Going to altitude? Bring your vitamins!

The author was treated for HAPE in the Capana Regina Margherita during studies in 1999.

More than 100 years ago Italian physiologist Angelo Mosso described a soldier who upon arrival to the then just build Capana Regina Margherita research hut on the summit of Monte Rosa (4559 m) developed severe headache, then cyanosis, dyspnoea, tachycardia, riles and pink frothy sputum, but had no high fever (Mosso, 1898). Although puzzling at the time, this soldier would very likely be diagnosed with high altitude pulmonary oedema (HAPE) today. HAPE is an uncommon form of non-cardiogenic pulmonary oedema which may occur if a person ascends to altitudes higher than 2500 m too fast. It usually occurs 1–2 days after arrival at high altitude, and the incidence rate is 0.1 to 15% depending on altitude, ascent rate, physical exhaustion, individual susceptibility to HAPE and likely coexisting cardiopulmonary disease (Bartsch et al. 2005). When exposed to high altitude a rapid shift in body fluids from intra- to extravascular compartments is a frequent observation. This is especially true for the lungs where hypoxic pulmonary vasoconstriction (HPV) leads to an augmented pulmonary artery pressure (PAP). HAPE usually begins when PAP exceeds 35–40 mmHg corresponding to pressures higher than 20 mmHg in the capillaries (Maggiorini et al. 2001). Pressures of this magnitude in the microcirculation, and the uneven distribution of HPV potentially leading to overperfusion of patent vessels, may lead to capillary stress failure in which the alveolar–capillary membrane becomes permeable to high molecular weight proteins and subsequently fluid leaks into the interstitial and alveolar space and thereby limits gas exchange.

In combination with increased microvasculature pressures, several other hypotheses have been proposed to contribute to the further development of HAPE. One suggests hypoxia leads to a pulmonary inflammatory reaction and secondary to this an increase capillary permeability. Based on broncho-alveolar lavage studies, however, it is felt that HAPE is a hydrostatic ‘non-inflammatory’ breach of the alveolar capillary membrane (Swenson et al. 2002). In essence, inflammation was considered to be a consequential as opposed to a causative risk factor. However, these investigators focused on biomarkers with relatively long half-lives, which have interpretive limitations when assessing any relationship between metabolic change and clinical status at high altitude.

In this issue of The Journal of Physiology a research group led by Peter Bärtsch report on the involvement of free radical mediated reduction in pulmonary nitric oxide bioavailability in the development of HAPE from studies conducted at the very site where HAPE was first described by Mosso (Bailey et al. 2010). Bailey and co-workers have conducted a well-designed, sophisticated clinical investigation in the mountains using HAPE-susceptible (prior radiographic evidence of HAPE) volunteers as a study population. Despite risking the development of HAPE, the subjects willingly had a radial arterial and a central venous catheter placed at sea level and upon arrival at the Capana Regina Margherita. This feat in its self is admirable! In this study, the authors chose to focus on oxidative–nitrosative stress since the metabolites that cause this are far more reactive with shorter half-lives than those investigated in a previous study (including some of the same authors) (Swenson et al. 2002). For this thermodynamic reason, oxidation (formation of free radicals) should precede inflammation and thus provide a clearer ‘snapshot’ into the pathophysiology underlying HAPE.

It is clearly demonstrates that high-altitude (HA)-induced pulmonary hypertension is associated with regional (pulmonary) oxidative-nitrosative stress which precedes HAPE. The trans-pulmonary loss of NO has been posited as a potential mechanism and this study demonstrates that oxidative inactivation of NO may contribute to its loss across the pulmonary circulation. The authors have previously demonstrated that pulmonary hypertension is associated with an increase in the trans-pulmonary gain of the potent vasoconstrictor endothelin-1 (Berger et al. 2009). This peptide is also subject to redox regulation, that is, protein expression can be activated by an increase in free radicals. Thus, the increase in free radicals may prove the upstream, initiating stimulus with the balance between vasodilatation over vasoconstriction as the likely determinant of pulmonary hypertension.

Acute mountain sickness (AMS), a separate syndrome that affects the brain at high altitude, is also associated with an increased regional (cerebral) output of free radicals (Bailey et al. 2009). In combination, these findings indicate that trans-vascular free radical output is common to many organ systems when challenged by hypoxia. In this sense, AMS and HAPE may simply represent the cerebral and pulmonary manifestations of a pan-endothelial free radical-mediated insult that when at its most severe, can lead to microvascular injury, interstitial oedema and impaired tissue oxygenation.

These findings (Bailey et al. 2010) demonstrate that pulmonary oxidative–nitrosative stress and the subsequent rise in PAP are preceded by a regional depletion of the major water and fat soluble chain-breaking antioxidants, vitamins C and E. Both work together synergistically, which justifies future infusion studies to determine their potential prophylactic benefits.