement of lung deposition of inhaled fine particles in normal subjects and patients with obstructive airway disease. Am J Respir Crit Care Med 155: 899‐905, 1997.
 123. Kim HP, Ryter SW, Choi AM. CO as a cellular signaling molecule. Annu Rev Pharmacol Toxicol 46: 411‐449, 2006.
 124. Kleeberger SR, Bassett DJ, Jakab GJ, Levitt RC. A genetic model for evaluation of susceptibility to ozone‐induced inflammation. Am J Physiol 258: L313‐320., 1990.
 125. Kleeberger SR, Hudak BB. Acute ozone‐induced change in airway permeability: Role of infiltrating leukocytes. J Appl Physiol 72: 670‐676, 1992.
 126. Kleeberger SR, Levitt RC, Zhang LY, Longphre M, Harkema J, Jedlicka A, Eleff SM, DiSilvestre D, Holroyd KJ. Linkage analysis of susceptibility to ozone‐induced lung inflammation in inbred mice. Nat Genet 17: 475‐478, 1997.
 127. Kleeberger SR, Ohtsuka Y. Gene‐particulate matter‐health interactions. Toxicol Appl Pharmacol 207: 276‐281, 2005.
 128. Kleeberger SR, Peden D. Gene‐environment interactions in asthma and other respiratory diseases. Annu Rev Med 56: 383‐400, 2005.
 129. Kleeberger SR, Reddy SP, Zhang LY, Cho HY, Jedlicka AE. Toll‐like receptor 4 mediates ozone‐induced murine lung hyperpermeability via inducible nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 280: L326‐333., 2001.
 130. Kleinschmidt T, Nevo E, Braunitzer G. The primary structure of the hemoglobin of the mole rat (Spalax ehrenbergi, rodentia, chromosome species 60). Hoppe Seylers Z Physiol Chem 365: 531‐537, 1984.
 131. Knorst MM, Kienast K, Muller‐Quernheim J, Ferlinz R. Effect of sulfur dioxide on cytokine production of human alveolar macrophages in vitro. Arch Environ Health 51: 150‐156, 1996.
 132. Koenig JQ, Mar TF, Allen RW, Jansen K, Lumley T, Sullivan JH, Trenga CA, Larson T, Liu LJ. Pulmonary effects of indoor‐ and outdoor‐generated particles in children with asthma. Environ Health Perspect 113: 499‐503, 2005.
 133. Kraft M. Asthma and chronic obstructive pulmonary disease exhibit common origins in any country! Am J Respir Crit Care Med 174: 238‐240; discussion 243‐234, 2006a.
 134. Kraft M. Rebuttal by Dr. Kraft. Am J Respir Crit Care Med 174: 243‐244, 2006b.
 135. Kreukniet J, Orie NG. Chronic bronchitis, bronchial asthma, a host factor in patients with pulmonary tuberculosis. Allerg Asthma (Leipz) 7: 220‐230, 1961.
 136. Kristof AS, Goldberg P, Laubach V, Hussain SN. Role of inducible nitric oxide synthase in endotoxin‐induced acute lung injury. Am J Respir Crit Care Med 158: 1883‐1889, 1998.
 137. Kucukaycan M, Van Krugten M, Pennings HJ, Huizinga TW, Buurman WA, Dentener MA, Wouters EF. Tumor necrosis factor‐alpha +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res 3: 29, 2002.
 138. Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem J 420: 1‐16, 2009.
 139. Laden F, Neas LM, Dockery DW, Schwartz J. Association of fine particulate matter from different sources with daily mortality in six U.S. cities. Environ Health Perspect 108: 941‐947, 2000.
 140. Laniado‐Laborin R. Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21 century. Int J Environ Res Public Health 6: 209‐224, 2009.
 141. Laskin DL, Heck DE, Laskin JD. Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity. Toxicol Lett 102‐103: 289‐293, 1998.
 142. Lavoie PM, Pham C, Jang KL. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics 122: 479‐485, 2008.
 143. Lee YL, Lin YC, Lee YC, Wang JY, Hsiue TR, Guo YL. Glutathione S‐transferase P1 gene polymorphism and air pollution as interactive risk factors for childhood asthma. Clin Exp Allergy 34: 1707‐1713, 2004.
 144. Levine BD, Stray‐Gundersen J. Point: Positive effects of intermittent hypoxia (live high:train low) on exercise performance are mediated primarily by augmented red cell volume. J Appl Physiol 99: 2053‐2055, 2005.
 145. Levy JI, Hammitt JK, Spengler JD. Estimating the mortality impacts of particulate matter: What can be learned from between‐study variability? Environ Health Perspect 108: 109‐117, 2000.
 146. Lewis BS, Flugelman MY, Weisz A, Keren‐Tal I, Schaper W. Angiogenesis by gene therapy: A new horizon for myocardial revascularization? Cardiovasc Res 35: 490‐497, 1997.
 147. Leynaert B, Bousquet J, Henry C, Liard R, Neukirch F. Is bronchial hyperresponsiveness more frequent in women than in men? A population‐based study. Am J Respir Crit Care Med 156: 1413‐1420, 1997.
 148. Li XY, Gilmour PS, Donaldson K, MacNee W. Free radical activity and pro‐inflammatory effects of particulate air pollution (PM10) in vivo and in vitro. Thorax 51: 1216‐1222, 1996.
 149. Li YF, Gauderman WJ, Avol E, Dubeau L, Gilliland FD. Associations of tumor necrosis factor G‐308A with childhood asthma and wheezing. Am J Respir Crit Care Med 173: 970‐976, 2006.
 150. Linn WS, Shamoo DA, Avol EL, Whynot JD, Anderson KR, Venet TG, Hackney JD. Dose‐response study of asthmatic volunteers exposed to nitrogen dioxide during intermittent exercise. Arch Environ Health 41: 292‐296, 1986.
 151. Liu W, Selever J, Wang D, Lu MF, Moses KA, Schwartz RJ, Martin JF. Bmp4 signaling is required for outflow‐tract septation and branchial‐arch artery remodeling. Proc Natl Acad Sci U S A 101: 4489‐4494, 2004.
 152. Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: A 25 year follow up study of the general population. Thorax 61: 935‐939, 2006.
 153. Loyd JE, Phillips JA. Heritable Pulmonary Arterial Hypertension. 1993.
 154. Lv T, Shen X, Shi Y, Song Y. TLR4 is essential in acute lung injury induced by unresuscitated hemorrhagic shock. J Trauma‐ Inj Infect Crit Care 66: 124‐131, 2009.
 155. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC. Mutations of the TGF‐beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27: 121‐132, 2006.
 156. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, 3rd, Soubrier F, Trembath RC, Chung WK. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54: S32‐42, 2009.
 157. MacLean MR, Dempsie Y. Serotonin and pulmonary hypertension‐from bench to bedside? Curr Opin Pharmacol 9: 281‐286, 2009.
 158. Madrigano J, Baccarelli A, Wright RO, Suh H, Sparrow D, Vokonas PS, Schwartz J. Air pollution, obesity, genes and cellular adhesion molecules. Occup Environ Med 67: 312‐317, 2009.
 159. Maina JN. What it takes to fly: The structural and functional respiratory refinements in birds and bats. J Exp Biol 203: 3045‐3064, 2000.
 160. Maina JN, Madan AK, Alison B. Expression of fibroblast growth factor‐2 (FGF‐2) in early stages (days 3‐11) of the development of the avian lung, Gallus gallus variant domesticus: An immunocytochemical study. J Anat 203: 505‐512, 2003.
 161. Makri V, Hospes B, Stoll‐Becker S, Borkhardt A, Gortner L. Polymorphisms of surfactant protein B encoding gene: Modifiers of the course of neonatal respiratory distress syndrome? Eur J Pediatr 161: 604‐608, 2002.
 162. Marthan R, Castaing Y, Manier G, Guenard H. Gas exchange alterations in patients with chronic obstructive lung disease. Chest 87: 470‐475, 1985.
 163. Maxwell PH. Hypoxia‐inducible factor as a physiological regulator. Exp Physiol 90: 791‐797, 2005.
 164. Mazzoli‐Rocha F, Fernandes S, Einicker‐Lamas M, Zin WA. Roles of oxidative stress in signaling and inflammation induced by particulate matter. Cell Biol Toxicol 26: 481‐498, 2010.
 165. McCunney RJ. Asthma, genes, and air pollution. J Occup Environ Med 47: 1285‐1291, 2005.
 166. McFadden ER, Lyons HA. Arterial‐blood gas tension in asthma. N Engl J Med 278: 1027‐1032, 1968.
 167. McGrath‐Morrow S, Lauer T, Yee M, Neptune E, Podowski M, Thimmulappa RK, O'Reilly M, Biswal S. Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol 296: L565‐573, 2009.
 168. Melot C, Naeije R, Mols P, Vandenbossche JL, Denolin H. Effects of nifedipine on ventilation/perfusion matching in primary pulmonary hypertension. Chest 83: 203‐207, 1983.
 169. Meng Z, Liu Y, Wu D. Effect of sulfur dioxide inhalation on cytokine levels in lungs and serum of mice. Inhal Toxicol 17: 303‐307, 2005.
 170. Minoo P, Su G, Drum H, Bringas P, Kimura S. Defects in tracheoesophageal and lung morphogenesis inNkx2.1(‐/‐) mouse embryos. Dev Biol 209: 60‐71, 1999.
 171. Mishina Y. Function of bone morphogenetic protein signaling during mouse development. Front Biosci 8: d855‐869, 2003.
 172. Mohsenin V. Airway responses to nitrogen dioxide in asthmatic subjects. J Toxicol Environ Health 22: 371‐380, 1987.
 173. Moldeus P. Toxicity induced by nitrogen dioxide in experimental animals and isolated cell systems. Scand J Work Environ Health 19Suppl 2: 28‐36, 1993.
 174. Moore LG, Rohr AL, Maisenbach JK, Reeves JT. Emphysema mortality is increased in Colorado residents at high altitude. Am Rev Respir Dis 126: 225‐228, 1982.
 175. Mooren F, Völker K. Molecular and Cellular Exercise Physiology. Champaign, IL: Human Kinetics, 2005.
 176. Mordukhovich I, Wilker E, Suh H, Wright R, Sparrow D, Vokonas PS, Schwartz J. Black carbon exposure, oxidative stress genes, and blood pressure in a repeated‐measures study. Environ Health Perspect 117: 1767‐1772, 2009.
 177. Mulloy E, McNicholas WT. Ventilation and gas exchange during sleep and exercise in severe COPD. Chest 109: 387‐394, 1996.
 178. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990‐2020: Global Burden of Disease Study. Lancet 349: 1498‐1504, 1997.
 179. Nebert DW. Inter‐individual susceptibility to environmental toxicants‐a current assessment. Toxicol Appl Pharmacol 207: 34‐42, 2005.
 180. Nemery B, Bast A, Behr J, Borm PJ, Bourke SJ, Camus PH, De Vuyst P, Jansen HM, Kinnula VL, Lison D, Pelkonen O, Saltini C. Interstitial lung disease induced by exogenous agents: Factors governing susceptibility. Eur Respir J Suppl 32: 30s‐42s, 2001.
 181. Nishigaki Y, Fujiuchi S, Yamazaki Y, Matsumoto H, Takeda A, Fujita Y, Okamoto K, Fujikane T, Shimizu T, Kikuchi K. Increased vascular endothelial growth factor in acute eosinophilic pneumonia. Eur Respir J 21: 774‐778, 2003.
 182. Northway WH, Jr., Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline‐membrane disease. Bronchopulmonary dysplasia. N Engl J Med 276: 357‐368, 1967.
 183. Ohtsuka Y, Brunson KJ, Jedlicka AE, Mitzner W, Clarke RW, Zhang LY, Eleff SM, Kleeberger SR. Genetic linkage analysis of susceptibility to particle exposure in mice. Am J Respir Cell Mol Biol 22: 574‐581, 2000.
 184. Ohtsuka Y, Clarke RW, Mitzner W, Brunson K, Jakab GJ, Kleeberger SR. Interstrain variation in murine susceptibility to inhaled acid‐coated particles. Am J Physiol Lung Cell Mol Physiol 278: L469‐L476, 2000.
 185. Padgaonkar VA, Giblin FJ, Fowler K, Leverenz VR, Reddan JR, Dziedzic DC. Heme oxygenase synthesis is induced in cultured lens epithelium by hyperbaric oxygen or puromycin. Exp Eye Res 65: 435‐443, 1997.
 186. Palmer LJ, Celedon JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK. Genome‐wide linkage analysis of bronchodilator responsiveness and post‐bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet 12: 1199‐1210, 2003.
 187. Paquette NC, Tankersley CG, Zhang LY, Kleeberger SR. Repeated subacute ozone exposure of inbred mice: Airway inflammation and ventilation. Exp Lung Res 20: 579‐594, 1994.
 188. Park SK, Hu H, Wright RO, Schwartz J, Cheng Y, Sparrow D, Vokonas PS, Weisskopf MG. Iron metabolism genes, low‐level lead exposure, and QT interval. Environ Health Perspect 117: 80‐85, 2009.
 189. Parker RA, Lindstrom DP, Cotton RB. Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia. Semin Perinatol 20: 206‐209, 1996.
 190. Parton LA, Strassberg SS, Qian D, Galvin‐Parton PA, Cristea IA. The genetic basis for bronchopulmonary dysplasia. Front Biosci 11: 1854‐1860, 2006.
 191. Patuzzo C, Gile LS, Zorzetto M, Trabetti E, Malerba G, Pignatti PF, Luisetti M. Tumor necrosis factor gene complex in COPD and disseminated bronchiectasis. Chest 117: 1353‐1358, 2000.
 192. Peao MN, Aguas AP, de Sa CM, Grande NR. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat Rec 238: 57‐67, 1994.
 193. Peden DB. The epidemiology and genetics of asthma risk associated with air pollution. J Allergy Clin Immunol 115: 213‐219; quiz 220, 2005.
 194. Pereira LAA, Loomis D, Conceicao GMS, Braga ALF, Arcas RM, Kishi HS, Singer RM, Bohm GM, Saldiva PHN. Association between air pollution and intrauterine mortality in Sao Paulo, Brazil. Environ Health Perspect 106: 325‐329, 1998.
 195. Pham I, Uchida T, Planes C, Ware LB, Kaner R, Matthay MA, Clerici C. Hypoxia upregulates VEGF expression in alveolar epithelial cells in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 283: L1133‐L1142, 2002.
 196. Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, Scales DC, Stather DR, Li A, Jones A, Gattas DJ, Hallett D, Tomlinson G, Stewart TE, Ferguson ND. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med 179: 220‐227, 2009.
 197. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med 141: 460‐470, 2004.
 198. Pope CA, 3rd, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long‐term exposure to particulate air pollution: Epidemiological evidence of general pathophysiological pathways of disease. Circulation 109: 71‐77, 2004.
 199. Pope CA, 3rd, Thun MJ, Namboodiri MM, Dockery DW, Evans JS, Speizer FE, Heath CW, Jr. Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults. Am J Respir Crit Care Med 151: 669‐674, 1995.
 200. Powell FL. Functional genomics and the comparative physiology of hypoxia. Annu Rev Physiol 65: 203‐230, 2003.
 201. Prows DR, Winterberg AV, Gibbons WJ, Jr., Burzynski BB, Liu C, Nick TG. Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time. Physiol Genomics 38: 158‐168, 2009.
 202. Pugh LG, Gill MB, Lahiri S, Milledge JS, Ward MP, West JB. Muscular exercise at great altitudes. J Appl Physiol 19: 431‐440, 1964.
 203. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez‐Roisin R, van Weel C, Zielinski J. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176: 532‐555, 2007.
 204. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 154: 1055‐1060, 1996.
 205. Ramirez JM, Folkow LP, Blix AS. Hypoxia tolerance in mammals and birds: From the wilderness to the clinic. Annu Rev Physiol 69: 113‐143, 2007.
 206. Reddy NM, Kleeberger SR, Kensler TW, Yamamoto M, Hassoun PM, Reddy SP. Disruption of Nrf2 impairs the resolution of hyperoxia‐induced acute lung injury and inflammation in mice. J Immunol 182: 7264‐7271, 2009.
 207. Ren C, Baccarelli A, Wilker E, Suh H, Sparrow D, Vokonas P, Wright R, Schwartz J. Lipid and endothelium‐related genes, ambient particulate matter, and heart rate variability‐the VA Normative Aging Study. J Epidemiol Community Health 64: 49‐56, 2010.
 208. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107: 216‐223, 1987.
 209. Roberts KE, McElroy JJ, Wong WP, Yen E, Widlitz A, Barst RJ, Knowles JA, Morse JH. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24: 371‐374, 2004.
 210. Rodkey FL, O'Neal JD, Collison HA, Uddin DE. Relative affinity of hemoglobin S and hemoglobin A for carbon monoxide and oxygen. Clin Chem 20: 83‐84, 1974.
 211. Rodriguez‐Roisin R. Acute severe asthma: Pathophysiology and pathobiology of gas exchange abnormalities. Eur Respir J 10: 1359‐1371, 1997.
 212. Rodriguez‐Roisin R, Roca J. Contributions of multiple inert gas elimination technique to pulmonary medicine.3. Bronchial asthma. Thorax 49: 1027‐1033, 1994.
 213. Roger LJ, Kehrl HR, Hazucha M, Horstman DH. Bronchoconstriction in asthmatics exposed to sulfur dioxide during repeated exercise. J Appl Physiol 59: 784‐791, 1985.
 214. Romieu I, Meneses F, Ramirez M, Ruiz S, Perez Padilla R, Sienra JJ, Gerber M, Grievink L, Dekker R, Walda I, Brunekreef B. Antioxidant supplementation and respiratory functions among workers exposed to high levels of ozone. Am J Respir Crit Care Med 158: 226‐232, 1998.
 215. Romieu I, Ramirez‐Aguilar M, Sienra‐Monge JJ, Moreno‐Macias H, del Rio‐Navarro BE, David G, Marzec J, Hernandez‐Avila M, London S. GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur Respir J 28: 953‐959, 2006.
 216. Romieu I, Sienra‐Monge JJ, Ramirez‐Aguilar M, Moreno‐Macias H, Reyes‐Ruiz NI, Estela del Rio‐Navarro B, Hernandez‐Avila M, London SJ. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City. Thorax 59: 8‐10, 2004.
 217. Rondelet B, Van Beneden R, Kerbaul F, Motte S, Fesler P, McEntee K, Brimioulle S, Ketelslegers JM, Naeije R. Expression of the serotonin 1b receptor in experimental pulmonary hypertension. Eur Respir J 22: 408‐412, 2003.
 218. Ruse CE, Hill MC, Tobin M, Neale N, Connolly MJ, Parker SG, Wardlaw AJ. Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease. Respir Med 101: 340‐344, 2007.
 219. Ruse CE, Parker SG. Genetics and the Dutch Hypothesis. Chron Respir Dis 1: 105‐113, 2004.
 220. Ryter SW, Alam J, Choi AM. Heme oxygenase‐1/carbon monoxide: From basic science to therapeutic applications. Physiol Rev 86: 583‐650, 2006.
 221. Sakao S, Tatsumi K, Igari H, Shino Y, Shirasawa H, Kuriyama T. Association of tumor necrosis factor alpha gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163: 420‐422, 2001.
 222. Sakao S, Tatsumi K, Igari H, Watanabe R, Shino Y, Shirasawa H, Kuriyama T. Association of tumor necrosis factor‐alpha gene promoter polymorphism with low attenuation areas on high‐resolution CT in patients with COPD. Chest 122: 416‐420, 2002.
 223. Salam MT, Islam T, Gauderman WJ, Gilliland FD. Roles of arginase variants, atopy, and ozone in childhood asthma. J Allergy Clin Immunol 123: 596‐602, e591‐598, 2009.
 224. Sandford AJ, Chagani T, Weir TD, Connett JE, Anthonisen NR, Pare PD. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med 163: 469‐473, 2001.
 225. Sato K, Balla J, Otterbein L, Smith RN, Brouard S, Lin Y, Csizmadia E, Sevigny J, Robson SC, Vercellotti G, Choi AM, Bach FH, Soares MP. Carbon monoxide generated by heme oxygenase‐1 suppresses the rejection of mouse‐to‐rat cardiac transplants. J Immunol 166: 4185‐4194, 2001.
 226. Schraufnagel DE. Monocrotaline‐induced angiogenesis. Differences in the bronchial and pulmonary vasculature. Am J Pathol 137: 1083‐1090, 1990.
 227. Schwartz J, Park SK, O'Neill MS, Vokonas PS, Sparrow D, Weiss S, Kelsey K. Glutathione‐S‐transferase M1, obesity, statins, and autonomic effects of particles: Gene‐by‐drug‐by‐environment interaction. Am J Respir Crit Care Med 172: 1529‐1533, 2005.
 228. Seifart C, Plagens A. Genetics of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2: 541‐550, 2007.
 229. Sheppard D, Epstein J, Bethel RA, Nadel JA, Boushey HA. Tolerance to sulfur dioxide‐induced bronchoconstriction in subjects with asthma. Environ Res 30: 412‐419, 1983.
 230. Sheppard D, Wong WS, Uehara CF, Nadel JA, Boushey HA. Lower threshold and greater bronchomotor responsiveness of asthmatic subjects to sulfur dioxide. Am Rev Respir Dis 122: 873‐878, 1980.
 231. Shu W, Jiang YQ, Lu MM, Morrisey EE. Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development 129: 4831‐4842, 2002.
 232. Silverman EK, Mosley JD, Palmer LJ, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST. Genome‐wide linkage analysis of severe, early‐onset chronic obstructive pulmonary disease: Airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet 11: 623‐632, 2002.
 233. Silverman EK, Palmer LJ, Mosley JD, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST. Genomewide linkage analysis of quantitative spirometric phenotypes in severe early‐onset chronic obstructive pulmonary disease. Am J Hum Genet 70: 1229‐1239, 2002.
 234. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R. Genetic evidence for high‐altitude adaptation in Tibet. Science 329: 72‐75, 2010.
 235. Singh MV, Rawal SB, Tyagi AK. Body fluid status on induction, reinduction and prolonged stay at high altitude of human volunteers. Int J Biometeorol 34: 93‐97, 1990.
 236. Slama K, Gesch M, Bock JC, Pietschmann SM, Schaffartzik W, Pison U. Unilateral lung edema: Effects on pulmonary gas exchange, hemodynamics, and pulmonary perfusion distribution. J Appl Physiol 89: 1513‐1521, 2000.
 237. Slutsky AS. Lung injury caused by mechanical ventilation. Chest 116: 9S‐15S, 1999.
 238. Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia‐inducible factor. Br J Haematol 141: 325‐334, 2008.
 239. Stray‐Gundersen J, Chapman RF, Levine BD. “Living high‐training low” altitude training improves sea level performance in male and female elite runners. J Appl Physiol 91: 1113‐1120, 2001.
 240. Sunyer J, Schwartz J, Tobias A, Macfarlane D, Garcia J, Anto JM. Patients with chronic obstructive pulmonary disease are at increased risk of death associated with urban particle air pollution: A case‐crossover analysis. Am J Epidemiol 151: 50‐56, 2000.
 241. Taeusch HW, Ballard RA, Gleason CA. Avery's Diseases of the Newborn. Philadelphia: Elsevier Saunders, 2005.
 242. Tager IB, Rosner B, Tishler PV, Speizer FE, Kass EH. Household aggregation of pulmonary function and chronic bronchitis. Am Rev Respir Dis 114: 485‐492, 1976.
 243. Tanaka G, Sandford AJ, Burkett K, Connett JE, Anthonisen NR, Pare PD, He JQ. Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers. Eur Respir J 29: 34‐41, 2007.
 244. Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, Cantone L, Rizzo G, Hou L, Schwartz J, Bertazzi PA, Baccarelli A. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117: 217‐222, 2009.
 245. 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.
 246. Tin W, Gupta S. Optimum oxygen therapy in preterm babies. Arch Dis Child Fetal Neonatal Ed 92: F143‐F147, 2007.
 247. Tin W, Wiswell TE. Drug therapies in bronchopulmonary dysplasia: Debunking the myths. Semin Fetal Neonatal Med 14: 383‐390, 2009.
 248. Togbe D, Schnyder‐Candrian S, Schnyder B, Doz E, Noulin N, Janot L, Secher T, Gasse P, Lima C, Coelho FR, Vasseur V, Erard F, Ryffel B, Couillin I, Moser R. Toll‐like receptor and tumour necrosis factor dependent endotoxin‐induced acute lung injury. Int J Exp Pathol 88: 387‐391, 2007.
 249. Torday JS, Rehan VK, Hicks JW, Wang T, Maina J, Weibel ER, Hsia CC, Sommer RJ, Perry SF. Deconvoluting lung evolution: From phenotypes to gene regulatory networks. Integr Comp Biol 47: 601‐609, 2007.
 250. Truog WE, Xu D, Ekekezie, II, Mabry S, Rezaiekhaligh M, Svojanovsky S, Soares MJ. Chronic hypoxia and rat lung development: Analysis by morphometry and directed microarray. Pediatr Res 64: 56‐62, 2008.
 251. Tung KY, Tsai CH, Lee YL. Microsomal epoxide hydroxylase genotypes/diplotypes, traffic air pollution, and childhood asthma. Chest 139: 839‐848, 2011.
 252. Turato G, Zuin R, Saetta M. Pathogenesis and pathology of COPD. Respiration 68: 117‐128, 2001.
 253. Turner J, Jones CE. Regulation of mucin expression in respiratory diseases. Biochem Soc Trans 37: 877‐881, 2009.
 254. Van Hee VC, Adar SD, Szpiro AA, Barr RG, Bluemke DA, Diez Roux AV, Gill EA, Sheppard L, Kaufman JD. Exposure to traffic and left ventricular mass and function: The Multi‐Ethnic Study of Atherosclerosis. Am J Respir Crit Care Med 179: 827‐834, 2009.
 255. van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia‐inducible factor‐1alpha by NF‐kappaB. Biochem J 412: 477‐484, 2008.
 256. Villeneuve PJ, Burnett RT, Shi Y, Krewski D, Goldberg MS, Hertzman C, Chen Y, Brook J. A time‐series study of air pollution, socioeconomic status, and mortality in Vancouver, Canada. J Expo Anal Environ Epidemiol 13: 427‐435, 2003.
 257. Wagenvoort CA. The pathology of primary pulmonary hypertension. J Pathol 101: Pi, 1970.
 258. Wagner PD, Dantzker DR, Dueck R, Clausen JL, West JB. Ventilation‐perfusion inequality in chronic obstructive pulmonary disease. J Clin Invest 59: 203‐216, 1977.
 259. Wang XB, Ding H, Ryan L, Xu XP. Association between air pollution and low birth weight: A community‐based study. Environ Health Perspect 105: 514‐520, 1997.
 260. Wang Z, Neuburg D, Li C, Su L, Kim JY, Chen JC, Christiani DC. Global gene expression profiling in whole‐blood samples from individuals exposed to metal fumes. Environ Health Perspect 113: 233‐241, 2005.
 261. Warburton D, Bellusci S, De Langhe S, Del Moral PM, Fleury V, Mailleux A, Tefft D, Unbekandt M, Wang K, Shi W. Molecular mechanisms of early lung specification and branching morphogenesis. Pediatr Res 57: 26R‐37R, 2005.
 262. Warburton D, Schwarz M, Tefft D, Flores‐Delgado G, Anderson KD, Cardoso WV. The molecular basis of lung morphogenesis. Mech Dev 92: 55‐81, 2000.
 263. Weaver M, Dunn NR, Hogan BL. Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 127: 2695‐2704, 2000.
 264. Weber B, Borkhardt A, Stoll‐Becker S, Reiss I, Gortner L. Polymorphisms of surfactant protein A genes and the risk of bronchopulmonary dysplasia in preterm infants. Turk J Pediatr 42: 181‐185, 2000.
 265. Wehrlin JP, Marti B. Live high‐train low associated with increased haemoglobin mass as preparation for the 2003 World Championships in two native European world class runners. Br J Sports Med 40: e3; discussion e3, 2006.
 266. Wehrlin JP, Zuest P, Hallen J, Marti B. Live high‐train low for 24 days increases hemoglobin mass and red cell volume in elite endurance athletes. J Appl Physiol 100: 1938‐1945, 2006.
 267. Weiss ST. What genes tell us about the pathogenesis of asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 181: 1170‐1173, 2010.
 268. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 103: 19093‐19098, 2006.
 269. Weitzenblum E, Chaouat A. Cor pulmonale. Chron Respir Dis 6: 177‐185, 2009.
 270. Weitzenblum E, Chaouat A. Hypoxic pulmonary hypertension in man: What minimum daily duration of hypoxaemia is required? Eur Respir J 18: 251‐253, 2001.
 271. Wenten M, Gauderman WJ, Berhane K, Lin PC, Peters J, Gilliland FD. Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory‐related school absences: An example of epistasis in gene‐environment interactions. Am J Epidemiol 170: 1494‐1501, 2009.
 272. West JB. The physiologic basis of high‐altitude diseases. Ann Intern Med 141: 789‐800, 2004.
 273. Wheeler AP, Jesmok G, Brigham KL. Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep. J Appl Physiol 68: 2542‐2549, 1990.
 274. Wilk JB, DeStefano AL, Arnett DK, Rich SS, Djousse L, Crapo RO, Leppert MF, Province MA, Cupples LA, Gottlieb DJ, Myers RH. A genome‐wide scan of pulmonary function measures in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Respir Crit Care Med 167: 1528‐1533, 2003.
 275. Winnier G, Blessing M, Labosky PA, Hogan BL. Bone morphogenetic protein‐4 is required for mesoderm formation and patterning in the mouse. Genes Dev 9: 2105‐2116, 1995.
 276. Winterton DL, Kaufman J, Keener CV, Quigley S, Farin FM, Williams PV, Koenig JQ. Genetic polymorphisms as biomarkers of sensitivity to inhaled sulfur dioxide in subjects with asthma. Ann Allergy Asthma Immunol 86: 232‐238, 2001.
 277. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 14: 59‐88, 1998.
 278. Woodruff TJ, Grillo J, Schoendorf KC. The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environ Health Perspect 105: 608‐612, 1997.
 279. Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Thorax 63: 555‐563, 2008.
 280. Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Postgrad Med J 85: 428‐436, 2009.
 281. Yang IA, Holz O, Jorres RA, Magnussen H, Barton SJ, Rodriguez S, Cakebread JA, Holloway JW, Holgate ST. Association of tumor necrosis factor‐alpha polymorphisms and ozone‐induced change in lung function. Am J Respir Crit Care Med 171: 171‐176, 2005.
 282. Yi X, Liang Y, Huerta‐Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Asan, Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G, Huasang, Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H, Zheng H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y, Zhang Y, Zhang X, Li R, Li S, Yang H, Nielsen R, Wang J, Wang J. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329: 75‐78, 2010.
 283. Zambon M, Vincent JL. Mortality rates for patients with acute lung injury/ARDS have decreased over time. Chest 133: 1120‐1127, 2008.
 284. Zanobetti A, Baccarelli A, Schwartz J. Gene‐air pollution interaction and cardiovascular disease: A review. Prog Cardiovasc Dis 53: 344‐352, 2011.
 285. Zhan P, Wang J, Wei SZ, Qian Q, Qiu LX, Yu LK, Song Y. TNF‐308 gene polymorphism is associated with COPD risk among Asians: Meta‐analysis of data for 6,118 subjects. Mol Biol Rep 38: 219‐227, 2010.
 286. Zhang H, Bradley A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development 122: 2977‐2986, 1996.
 287. Zhang X, Shan P, Qureshi S, Homer R, Medzhitov R, Noble PW, Lee PJ. Cutting edge: TLR4 deficiency confers susceptibility to lethal oxidant lung injury. J Immunol 175: 4834‐4838, 2005.
 288. Zhao GQ. Consequences of knocking out BMP signaling in the mouse. Genesis 35: 43‐56, 2003.
 289. Zhu NL, Li C, Xiao J, Minoo P. NKX2.1 regulates transcription of the gene for human bone morphogenetic protein‐4 in lung epithelial cells. Gene 327: 25‐36, 2004.

Related Articles:

Pulmonary Vascular Disease

Contact Editor

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

* Required Field

Article Title: Genetic and Environmental Influences on Gas Exchange
 

How to Cite

Reuben Howden, Steven R. Kleeberger. Genetic and Environmental Influences on Gas Exchange. Compr Physiol 2012, 2: 2595-2614. doi: 10.1002/cphy.c110060