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High‐Altitude Pulmonary Edema

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Abstract

High‐altitude pulmonary edema (HAPE), a not uncommon form of acute altitude illness, can occur within days of ascent above 2500 to 3000 m. Although life‐threatening, it is avoidable by slow ascent to permit acclimatization or with drug prophylaxis. The critical pathophysiology is an excessive rise in pulmonary vascular resistance or hypoxic pulmonary vasoconstriction (HPV) leading to increased microvascular pressures. The resultant hydrostatic stress causes dynamic changes in the permeability of the alveolar capillary barrier and mechanical injurious damage leading to leakage of large proteins and erythrocytes into the alveolar space in the absence of inflammation. Bronchoalveolar lavage and hemodynamic pressure measurements in humans confirm that elevated capillary pressure induces a high‐permeability noninflammatory lung edema. Reduced nitric oxide availability and increased endothelin in hypoxia are the major determinants of excessive HPV in HAPE‐susceptible individuals. Other hypoxia‐dependent differences in ventilatory control, sympathetic nervous system activation, endothelial function, and alveolar epithelial active fluid reabsorption likely contribute additionally to HAPE susceptibility. Recent studies strongly suggest nonuniform regional hypoxic arteriolar vasoconstriction as an explanation for how HPV occurring predominantly at the arteriolar level causes leakage. In areas of high blood flow due to lesser HPV, edema develops due to pressures that exceed the dynamic and structural capacity of the alveolar capillary barrier to maintain normal fluid balance. This article will review the pathophysiology of the vasculature, alveolar epithelium, innervation, immune response, and genetics of the lung at high altitude, as well as therapeutic and prophylactic strategies to reduce the morbidity and mortality of HAPE. Published 2012. Compr Physiol 2:2753‐2773, 2012.

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Figure 1. Figure 1.

Chest radiograph with bronchoalveolar lavage fluid aliquots (first and fifth) from a representative subject with early high‐altitude pulmonary edema. The radiograph shows interstitial and alveolar infiltrates and the lavage performed after the x‐ray was taken shows mild alveolar hemorrhage 204.

Figure 2. Figure 2.

Pulmonary artery pressure (PAP) in high‐altitude pulmonary edema (HAPE)‐susceptible individuals (continuous lines and filled symbols) and in nonsusceptible controls (dashed lines and open symbols) during exposure to normobaric hypoxia (left) and before and during exercise on a bicycle ergometer (right). The highest PAP recordings during exercise (75‐150 W) are shown 75.

Figure 3. Figure 3.

Mean pulmonary artery pressure (Ppa) and pulmonary capillary pressure (Pcap) in 14 controls and in 16 high‐altitude edema susceptible (HAPE‐s) subjects at high altitude. HAPE‐s is further divided in those who developed HAPE (HAPE) and those who did not develop HAPE (non‐HAPE). Bars indicate the mean values in each group. *P < 0.05, **P < 0.01 versus control, †P < 0.01 versus non‐HAPE 134.

Figure 4. Figure 4.

(A) Exhaled nitric oxide (NO) after 40 h at 4559 m in individuals developing high‐altitude edema susceptible (HAPE) (left) and in individuals not developing HAPE (HAPE‐R) despite identical exposure to high altitude 56. (B) Exhaled NO in individuals with (HAPE‐S) and without susceptibility (HAPE‐R) to HAPE after 4 h of exposure to hypoxia (FIO2 = 0.12) at low altitude (elevation 100 m) 32.

Figure 5. Figure 5.

Individual bronchoalveolar lavage (BAL) red blood cell count and albumin concentrations plotted against pulmonary artery systolic pressures at high altitude (4559 m). Acronyms: BAL, bronchoalveolar lavage; HAPE, high‐altitude pulmonary edema. The vertical lines denote a threshold systolic pulmonary artery (PA) pressure (> 60 mmHg) above which red blood cell (A) appear in the BAL fluid in contrast to the lower pressure (35 mmHg) at which albumin leakage occurs (B). The open circles in the lower left of both panels show the normal values for these at low altitude. The correlation coefficients are given for the best‐fit curves of the values at high altitude (P < 0.05 for both curves) 204.

Figure 6. Figure 6.

Schematic sequence of events in the progression of edema with pulmonary artery pressure rise in high‐altitude pulmonary edema (HAPE) from dynamic changes in alveolar capillary barrier permeability to mechanical injury.



Figure 1.

Chest radiograph with bronchoalveolar lavage fluid aliquots (first and fifth) from a representative subject with early high‐altitude pulmonary edema. The radiograph shows interstitial and alveolar infiltrates and the lavage performed after the x‐ray was taken shows mild alveolar hemorrhage 204.



Figure 2.

Pulmonary artery pressure (PAP) in high‐altitude pulmonary edema (HAPE)‐susceptible individuals (continuous lines and filled symbols) and in nonsusceptible controls (dashed lines and open symbols) during exposure to normobaric hypoxia (left) and before and during exercise on a bicycle ergometer (right). The highest PAP recordings during exercise (75‐150 W) are shown 75.



Figure 3.

Mean pulmonary artery pressure (Ppa) and pulmonary capillary pressure (Pcap) in 14 controls and in 16 high‐altitude edema susceptible (HAPE‐s) subjects at high altitude. HAPE‐s is further divided in those who developed HAPE (HAPE) and those who did not develop HAPE (non‐HAPE). Bars indicate the mean values in each group. *P < 0.05, **P < 0.01 versus control, †P < 0.01 versus non‐HAPE 134.



Figure 4.

(A) Exhaled nitric oxide (NO) after 40 h at 4559 m in individuals developing high‐altitude edema susceptible (HAPE) (left) and in individuals not developing HAPE (HAPE‐R) despite identical exposure to high altitude 56. (B) Exhaled NO in individuals with (HAPE‐S) and without susceptibility (HAPE‐R) to HAPE after 4 h of exposure to hypoxia (FIO2 = 0.12) at low altitude (elevation 100 m) 32.



Figure 5.

Individual bronchoalveolar lavage (BAL) red blood cell count and albumin concentrations plotted against pulmonary artery systolic pressures at high altitude (4559 m). Acronyms: BAL, bronchoalveolar lavage; HAPE, high‐altitude pulmonary edema. The vertical lines denote a threshold systolic pulmonary artery (PA) pressure (> 60 mmHg) above which red blood cell (A) appear in the BAL fluid in contrast to the lower pressure (35 mmHg) at which albumin leakage occurs (B). The open circles in the lower left of both panels show the normal values for these at low altitude. The correlation coefficients are given for the best‐fit curves of the values at high altitude (P < 0.05 for both curves) 204.



Figure 6.

Schematic sequence of events in the progression of edema with pulmonary artery pressure rise in high‐altitude pulmonary edema (HAPE) from dynamic changes in alveolar capillary barrier permeability to mechanical injury.

References
 1. Adding LC, Agvald P, Artlich A, Persson MG, Gustafsson LE. Beta adrenoceptor agonist stimulation of pulmonary nitric oxide production in the rab. Br J Pharmacol 126: 833‐839, 1999.
 2. Agostoni P, Caldara G, Bussotti M, Revera M, Valentini M, Gregorini F, Faini A, Lombardi C, Bilo G, Giuliano A, Veglia F, Savia G, Modesti PA, Mancia G, Parati G. Continuous positive airway pressure increases haemoglobin O2 saturation after acute but not prolonged altitude exposure. Eur Heart J 31: 457‐463, 2009
 3. Ahsan A, Charu R, Pasha MAQ, Norboo T, Afrin F, Baig MA. eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax 59: 1000‐1002, 2004.
 4. Albert RK, Lakshminarayan S, Hildebrandt J, Kirk W, Butler J. Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs. J Clin Invest 63: 1015‐1018, 1979.
 5. Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NW. Characterization of high‐altitude pulmonary hypertension in the kyrgyz: Association with angiotensin‐converting enzyme genotype. Am J Respir Crit Care Med 166: 1396‐1402, 2002.
 6. Allemann Y, Hutter D, Lipp E, Sartori C, Duplain H, Egli M, Cook S, Scherrer U, Seiler C. Patent foramen ovale and high‐altitude pulmonary edema. J Am Med Assoc 296: 2954‐2958, 2006.
 7. Allemann Y, Rotter M, Hutter D, Lipp E, Sartori C, Scherrer U, Seiler C. Impact of acute hypoxic pulmonary hypertension on LV diastolic function in healthy mountaineers at high altitude. Am J Physiol Heart Circ Physiol 286: H856‐H862, 2004.
 8. Ambalavanan M, Li P, Bulger A, Murphy‐Ullrich J, Oparil S and Chen Y‐F. Endothelin‐1 mediates hypoxia‐induced increases in vascular collagen in the newborn mouse lung. Pediatr Res 61: 559‐564, 2007.
 9. Bachofen H, Schürch S, Weibel ER. Experimental hydrostatic pulmonary edema in rabbit lungs. Barrier lesions. Am Rev Respir Dis 147: 997‐1004, 1993.
 10. Bai C, She J, Goolaerts A, Song Y, Shen C, Shen J, Hong Q. Stress failure plays a major role in the development of high‐altitude pulmonary oedema in rats. Eur Respir J 35: 584‐591, 2010.
 11. Balanos GM, Talbot NP, Dorrington KL, Robbins PA. Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl Physiol 94: 1543‐1551, 2003.
 12. Baloglu E, Ke A, Abu‐Taha IH, Bartsch P, Mairbaurl H. In vitro hypoxia impairs beta 2‐adrenergic receptor signaling in primary rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 296: L500‐L509, 2009.
 13. Bärtsch P. High altitude pulmonary edema. Respiration 64: 435‐443, 1997.
 14. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high‐altitude pulmonary edema by nifedipine. N Engl J Med 325: 1284‐1289, 1991.
 15. Bärtsch P, Mairbäurl H. Salmeterol for the prevention of high‐altitude pulmonary edema. N Engl J Med 347: 1283, 2002.
 16. Bärtsch P, Pfluger N, Audétat M, Shaw S, Weidmann P, Vock P, Vetter W, Rennie D, Olez O. Effects of slow ascent to 4559 M on fluid homeostasis. Aviat Space Environ Med 62: 105‐110, 1991.
 17. Bärtsch P, Shaw S, Franciolli M, Gnadinger MP, Weidmann P. Atrial natriuretic peptide in acute mountain sickness. J Appl Physiol 65: 1929‐1937, 1988.
 18. Bärtsch P, Waber U, Haeberli A, Maggiorini M, Kriemler S, Oelz O, Straub WP. Enhanced fibrin formation in high‐altitude pulmonary edema. J Appl Physiol 63: 752‐757, 1987.
 19. Basnyat B, Hargrove J, Holck PS, Srivastav S, Alekh K, Ghimire LV, Pandey K, Griffiths A, Shankar R, Kaul K, Paudyal A, Stasiuk D, Basnyat R, Davis C, Southard A, Robinson C, Shandley T, Johnson DW, Zafren K, Williams S, Weiss EA, Farrar JJ, Swenson ER. Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans. High Alt Med Biol 9: 209‐216, 2008.
 20. Beall CM, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, Alarcon AM, Gonzales C, Erzurum SC. Pulmonary nitric oxide in mountain dwellers. Nature 414: 411‐412, 2001.
 21. Bebok Z, Tousson A, Schwiebert LM, Venglarik CJ. Improved oxygenation promotes CFTR maturation and trafficking in MDCK monolayers. Am J Physiol Cell Physiol 280: C135‐C145, 2001.
 22. Behn C, Araneda OF, Llanos AJ, Celedón G, González G. Hypoxia‐related lipid peroxidation: Evidences, implications and approaches. Respir Physiol Neurobiol 158: 143‐150, 2007.
 23. Belik J, Pan J, Jankov RP, Tanswell AK. A bronchial epithelium‐derived factor reduces pulmonary vascular tone in the newborn rat. J Appl Physiol 96: 1399‐1405, 2004.
 24. Berg JT, Breen EC, Fu Z, Mathieu‐Costello O, West JB. Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet‐derived growth factor‐B in lung parenchyma. Am J Respir Crit Care Med 158: 1920‐1928, 1998.
 25. Berg JT, Ramanathan S, Swenson ER. Inhibitors of hypoxic pulmonary vasoconstriction prevent high‐altitude pulmonary edema in rats. Wilderness Environ Med 15: 32‐37, 2004.
 26. Berger MM, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Bardenheuer HJ, Kelm M, Bartsch P, Haefeli WE. Hypoxia impairs systemic endothelial function in individuals prone to high‐altitude pulmonary edema. Am J Respir Crit Care Med 172: 763‐767, 2005.
 27. Berger MM, Rozendal CS, Schieber C, Dehler M, Zagel S, Bardenheuer HJ, Bartsch P, Mairbaurl H. The effect of endothelin‐1 on alveolar fluid clearance and pulmonary edema formation in the rat. Anesth Analg 108: 225‐231, 2009.
 28. Bernheim AM, Kiencke S, Fischler M, Dorschner L, Debrunner J, Mairbaeurl H, Maggiorini M, Brunner‐La Rocca HP. Acute changes in pulmonary artery pressures due to exercise and exposure to high altitude do not cause left ventricular diastolic dysfunction*. Chest 132: 380‐387, 2007.
 29. Bouvry D, Planes C, Malbert‐Colas L, Escabasse V, Clerici C. Hypoxia‐induced cytoskeleton disruption in alveolar epithelial cells. Am J Respir Cell Mol Biol 35: 519‐527, 2006.
 30. Brimioulle S, Vachiery J‐L, Brichant J‐Fo, Delcroix M, Lejeune P, Naeije R. Sympathetic modulation of hypoxic pulmonary vasoconstriction in intact dogs. Cardiovasc Res 34: 384‐392, 1997.
 31. Burnham KJ, Arai TJ, Dubowitz DJ, Henderson AC, Holverda S, Buxton RB, Prisk GK, Hopkins SR. Pulmonary perfusion heterogeneity is increased by sustained, heavy exercise in humans. J Appl Physiol 107: 1559‐1568, 2009.
 32. Busch T, Bartsch P, Pappert D, Grunig E, Hildebrandt W, Elser H, Falke KJ, Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high‐altitude pulmonary edema. Am J Respir Crit Care Med 163: 368‐373, 2001.
 33. Carpenter TC, Reeves JT, Durmowicz AG. Viral respiratory infection increases susceptibility of young rats to hypoxia‐induced pulmonary edema. J Appl Physiol 84: 1048‐1054, 1998.
 34. Cavanaugh KJ, Jr., Oswari J, Margulies SS. Role of stretch on tight junction structure in alveolar epithelial cells. Am J Respir Cell Mol Biol 25: 584‐591, 2001.
 35. Chao J, Wood JG, Blanco VG, Gonzalez NC. The systemic inflammation of alveolar hypoxia is initiated by alveolar macrophage‐borne mediator(s). Am J Respir Cell Mol Biol 41: 573‐582, 2009.
 36. Chapleau MW, Wilson LB, Gregory TJ, Levitzky MG. Chemoreceptor stimulation interferes with regional hypoxic pulmonary vasoconstriction. Respir Physiol 71: 185‐200, 1988.
 37. Chen X‐J, Seth S, Yue G, Kamat P, Compans RW, Guidot D, Brown LA, Eaton DC, Jain L. Influenza virus inhibits ENaC and lung fluid clearance. Am J Physiol Lung Cell Mol Physiol 287: L366‐L373, 2004.
 38. Clerici C, Planes C. Gene regulation in the adaptive process to hypoxia in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 296: L267‐L274, 2009.
 39. Coates G, Gray G, Mansell A, Nahmias C, Powles A, Sutton J, Webber C. Changes in lung volume, lung density, and distribution of ventilation during hypobaric decompression. J Appl Physiol 46: 752‐755, 1979.
 40. Comellas AP, Briva A, Dada LA, Butti ML, Trejo HE, Yshii C, Azzam ZS, Litvan J, Chen J, Lecuona E, Pesce LM, Yanagisawa M, Sznajder JI. Endothelin‐1 impairs alveolar epithelial function via endothelial ETB receptor. Am J Respir Crit Care Med 179: 113‐122, 2009.
 41. Cremona G, Asnaghi R, Baderna P, Brunetto A, Brutsaert T, Cavallaro C, Clark TM, Cogo A, Donis R, Lanfranchi P, Luks A, Novello N, Panzetta S, Perini L, Putnam M, Spagnolatti L, Wagner H, Wagner PD. Pulmonary extravascular fluid accumulation in recreational climbers: A prospective study. Lancet 359: 303‐309, 2002.
 42. Cummings JJ. Nitric oxide decreases lung liquid production in fetal lambs. J Appl Physiol 83: 1538‐1544, 1997.
 43. Curry FE CG. Flow‐dependent changes in microvascular permeability ‐ an important adaptive phenomenon. J Physiol 543: 729‐732, 2002.
 44. Das BB, Wolfe RR, Chan K‐C, Larsen GL, Reeves JT, Ivy D. High‐altitude pulmonary edema in children eith underlying cardiopulmonary disorders and pulmonary hypertension living at altitude. Arch Pediatr Adolesc Med 158: 1170‐1176, 2004.
 45. Davis KL, Mehlhorn U, Laine GA, Allen SJ. Myocardial edema, left ventricular function, and pulmonary hypertension. J Appl Physiol 78: 132‐137, 1995.
 46. DeFouw DO. Ultrastructural freatures of alveolar epithelial transport. Am Rev Respir Dis 127: S9‐S13, 1983.
 47. Dehnert C, Grunig E, Mereles D, von Lennep N, Bartsch P. Identification of individuals susceptible to high‐altitude pulmonary oedema at low altitude. Eur Respir J 25: 545‐551, 2005.
 48. Dehnert C, Luks AM, Schendler G, Menold E, Berger MM, Mairbaurl H, Faoro V, Bailey DM, Castell C, Hahn G, Vock P, Swenson ER, Bärtsch P. No evidence for interstitial lung oedema by extensive pulmonary function testing at 4,559 m. Eur Respir J 35: 812‐820, 2010.
 49. Dehnert C, Miltenberger‐Miltenyi G, Grunig E. Normal BMPR‐2 gene in individuals susceptible to high altitude pulmonary edema. High Alt Med Biol 3: 100, 2002.
 50. Dehnert C, Risse F, Ley S, Kuder TA, Buhmann R, Puderbach M, Menold E, Mereles D, Kauczor H‐U, Bärtsch P, Fink C. Magnetic resonance imaging of uneven pulmonary perfusion in hypoxia in humans. Am J Respir Crit Care Med 174: 1132‐1138, 2006.
 51. Dehnert C, Weymann JR, Montgomery HE, Woods D, Maggiorini M, Scherrer URS, Gibbs JSR, Bärtsch P. No association between high‐altitude tolerance and the ACE I/D gene polymorphism. Med Sci Sports Exerc 34: 1928‐1933, 2002.
 52. de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia‐reperfusion‐induced lung injury. Am J Respir Crit Care Med 167: 490‐511, 2003.
 53. DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: Clinical implications. J Steroid Biochem Mol Biol 81: 103‐122, 2002.
 54. Droma Y, Ge RL, Tanaka M, Koizumi T, Hanaoka M, Miyahara T, Yamaguchi S, Okada K, Yoshikawa S, Fujimoto K, Matsuzawa Y, Kubo K, Kobayashi T, Sekiguchi M. Acute hypoxic pulmonary vascular response does not accompany plasma endothelin‐1 elevation in subjects susceptible to high altitude pulmonary edema. Intern Med 35: 257‐260, 1996.
 55. Droma Y, Hayano T, Takabayashi Y, Koizumi T, Kubo K, Kobayashi T, Sekiguchi M. Endothelin‐1 and interleukin‐8 in high altitude pulmonary oedema. Eur Respir J 9: 1947‐1949, 1996.
 56. Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, Scherrer URS. Exhaled nitric oxide in high‐altitude pulmonary edema. Role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med 162: 221‐224, 2000.
 57. Duplain H, Vollenweider L, Delabays A, Nicod P, Bärtsch P, Scherrer U. Augmented sympathetic activation during short‐term hypoxia and high‐altitude exposure in subjects susceptible to high‐altitude pulmonary edema. Circulation 99: 1713‐1718, 1999.
 58. Durmowicz AG, Noordeweir E, Nicholas R, Reeves JT. Inflammatory processes may predispose children to develop high altitude pulmonary edema. J Pediatr 130: 838‐840, 1997.
 59. Dvorak AM, Feng D. The vesiculo‐vacuolar organelle (VVO): A new endothelial cell permeability organelle. J Histochem Cytochem 49: 419‐432, 2001.
 60. Easton PA, Katagiri M, Johnson MW, Rothwell BC, Holroyde MC, Kusuhara N. Effect of salbutamol on respiratory muscle function and ventilation in awake canines. Respir Physiol Neurobiol 161: 253‐260, 2008.
 61. Egli M, Cook S, Hugli O. Delayed resolution of pulmonary edema in mice with defective sodium transport‐dependent alveolar fluid clearance. FASEB J 15: 860, 2001.
 62. Egli M, Duplain H, Lepori M, Cook Sp, Nicod P, Hummler E, Sartori C, Scherrer U. Defective respiratory amiloride‐sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J Physiol 560: 857‐865, 2004.
 63. Eldridge MW, Podolsky A, Richardson RS, Johnson DH, Knight DR, Johnson EC, Hopkins SR, Michimata H, Grassi B, Feiner J, Kurdak SS, Bickler PE, Wagner PD, Severinghaus JW. Pulmonary hemodynamic response to exercise in subjects with prior high‐altitude pulmonary edema. J Appl Physiol 81: 911‐921, 1996.
 64. Engebretsen BJ, Irwin D, Valdez ME, O'Donovan MK, Tucker A, Tissot van Patot MT. Acute hypobaric hypoxia (5486 M) induces greater pulmonary HIF‐1 activation in Hilltop compared to Madison rats. High Alt Med Biol 8: 812‐821, 2007.
 65. Fagenholz PJ, Gutman JA, Murray AF, Harris NS. Treatment of high altitude pulmonary edema at 4240 m in Nepal. High Alt Med Biol 8: 139‐146, 2007.
 66. Fagenholz PJ, Gutman JA, Murray AF, Noble VE, Thomas SH, Harris NS. Chest ultrasonography for the diagnosis and monitoring of high‐altitude pulmonary edema. Chest 131: 1013‐1018, 2007.
 67. Faoro V, Huez S, Giltaire S, Pavelescu A, van Osta A, Moraine J‐J, Guenard H, Martinot J‐B, Naeije R. Effects of acetazolamide on aerobic exercise capacity and pulmonary hemodynamics at high altitudes. J Appl Physiol 103: 1161‐1165, 2007.
 68. Farney RJ, Morris AH, Gardner RM, Armstrong JD, Jr. Rebreathing pulmonary capillary and tissue volume in normals after saline infusion. J Appl Physiol 43: 246‐253, 1977.
 69. Gabry AL, Ledoux X, Mozziconacci M, Martin C. High‐altitude pulmonary edema at moderate altitude (< 2,400 m; 7,870 feet). Chest 123: 49‐53, 2003.
 70. Gao Y, Usha Raj J. Role of veins in regulation of pulmonary circulation. Am J Physiol 288: L213‐L226, 2005.
 71. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, Grimminger F. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp. Ann Intern Med 141: 169‐177, 2004.
 72. Gonzalez NC, Wood JG. Leukocyte‐endothelial interactions in environmental hypoxia. Exp Med Biol 502: 39‐60, 2001.
 73. Graca‐Souza AV, Arruda MAB, de Freitas MS, Barja‐Fidalgo C, Oliveira PL. Neutrophil activation by heme: Implications for inflammatory processes. Blood 99: 4160‐4165, 2002.
 74. Greene KE, Wright JR, Steinberg KP, Ruzinski JT, Caldwell E, Wong WB, Hull W, Whitsett JA, Akino T, Kuroki Y, Nagae H, Hudson LD, Martin TR. Serial changes in surfactant‐associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 160: 1843‐1850, 1999.
 75. Grünig E, Mereles D, Hildebrandt W, Swenson ER, Kübler W, Kuecherer H, Bärtsch P. Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema. J Am Coll Cardiol 35: 980‐987, 2000.
 76. Grunig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galie N, Ghofrani A, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W. Stress doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: Results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia. Circulation 119: 1747‐1757, 2009.
 77. Guazzi M, Arena R, Vicenzi M, Guazzi MD. Regulation of alveolar gas conductance by NO in man, as based on studies with NO donors and inhibitors of NO production. Acta Physiol 196: 267‐277, 2009.
 78. Guimbellot JS, Fortenberry JA, Siegal GP, Moore B, Wen H, Venglarik C, Chen Y‐F, Oparil S, Sorscher EJ, Hong JS. Role of oxygen availability in CFTR expression and function. Am J Respir Cell Mol Biol 39: 514‐521, 2008.
 79. Guney S, Schuler A, Ott A, Hoschele S, Zugel S, Baloglu E, Bartsch P, Mairbaurl H. Dexamethasone prevents transport inhibition by hypoxia in rat lung and alveolar epithelial cells by stimulating activity and expression of Na+‐K+‐ATPase and epithelial Na +channels. Am J Physiol Lung Cell Mol Physiol 293: L1332‐L1338, 2007.
 80. Hackett PH, Creagh CE, Grover RF, Honigman B, Houston CS, Reeves JT, Sophocles AM, Van Hardenbroek M. High‐altitude pulmonary edema in persons without the right pulmonary artery. N Engl J Med 302: 1070‐1073, 1980.
 81. Hackett PH, Roach RC, Hartig GS, Greene ER, Levine BD. Effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema. Int J Sports Med 13: S68‐S71, 1992.
 82. Hackett PH, Roach RC, Schoene RB, Harrison GL, Mills WJ, Jr. Abnormal control of ventilation in high‐altitude pulmonary edema. J Appl Physiol 64: 1268‐1272, 1988.
 83. Hagobian TA, Jacobs KA, Subudhi AW, Fattor JA, Rock PB, Muza SR, Fulco CS, Braun B, Grediagin ANN, Mazzeo RS, Cymerman A, Friedlander AL. Cytokine responses at high altitude: Effects of exercise and antioxidants at 4300 m. Med Sci Sports Exerc 38: 276‐285, 2006.
 84. Hakim TS, Kelly S. Occlusion pressures vs. micropipette pressures in the pulmonary circulation. J Appl Physiol 67: 1277‐1285, 1989.
 85. Hanaoka M, Droma Y OM, Ito M, Katsuyama Y, Kubo K. Polymorphisms of human vascular endothelial growth factor gene in high‐altitude pulmonary oedema susceptible subjects. Respirology 14: 46‐52, 2009.
 86. Hardiman KM, McNicholas‐Bevensee CM, Fortenberry J, Myles CT, Malik B, Eaton DC, Matalon S. Regulation of amiloride‐Sensitive Na+ transport by basal nitric oxide. Am J Respir Cell Mol Biol 30: 720‐728, 2004.
 87. Heinicke I, Boehler A, Rechsteiner T, Bogdanova A, Jelkmann W, Hofer M, Rawlings P, Araneda O, Behn C, Gassmann M, Heinicke K. Moderate altitude but not additional endurance training increases markers of oxidative stress in exhaled breath condensate. Eur J Appl Physiol 106: 599‐604, 2009.
 88. Helms MN, Jain L, Self JL, Eaton DC. Redox regulation of epithelial sodium channels examined in alveolar Type 1 and 2 cells patch‐clamped in lung slice tissue. J Biol Chem 283: 22875‐22883, 2008.
 89. Herigstad M, Robbins PA. Pulmonary vascular response to air‐breathing exercise in humans following an 8‐h exposure to hypoxia. Respir Physiol Neurobiol 169: 11‐15, 2009.
 90. Hohenhaus E, Paul A, McCullough RE, Kucherer H, Bartsch P. Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J 8: 1825‐1833, 1995.
 91. Höhne C, Pickerodt PA, Francis RC, Boemke W, Swenson ER. Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition. Am J Physiol Lung Cell Mol Physiol 292: L178‐L184, 2007.
 92. Homik LA, Bshouty Z, Light RB, Younes M. Effect of alveolar hypoxia on pulmonary fluid filtration in in situ dog lungs. J Appl Physiol 65: 46‐52, 1988.
 93. Hopkins SR, Garg J, Bolar DS, Balouch J, Levin DL. Pulmonary blood flow heterogeneity during hypoxia and high‐altitude pulmonary edema. Am J Respir Crit Care Med 171: 83‐87, 2005.
 94. Hopkins SR, Schoene RB, Henderson WR, Spragg RG, Martin TR, West JB. Intense exercise impairs the integrity of the pulmonary blood‐gas barrier in elite athletes. Am J Respir Crit Care Med 155: 1090‐1094, 1997.
 95. Hopkins SR, Sheel AW, McKenzie DC. Point: Counterpoint “Pulmonary edema does/does not occur in human athletes performing heavy sea‐level exercise.” J Appl Physiol 109: 1270‐1972, 2010.
 96. Houston CS. Acute pulmonary edema of high altitude. N Engl J Med 263: 478‐480, 1960.
 97. Hultgren HN, Honigman B, Theis K, Nicholas D. High altitude pulmonary edema at a ski resort. West J Med 164: 222‐227, 1996.
 98. Hultgren HN, Lopez CE, Lundberg E, Miller H. Physiologic studies of pulmonary edema at high altitude. Circulation 29: 393‐408, 1964.
 99. Hultgren HN, Martcorena E. High altitude pulmonary edema. Epidemiologic observations in Peru. Chest 74: 372‐376, 1978.
 100. Hultgern HN and Spickard W. Medical experiences in Peru. Stanford Med Bull 18: 76‐95, 1960.
 101. Hyers TM, Fowler AA, Wicks AB. Focal pulmonary edema after massive pulmonary embolism. Am Rev Respir Dis 123: 232‐233, 1981.
 102. Ide H, Nakano H, Ogasa T, Osanai S, Kikuchi K, Iwamoto J. Regulation of pulmonary circulation by alveolar oxygen tension via airway nitric oxide. J Appl Physiol 87: 1629‐1636, 1999.
 103. Imoberdorf R, Garlick PJ, McNurlan MA, Casella GA, Peheim E, Turgay M, Bartsch P, Ballmer PE. Enhanced synthesis of albumin and fibrinogen at high altitude. J Appl Physiol 90: 528‐537, 2001.
 104. Irwin DC, McCord JM, Nozik‐Grayck E, Beckly G, Foreman B, Sullivan T, White MT, Crossno J, Jr., Bailey D, Flores SC, Majka S, Klemm D, Tissot van Patot MC. A potential role for reactive oxygen species and the HIF‐1[alpha]‐VEGF pathway in hypoxia‐induced pulmonary vascular leak. Free Rad Biol Med 47: 55‐61, 2009.
 105. Irwin DC, Subudhi AW, Klopp L, Peterson D, Roach R, Monnet E. Pulmonary edema induced by cerebral hypoxic insult in a canine model. Aviat Space Environ Med 79: 472‐478, 2008.
 106. Jaeger JJ, Sylvester JT, Cymerman A, Berberich JJ, Denniston JC, Maher JT. Evidence for increased intrathoracic fluid volume in man at high altitude. J Appl Physiol 47: 670‐676, 1979.
 107. Jonk AM, van den Berg IP, Olfert IM, Wray DW, Arai T, Hopkins SR, Wagner PD. Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic and hypoxic exercise. J Physiol 579: 909‐921, 2007.
 108. Kanazawa H, Okamoto T, Hirata K, Yoshikawa J. Deletion polymorphisms in the angiotensin converting enzyme gene are associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 162: 1235‐1238, 2000.
 109. Kaner RJ, Crystal RG. Pathogenesis of high altitude pulmonary edema: Does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak. High Alt Med Biol 5: 399‐499, 2004.
 110. Kawashima A, Kubo K, Kobayashi T, Sekiguchi M. Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high‐altitude pulmonary edema. J Appl Physiol 67: 1982‐1989, 1989.
 111. Khan DA, Hashim R, Mizra TM. Differentiation of pulmonary embolism form high altitude pulmonary edema. J Coll Phys Surg Pak 13: 267‐270, 2003.
 112. Kleger G‐R, Bartsch P, Vock P, Heilig B, Roberts LJ, II, Ballmer PE. Evidence against an increase in capillary permeability in subjects exposed to high altitude. J Appl Physiol 81: 1917‐1923, 1996.
 113. Kleinsasser A, Levin DL, Loeckinger A, Hopkins SR. A pig model of high altitude pulmonary edema. High Alt Med Biol 4: 465‐474, 2003.
 114. Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ. Effect of ascorbate on the activity of hypoxia‐inducible factor in cancer cells. Cancer Res 63: 1764‐1768, 2003.
 115. Koch RO, Hinterhuber L, Faulhaber M, Gatterer H, Graupner S, Muenzel K, Burtscher M. A successful therapy of high‐altitude pulmonary edema with a CPAP helmet on lenin peak. Clin J Sport Med 19: 72‐73, 2009.
 116. Kriemler S, Jansen C, Linka A, Kessel‐Schaefer A, Zehnder M, Schurmann T, Kohler M, Bloch K, Brunner‐La Rocca HP. Higher pulmonary artery pressure in children than in adults upon fast ascent to high altitude. Eur Respir J 32: 664‐669, 2008.
 117. Kriemler S, Kohler M, Zehnder M, Bloch KE, Rocca HB‐L. Successful treatment of severe acute mountain sickness and excessive pulmonary hypertension with dexamethasone in a prepubertal girl. High Alt Med Biol 7: 256‐261, 2006.
 118. Kubo K, Hanaoka M, Hayano T, Miyahara T, Hachiya T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, Honda T. Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high‐altitude pulmonary edema. Respir Physiol 111: 301‐310, 1998.
 119. Kubo K, Hanaoka M, Yamaguchi S, Hayano T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, Honda T. Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan. Thorax 51: 739‐742, 1996.
 120. Kuebler WM, Ying X, Singh B, Issekutz AC, Bhattacharya J. Pressure is pro‐inflammatory in lung venular capillaries. J Clin Invest 104: 495‐502, 1999.
 121. Kumar R PQ, Khan AP, Gupta V. Renin angiotensin aldosterone system and ACE I/D gene polymorphism in high altitude pulmonary edema. Aviat Space Environ Med 75: 981‐983, 2004.
 122. Lahm T, Crisostomo PR, Markel TA, Wang M, Wang Y, Tan J, Meldrum DR. Selective estrogen receptor‐{alpha} and estrogen receptor‐{beta} agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide‐dependent mechanism. Am J Physiol 295: R1486‐R1493, 2008.
 123. Lamm WJE, Starr IR, Neradilek B, Polissar NL, Glenny RW, Hlastala MP. Hypoxic pulmonary vasoconstriction is heterogeneously distributed in the prone dog. Respir Physiol Neurobiol 144: 281‐294, 2004.
 124. Laufs U, Fata VL, Liao JK. Inhibition of 3‐hydroxy‐3‐methylglutaryl (HMG)‐CoA reductase blocks hypoxia‐mediated down‐regulation of endothelial nitric oxide synthase. J Biol Chem 272: 31725‐31729, 1997.
 125. Lindert J, Perlman CE, Parthasarathi K, Bhattacharya J. Chloride‐dependent secretion of alveolar wall liquid determined by optical‐sectioning microscopy. Am J Respir Cell Mol Biol 36: 688‐696, 2007.
 126. Liu C, Smith TG, Balanos GM, Brooks J, Crosby A, Herigstad M, Dorrington KL, Robbins PA. Lack of involvement of the autonomic nervous system in early ventilatory and pulmonary vascular acclimatization to hypoxia in humans. J Physiol 579: 215‐225, 2007.
 127. Lizarraga L. Soroche agudo: Edema agudo del pulmón. An Fac Med (San Marco, Lima) 38: 244‐274, 1955.
 128. Loeh B, Baloglu E, Ke A, Bärtsch P, Mairbäurl H. Beta2‐adrenergic stimulation blunts inhibition of epithelial ion transport by hypoxia of rat alveolar epithelial cells. Cell Physiol Biochem 25: 123‐134, 2010.
 129. Luhrs H, Papadopoulos T, Schmidt HH, Menzel T. Type I nitric oxide synthase in the human lung expressed in capillary endothelial cells. Respir Physiol 129: 367‐374, 2002.
 130. Luks AM. Do we have a ‘best practice’ for treating high altitude pulmonary edema. High Alt Med Biol 9: 111‐114, 2008.
 131. Luks AM, Swenson ER. Travel to high altitude with pre‐existing lung disease. Eur Respir J 29: 770‐792, 2007.
 132. Maggiorini M, Brunner‐La Rocca H‐P, Peth S, Fischler M, Böhm T, Bernheim A, Kiencke S, Bloch KE, Dehnert C, Naeije R, Lehmann T, Bartsch P, Mairbaeurl H. Both tadalafil and dexamethasone may reduce the incidence of high‐altitude pulmonary edema. Ann Intern Med 145: 497‐506, 2006.
 133. Maggiorini M, Leon‐Velarde F. High‐altitude pulmonary hypertension: A pathophysiological entity to different diseases. Eur Respir J 22: 1019‐1025, 2003.
 134. Maggiorini M, Melot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U, Naeije R. High‐altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 103: 2078‐2083, 2001.
 135. Maggiorini M, Streit M, Siebenmann C. Dexamethasone decreases systemic inflammatory and stress response and favors vasodilation in high altitude pulmonary edema susceptibles at 4559 m. International Hypoxia Symposium, Lake Louise, Canada 2009, p. 58.
 136. Mairbäurl H. Role of alveolar epithelial sodium transport in high altitude pulmonary edema (HAPE). Respir Physiol Neurobiol 151: 178‐191, 2006.
 137. Mairbäurl H, Schwobel F, Hoschele S, Maggiorini M, Gibbs S, Swenson ER, Bärtsch P. Altered ion transporter expression in bronchial epithelium in mountaineers with high‐altitude pulmonary edema. J Appl Physiol 95: 1843‐1850, 2003.
 138. Mairbäurl H, Weymann J, Mohrlein A, Swenson ER, Maggiorini M, Gibbs JSR, Bärtsch P. Nasal epithelium potential difference at high altitude (4,559 m): Evidence for secretion. Am J Respir Crit Care Med 167: 862‐867, 2003.
 139. Maron M, Pilati C. Neurogenic pulmonary edema. In: Matthay M, Ingbar D, editors. Pulmonary Edema, New York: Marcel Dekker, 1998, pp. 319‐354.
 140. Maron MB, Fu Z, Mathieu‐Costello O, West JB. Effect of high transcapillary pressures on capillary ultrastructure and permeability coefficients in dog lung. J Appl Physiol 90: 638‐648, 2001.
 141. Marshall BE, Marshall C, Magno M, Lilagan P, Pietra GG. Influence of bronchial arterial PO2 on pulmonary vascular resistance. J Appl Physiol 70: 405‐415, 1991.
 142. Mason NP, Petersen M, Melot C, Imanow B, Matveykine O, Gautier M‐T, Sarybaev A, Aldashev A, Mirrakhimov MM, Brown BH, Leathard AD, Naeije R. Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude. J Appl Physiol 94: 2043‐2050, 2003.
 143. Matsuzawa Y, Fujimoto K, Kobayashi T, Namushi NR, Harada K, Kohno H, Fukushima M, Kusama S. Blunted hypoxic ventilatory drive in subjects susceptible to high‐altitude pulmonary edema. J Appl Physiol 66: 1152‐1157, 1989.
 144. Mazzeo RS, Donovan D, Fleshner M, Butterfield GE, Zamudio S, Wolfel EE, Moore LG. Interleukin‐6 response to exercise and high‐altitude exposure: Influence of alpha‐adrenergic blockade. J Appl Physiol 91: 2143‐2149, 2001.
 145. Miller WT Jr, Osiason AW, Langlotz CP, Palevsky HI. Reperfusion edema after thromboendarterectomy: Radiographic patterns of disease. J Thorac Imaging 13: 178‐183, 1998.
 146. Ming Z, Wang D. Sympathetic innervation of lung circulation and its role in hypoxic pulmonary vasoconstriction. J Tongji Med Univ 9: 153‐159, 1989.
 147. Miserocchi G. Lung interstitial pressure and structure in acute hypoxia. Adv Exp Med Biol 618: 141‐157, 2007.
 148. Miserocchi G, Passi A, Negrini D, Del Fabbro M, De Luca G. Pulmonary interstitial pressure and tissue matrix structure in acute hypoxia. Am J Physiol Lung Cell Mol Physiol 280: L881‐L887, 2001.
 149. Modesti PA, Vanni S, Morabito M, Modesti A, Marchetta M, Gamberi T, Sofi F, Savia G, Mancia G, Gensini GF, Parati G. Role of endothelin‐1 in exposure to high altitude: Acute mountain sickness and endothelin‐1 (ACME‐1) study. Circulation 114: 1410‐1416, 2006.
 150. Mortimer H, Patel S, Peacock AJ. The genetic basis of high‐altitude pulmonary oedema. Pharmacol Ther 101: 183‐192, 2004.
 151. Muir AL, Flenley DC, Kirby BJ, Sudlow MF, Guyatt AR, Brash HM. Cardiorespiratory effects of rapid saline infusion in normal man. J Appl Physiol 38: 786‐775, 1975.
 152. Mundy AL, Dorrington KL. Inhibition of nitric oxide synthesis augments pulmonary edema in isolated perfused rabbit lung. Br J Anaesth 85: 570‐576, 2000.
 153. Murata T, Hori M, Sakamoto K, Karaki H, Ozaki H. Dexamethasone blocks hypoxia‐induced endothelial dysfunction in organ‐cultured pulmonary arteries. Am J Respir Crit Care Med 170: 647‐655, 2004.
 154. Mutlu GM, Adir Y, Jameel M, Akhmedov AT, Welch L, Dumasius V, Meng FJ, Zabner J, Koenig C, Lewis ER, Balagani R, Traver G, Sznajder JI, Factor P. Interdependency of beta‐adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ Res 96: 999‐1005, 2005.
 155. Myers JL, Wizorek JJ, Myers AK, O'Donoghue M, Pettit MT, Kouretas PC, Dalton HJ, Wang Y, Hopkins RA. Maturation alters the pulmonary arterial response to hypoxia and inhaled nitric oxide in the presence of endothelial dysfunction. J Thorac Cardiovasc Surg 113: 270‐277, 1997.
 156. Naeije R, Huez S, Lamotte M, Retailleau K, Neupane S, Abramowicz D, Faoro V. Pulmonary artery pressure limits exercise capacity at high altitude. Eur Respir J 36: 1049‐1055, 2010.
 157. Nagyova B, O'Neill M, Dorrington KL. Inhibition of active sodium absorption leads to a net liquid secretion into in vivo rabbit lung at two levels of alveolar hypoxia. Br J Anaesth 87: 897‐904, 2001.
 158. Nayak NC, Roy S, Narayanan TK. Pathologic features of altitude sickness. Am J Pathol 45: 381‐391, 1964.
 159. O'Brodovich H. Epithelial ion transport in the fetal and perinatal lung. Am J Physiol Cell Physiol 261: C555‐C564, 1991.
 160. Oelz O, Ritter M, Jenni R, Maggiorini M, Waber U, Vock P, Bärtsch P. Nifedipine for high altitude pulmonary edema. Lancet 334: 1241‐1244, 1989.
 161. Olson KR, Dombkowski RA, Russell MJ, Doellman MM, Head SK, Whitfield NL, Madden JA. Hydrogen sulfide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation. J Exp Biol 209: 4011‐4023, 2006.
 162. Olson KR, Whitfield NL, Bearden SE, St. Leger J, Nilson E, Gao Y, Madden JA. Hypoxic pulmonary vasodilation: A paradigm shift with a hydrogen sulfide mechanism. Am J Physiol 298: R51‐R60, 2010.
 163. Ono S, Westcott JY, Chang SW, Voelkel NF. Endotoxin priming followed by high altitude causes pulmonary edema in rats. J Appl Physiol 74: 1534‐1542, 1993.
 164. Parker JC, Ivey CL. Isoproterenol attenuates high vascular pressure‐induced permeability increases in isolated rat lungs. J Appl Physiol 83: 1962‐1967, 1997.
 165. Parker JC, Ivey CL, Tucker JA. Gadolinium prevents high airway pressure‐induced permeability increases in isolated rat lungs. J Appl Physiol 84: 1113‐1118, 1998.
 166. Parker JC, Stevens T, Randall J, Weber DS, King JA. Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers. Am J Physiol Lung Cell Mol Physiol 291: L30‐L37, 2006.
 167. Pavlicek V, Marti HH, Grad S, Gibbs JS, Kol C, Wenger RH, Gassmann M, Kohl J, Maly FE, Oelz O, Koller EA, Schirlo C. Effects of hypobaric hypoxia on vascular endothelial growth factor and the acute phase response in subjects who are susceptible to high‐altitude pulmonary oedema. Eur J Appl Physiol 81: 497‐503, 2000.
 168. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Focus on muscle‐derived interleukin‐6. Physiol Rev 88: 1379‐1406, 2008.
 169. Pellegrino R, Pompilio P, Quaranta M, Aliverti A, Kayser B, Miserocchi G, Fasano V, Cogo A, Milanese M, Cornara G, Brusasco V, Dellaca R. Airway responses to methacholine and exercise at high altitude in healthy lowlanders. J Appl Physiol 108: 256‐265, 2010.
 170. Pelletier N, Robinson NE, Kaiser L, Derksen FJ. Regional differences in endothelial function in horse lungs: Possible role in blood flow distribution? J Appl Physiol 85: 537‐542, 1998.
 171. Penaloza D, Sime F. Circulatory dynamics during high altitude pulmonary edema. Am J Cardiol 23: 369‐378, 1969.
 172. Penaloza D, Sime F, Ruiz L. Pulmonary hemodynamics in children living at high altitudes. High Alt Med Biol 9: 199‐207, 2008.
 173. Peth S, Karle C, Dehnert C, Bartsch P, Mairbaurl H. K+ Channel activation with minoxidil stimulates nasal‐epithelial ion transport and blunts exaggerated hypoxic pulmonary hypertension. High Alt Med Biol 7: 54‐63, 2006.
 174. Podolsky A, Eldridge MW, Richardson RS, Knight DR, Johnson EC, Hopkins SR, Johnson DH, Michimata H, Grassi B, Feiner J, Kurdak SS, Bickler PE, Severinghaus JW, Wagner PD. Exercise‐induced VA/Q inequality in subjects with prior high‐altitude pulmonary edema. J Appl Physiol 81: 922‐932, 1996.
 175. Predescu D, Predescu S, Shimizu J, Miyawaki‐Shimizu K, Malik AB. Constitutive eNOS‐derived nitric oxide is a determinant of endothelial junctional integrity. Am J Physiol Lung Cell Mol Physiol 289: L371‐L381, 2005.
 176. Prisk GK, Olfert IM, Arai TJ, Wagner PD, Hopkins SR. Rapid intravenous infusion of 20 ml/kg saline does not impair resting pulmonary gas exchange in the healthy human lung. J Appl Physiol 108: 53‐59, 2010.
 177. Prouillac C, Vicendo P, Garrigues J‐C, Poteau R, Rima G. Evaluation of new thiadiazoles and benzothiazoles as potential radioprotectors: Free radical scavenging activity in vitro and theoretical studies (QSAR, DFT). Free Rad Biol Med 46: 1139‐1148, 2009.
 178. Rashid H, Hashmi SN, Hussain T. Risk factors in high altitude pulmonary oedema. J Coll Physicians Surg Pak 15: 96‐99, 2005.
 179. Regensteiner JG, Woodard WD, Hagerman DD, Weil JV, Pickett CK, Bender PR, Moore LG. Combined effects of female hormones and metabolic rate on ventilatory drives in women. J Appl Physiol 66: 808‐813, 1989.
 180. Ricciardolo FLM, Sterk PJ, Gaston B, Folkerts G. Nitric oxide in health and disease of the respiratory system. Physiol Rev 84: 731‐765, 2004.
 181. Robertson HT, Pellegrino R, Pini D, Oreglia J, DeVita S, Brusasco V, Agostoni P. Exercise response after rapid intravenous infusion of saline in healthy humans. J Appl Physiol 97: 697‐703, 2004.
 182. Rock P, Patterson GA, Permutt S, Sylvester JT. Nature and distribution of vascular resistance in hypoxic pig lungs. J Appl Physiol 59: 1891‐1901, 1985.
 183. Runyon M, Bhargava M, Wangensteen D. Acetazolamide stimulates alveolar fluid clearance in ventilated adult rats. Crit Care Med 171: A561, 2005.
 184. Sartori C, Allemann Y, Trueb L, Lepori M, Maggiorini M, Nicod P, Scherrer U. Exaggerated pulmonary hypertension is not sufficient to trigger high‐altitude pulmonary oedema in humans. Schweiz Med Wochenschr 130: 385‐389, 2000.
 185. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, Scherrer U. Salmeterol for the prevention of high‐altitude pulmonary edema. N Engl J Med 346: 1631‐1636, 2002.
 186. Sartori C, Duplain H, Lepori M, Egli M, Maggiorini M, Nicod P, Scherrer U. High altitude impairs nasal transepithelial sodium transport in HAPE‐prone subjects. Eur Respir J 23: 916‐920, 2004.
 187. Sartori C, Vollenweider L, Loffler B‐M, Delabays A, Nicod P, Bärtsch P, Scherrer U. Exaggerated endothelin release in high‐altitude pulmonary edema. Circulation 99: 2665‐2668, 1999.
 188. Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger G‐R, Fikrle A, Ballmer PE, Nicod P, Bärtsch P. Inhaled nitric oxide for high‐altitude pulmonary edema. N Engl J Med 334: 624‐630, 1996.
 189. Scheult RD, Ruh K, Foster GP, Anholm JD. Prophylactic bosentan does not improve exercise capacity or lower pulmonary artery systolic pressure at high altitude. Respir Physiol Neurobiol 165: 123‐130, 2009.
 190. Schirlo C, Pavlicek V, Jacomet A, Gibbs JSR, Koller E, Oelz O, Seebauer M, Kohl J. Characteristics of the ventilatory response in subjects susceptible to high altitude Pulmonary edema during acute and prolonged hypoxia. High Alt Med Biol 3: 267‐276, 2002.
 191. Schoene RB, Hackett PH, Henderson WH, Sage EH, Chow M, Roach RS, Mills WJ, Martin TR. High altitude pulmonary edema: Characteristics of lung lavage fluid. J Am Med Assoc 256: 63‐69, 1986.
 192. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ, Jr., Henderson WR, Jr., Martin TR. The lung at high altitude: Bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 64: 2605‐2613, 1988.
 193. Scoggin CH, Hyers TM, Reeves JT, Grover RF. High‐altitude pulmonary edema in the children and young adults of Leadville, Colorado. N Engl J Med 297: 1269‐1272, 1977.
 194. Senn O, Clarenbach CF, Fischler M, Thalmann R, Brunner‐La Rocca H, Egger P, Maggiorini M, Bloch KE. Do changes in lung function predict high‐altitude pulmonary edema at an early stage? Med Sci Sports Exerc 38: 1565‐1570, 2006.
 195. She J, Shen J, Goolaerts A, Song Y, Shen C, Hong Q, Bai C. Stress failure plays a major role in the development of high altitude pulmonary oedema. Eur Respir J 35: 584‐591, 2010.
 196. Shimoda LA, Luke T, Sylvester JT, Shih H‐W, Jain A, Swenson ER. Inhibition of hypoxia‐induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition. Am J Physiol Lung Cell Mol Physiol 292: L1002‐L1012, 2007.
 197. Smith TG, Talbot NP, Privat C, Rivera‐Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, Leon‐Velarde F, Robbins PA. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: Two randomized controlled trials. J Am Med Assoc 302: 1444‐1450, 2009.
 198. Snyder EM, Beck KC, Hulsebus ML, Breen JF, Hoffman EA, Johnson BD. Short‐term hypoxic exposure at rest and during exercise reduces lung water in healthy humans. J Appl Physiol 101: 1623‐1632, 2006.
 199. Staub NC, Nagano H, Pearce ML. Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 22: 227‐240, 1967.
 200. Steinacker JM, Tobias P, Menold E, Reissnecker S, Hohenhaus E, Liu Y, Lehmann M, Bartsch P, Swenson ER. Lung diffusing capacity and exercise in subjects with previous high altitude pulmonary oedema. Eur Respir J 11: 643‐650, 1998.
 201. Stelzner TJ, O'Brien RF, Sato K, Weil JV. Hypoxia‐induced increases in pulmonary trans‐vascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest 82: 1840‐1847, 1988.
 202. Swenson ER, MacDonald A, Vatheuer M, Maks C, Treadwell A, Allen R, Schoene RB. Acute mountain sickness is not altered by a high carbohydrate diet nor associated with elevated circulating cytokines. Aviat Space Environ Med 68: 449‐503, 1997.
 203. Swenson ER, Duncan TB, Goldberg SV, Ramirez G, Ahmad S, Schoene RB. Diuretic effect of acute hypoxia in humans: Relationship to hypoxic ventilatory responsiveness and renal hormones. J Appl Physiol 78: 377‐383, 1995.
 204. Swenson ER, Maggiorini M, Mongovin S, Gibbs JSR, Greve I, Mairbaurl H, Bärtsch P. Pathogenesis of high‐altitude pulmonary edema: Inflammation is not an etiologic factor. J Am Med Assoc 287: 2228‐2235, 2002.
 205. Swenson ER, Mongovin S, Maggiorini M. Alveolar macrophage interleukin‐6 response to hypoxia and lipopolysaccharide in high altitude pulmonary edema‐susceptible and ‐resistant mountaineers. Am J Respir Crit Care Med 163: A618, 2001.
 206. Szidon JP, Pietra GG, Fishman AP. The alveolar‐capillary membrane and pulmonary edema. N Engl J Med 286: 1200‐1204, 1972.
 207. Taber RL. Protocols for use of portable hyperbaric chambers for treatment of high altitude disorders. J Wildern Med 1: 181‐192, 1990.
 208. Talbot NP, Balanos GM, Dorrington KL, Robbins PA. Two temporal components within the human pulmonary vascular response to ∼2 h of isocapnic hypoxia. J Appl Physiol 98: 1125‐1139, 2005.
 209. Talbot NP, Balanos GM, Robbins PA, Dorrington KL. Can intravenous endothelin‐1 be used to enhance hypoxic pulmonary vasoconstriction in healthy humans? Br J Anaesth 101: 466‐472, 2008.
 210. Taylor AE. The lymphatic edema safety factor: The role of edema dependent lymphatic factors. Lymphol 23: 111‐123, 1990.
 211. Teppema LJ, Balanos GM, Steinback CD, Brown AD, Foster GE, Duff HJ, Leigh R, Poulin MJ. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 175: 277‐281, 2007.
 212. Thomas LJJ, Griffo ZJ, Roos A. Effect of negative‐pressure inflation of the lung on pulmonary vascular resistance. J Appl Physiol 16: 451‐456, 1961.
 213. Tucker A, Greenlees KJ, Wright ML, Migally N. Altered vascular responsiveness in isolated perfused lungs from aging rats. Exp Lung Res 31: 29‐35, 1982.
 214. van Heerden PV, Cameron PD, Karanovic A, Goodman MA. Orthodeoxia: Uncommon presentation following bilateral sympathectomy. Anaesth Intensive Care 31: 581‐583, 2003.
 215. Vaughan DJ, Brogan TV, Kerr ME, Deem S, Luchtel DL, Swenson ER. Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs. J Appl Physiol 284: L834‐L843, 2003.
 216. Vivona ML, Matthay M, Chabaud MB, Friedlander G, Clerici C. Hypoxia reduces alveolar epithelial sodium and fluid transport in rats . Reversal by beta‐adrenergic agonist treatment. Am J Respir Cell Mol Biol 25: 554‐561, 2001.
 217. Vock P, Brutsche MH, Nanzer A, Bärtsch P. Variable radiomorphologic data of high altitude pulmonary edema. Features from 60 patients. Chest 100: 1306‐1311, 1991.
 218. Waypa GB, Marks JD, Guzy R, Mungai PT, Schriewer J, Dokic D, Schumacker PT. Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circ Res 106: 526‐535, 2010.
 219. Weil JV. Variation in human ventilatory control–genetic influence on the hypoxic ventilatory response. Respir Physiol Neurobiol 135: 239‐246, 2003.
 220. Weiss J, Haefeli WE, Gasse C, Hoffmann MM, Weyman J, Gibbs S, Mansmann U, Bärtsch P. Lack of evidence for association of high altitude pulmonary edema and polymorphisms of the NO Pathway. High Alt Med Biol 4: 355‐366, 2003.
 221. West JB. Thoughts on the pulmonary blood‐gas barrier. Am J Physiol Lung Cell Mol Physiol 285: L501‐L513, 2003.
 222. West JB, Colice GL, Lee YJ, Namba Y, Kurdak SS, Fu Z, Ou LC, Mathieu‐Costello O. Pathogenesis of high‐altitude pulmonary oedema: Direct evidence of stress failure of pulmonary capillaries. Eur Respir J 8: 523‐529, 1995.
 223. West JB, Mathieu‐Costello O, Jones JH, Birks EK, Logemann RB, Pascoe JR, Tyler WS. Stress failure of pulmonary capillaries in racehorses with exercise‐induced pulmonary hemorrhage. J Appl Physiol 75: 1097‐1109, 1993.
 224. Wetzel RC, Zacur HA, Sylvester JT. Effect of puberty and estradiol on hypoxic vasomotor response in isolated sheep lungs. J Appl Physiol 56: 1199‐1203, 1984.
 225. Whayne TF, Jr., Severinghaus JW. Experimental hypoxic pulmonary edema in the rat. J Appl Physiol 25: 729‐732, 1968.
 226. Wilson LB, Levitzky MG. Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated. J Appl Physiol 66: 782‐791, 1989.
 227. Wodopia R, Ko HS, Billian J, Wiesner R, Bärtsch P, Mairbäurl H. Hypoxia decreases proteins involved in epithelial electrolyte transport in A549 cells and rat lung. Am J Physiol Lung Cell Mol Physiol 279: L1110‐L1119, 2000.
 228. Yang C, Su L, Wang Y, Liu L. UTP regulation of ion transport in alveolar epithelial cells involves distinct mechanisms. Am J Physiol Lung Cell Mol Physiol 297: L439‐L454, 2009.
 229. Younes M, Bshouty Z, Ali J. Longitudinal distribution of pulmonary vascular resistance with very high pulmonary blood flow. J Appl Physiol 62: 344‐358, 1987.
 230. Young SL, Ho YS, Silbajoris RA. Surfactant apoprotein in adult rat lung compartments is increased by dexamethasone. Am J Physiol Lung Cell Mol Physiol 260: L161‐L167, 1991.
 231. Zhang F, Kaide JI, Yang L, Jiang H, Quan S, Kemp R, Gong W, Balazy M, Abraham NG, Nasjletti A. CO modulates pulmonary vascular response to acute hypoxia: Relation to endothelin. Am J Physiol 286: H137‐H144, 2004.
 232. Zheng W, Kuhlicke J, Jackel K, Eltzschig HK, Singh A, Sjoblom M, Riederer B, Weinhold C, Seidler U, Colgan SP, Karhausen J. Hypoxia inducible factor‐1 (HIF‐1)‐mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium. FASEB J 23: 204‐213, 2009.
 233. Zhou G, Dada LA, Sznajder JI. Regulation of alveolar epithelial function by hypoxia. Eur Respir J 31: 1107‐1113, 2008.
 234. Zielinski J. Effects of intermittent hypoxia on pulmonary haemodynamics: Animal models versus studies in humans. Eur Respir J 25: 173‐180, 2005.

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Erik R. Swenson, Peter Bärtsch. High‐Altitude Pulmonary Edema. Compr Physiol 2012, 2: 2753-2773. doi: 10.1002/cphy.c100029