Stress failure and high-altitude pulmonary oedema: mechanistic insights from physiology

Abstract

H igh-altitude pulmonary oedema (HAPE) is a potentially fatal altitude illness affecting individuals within 2-4 days of rapid ascent to altitudes above 3,000 m. Although a minority of high-altitude travellers develop HAPE [1], there is some suggestion that many develop subclinical fluid accumulation without overt alveolar flooding [2]. The inciting mechanism of the injury to the lung in HAPE still generates some controversy. However, there is an evergrowing body of evidence that mechanical injury to the pulmonary capillaries induced by high transmural pressures starts a cascade of events that ultimately results in the development of HAPE. This injury, termed ''stress failure'' described by WEST et al. [3], refers to mechanically induced breaks in the blood-gas barrier, and these have been suggested to be important the pathophysiology of a number of human diseases [4].In animals, when pulmonary capillaries are subjected to increased transmural pressure, ultrastructural changes consisting of discrete areas of damage to the blood-gas barrier, with rupture of the capillary endothelium, extracellular matrix and the alveolar epithelium, interspersed with large areas of structurally intact blood-gas barrier are observed [5]. Accompanying this is increased permeability of the lung to protein and red blood cells, as measured by increased concentrations in bronchoalveolar lavage fluid [6]. Leukotriene (LT)B 4 concentration is also increased in bronchoalveolar lavage fluid [6], perhaps representing cellular activation by exposed basement membrane. Similar findings are observed in some humans following maximal exercise in normoxia [7] where bronchoalveolar lavage fluid contains increased concentrations of red cells, protein and LTB 4 thought to result from high pulmonary capillary pressures. In both of these instances, the blood-gas barrier retains sieving function for large molecular weight proteins [6]. However, in established HAPE, permeability to macromolecules is increased [8], and an inflammatory response of the lung to hypoxia has been suggested as an alternate mechanism [9]. In addition, some authors have suggested that HAPE results from altered sodium and water handling by the susceptible lung [10].Stress failure has been suggested to be important in the development of HAPE largely because of the relationship between high pulmonary vascular pressures and the development of HAPE. A previous history of HAPE is the single greatest predictor of the development of HAPE in future exposures and HAPE-susceptible individuals generally have augmented hypoxic pulmonary vasoconstriction and increased pulmonary vascular pressures when exposed to hypoxia [11][12][13][14][15] and exercise [16]. In addition, drugs such as sidenafil, nifedipine, tadaphil and dexamethasone reduce pulmonary vascular pressures and reduce the severity of HAPE [17,18] or prevent the development when administered prophylactically [19]. Since the primary site of hypoxic pulmonary vasoconstriction is thought to be pre-capillary, hypoxic pulmonary vasoconst...

Genome Wide Expression Analysis Suggests Perturbation of Vascular Homeostasis during High Altitude Pulmonary Edema

“…However, it has also been argued in literature that initial damage to blood-gas barrier because of ‘stress failure’ is self limiting owing to the propensity for quick closure of this barrier after pressure reduction [23]. This strongly suggests the existence of confounding parallel factors complementing initial stress failure for clinical presentation of HAPE which may arise from conjunction of multiple factors besides capillary stress failure [24].…”

“…Vascular injury is usually induced by factors such as altered shear stress, oxidative stress, cytokine, and vascular tone modulators such as endothelin-1, angiotensin II amongst others . Notwithstanding the limitation of single time point study which is less likely to suggest cause/consequence relationship between various events, our global expression profiling for HAPE and acclimatized individuals evoked several interesting mechanistic possibilites besides generating molecular evidence for well known physiological processes involved in HAPE [23], [25]. We observed multiple pathways to be modulated under these conditions which appear to be reminiscent of three broad physiological processes: 1) regulation of capillary pressure (stress failure), 2) modulation of barrier function (endothelial permeability/dysfunction) and 3) differential regulation of hypoxia sensing/response pathways.…”

The trans-Himalayan flights of bar-headed geese ( Anser indicus )

“…These adaptations should significantly improve O 2 uptake and transport at high altitudes, and may contribute to this species' ability to climb thousands of meters of elevation without acclimatization. This feat is particularly impressive when considering that humans could suffer dizziness, altitude sickness, high-altitude pulmonary edema (HAPE) (17), and possibly even death when faced with a similarly extreme change in elevation. In the present study, we detail how the transHimalayan migration of bar-headed geese is achieved and provide insights into their aerobic flight capacity.…”

Unveiling the interactions among BMPR-2, ALK-1 and 5-HTT genes in the pathophysiology of HAPE

“…BMP-2, bone morphogenetic protein-2; 5-HT, 5-hydroxytryptamine; MAP, mean arterial pressure; SaO 2 , percent arterial oxygen saturation; HAPE-p, HAPE patients; HAPE-f, HAPE free sojourners. (Hopkins et al, 2005;West et al, 1991;Hopkins, 2010) and animals at HA (West et al, 1995). It was reported that differential expression of 5-HTT under hypoxia altered the 5-HT function (Machado et al, 2006;Eddahibi et al, 2001), causing pulmonary vessel remodeling (Machado et al, 2006;MacLean et al, 1996;Lee et al, 1994).…”