Interactions among Vascular-Tone Modulators Contribute to High Altitude Pulmonary Edema and Augmented Vasoreactivity in Highlanders

Ali, Zahara; Mishra, Aastha; Kumar, Rahul; Alam, Perwez; Pandey, Priyanka; Ram, Rekhbala; Thinlas, Tashi; Mohammad, Ghulam; Pasha, M. A. Qadar

doi:10.1371/journal.pone.0044049

Cited by 40 publications

(42 citation statements)

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“…Circulating ET-1 is elevated almost threefold at high altitude and to a greater degree in HAPE susceptibles and correlates with the rise in PA pressure [ 64 -66 ]. Other vascular mediators studied in over 400 subjects at 3,500 m with likely hypertensive effect on the pulmonary vasculature are greater in HAPE susceptibles, including plasma concentration of serotonin, 8-iso prostaglandin F, renin, and aldosterone [ 65 ].…”

Section: Neuro-humoral Responsesmentioning

confidence: 98%

“…While it is clear that altitude increases stable circulating markers of ROS production [ 80 , 81 ] and may play a role in AMS, it also appears that persons with higher HPV generate more ROS and less bioactive NO species across the lung [ 82 ]. In support of this, it was recently shown that HAPE-susceptible subjects have lower plasma concentrations of superoxide dismutase, an enzyme that converts oxygen radical (O 2 − ) to H 2 O 2 , a less potent oxidant species [ 65 ]. Isolated human PA endothelial cells exposed to 3 % oxygen produce more hydrogen peroxide and become more permeable to albumin, both of which are diminished in vitro and in vivo by antioxidants [ 83 ].…”

Section: Neuro-humoral Responsesmentioning

confidence: 99%

“…21.3 ), alveolar lavage fl uid, and blood [ 60 -63 ]. Systemic vascular endothelial NO generation as a surrogate for the pulmonary circu-lation is reduced more in hypoxic HAPE susceptibles [ 64 , 65 ], possibly as a result of greater circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous metabolite of arginine and inhibitor of endothelial NO synthase [ 65 ]. Circulating ET-1 is elevated almost threefold at high altitude and to a greater degree in HAPE susceptibles and correlates with the rise in PA pressure [ 64 -66 ].…”

Section: Neuro-humoral Responsesmentioning

confidence: 99%

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High-Altitude Pulmonary Edema (HAPE)

Schoene

Swenson

2013

High Altitude

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Much of the clinical impact of acute altitude illnesses stems from fl uid accumulation in interstitial spaces and nowhere is this more apparent than in the lungs as the edema escapes into the alveoli to cause life-threatening hypoxemia. This chapter will update our knowledge of HAPE over the past decade about the vasculature, alveolar epithelium, innervation, immune response, and genetics of the lung in hypoxia, as well as prophylactic and therapeutic strategies to reduce the toll of this most common alpine life-threatening illness. 406extend to HPV, would predict greater HAPE susceptibility. Although HAPE can develop in sedentary persons, exercise [ 6 ] and its pulmonary hemodynamic consequences (discussed below) are important precipitating factors.Symptoms, signs, and physiologic changes in lung function typical of pulmonary edema [ 1 -3 , 7 ] evolve in 2-4 days after ascent, often preceded or accompanying AMS (see Chap. 20 ), but can occur later with further ascent. Arterial saturations can fall as low as 40 % and PaO 2 s in the low 20 mmHg range. HAPE in its severest stage with profound hypoxemia can lead to high-altitude cerebral edema [ 8 ]. Repeat occurrences of HAPE do not always involve infi ltrates in the same areas, which suggests that fi xed structural aspects of lung parenchyma or vessels do not account for the timing of edema or its locale [ 9 ]. A special exception is unilateral absence of a pulmonary artery, in which edema always occurs in the contralateral lung receiving the entire cardiac output [ 10 ].It has been suggested that many persons (50-75 %) may have subclinical HAPE that resolves spontaneously despite remaining at altitude [ 11 -13 ]. This incidence equals that of AMS, which itself can cause mild gas exchange impairment [ 14 ] by unknown mechanisms perhaps related to altered autonomic infl uences on the pulmonary circulation and/or airways leading to ventilation-perfusion mismatching. Subclinical HAPE may be considerably overestimated without radiography [ 15 ] because indirect measures of interstitial edema such as spirometry, closing volume, and/or transthoracic impedance can vary for other reasons related to mountaineering including intense exercise and increased cardiac output, cold/dry air-induced bronchoconstriction, and hypocapnia [ 16 ]. With radiographically mild HAPE, only modest abnormalities were detectable [ 15 ] suggesting many lung function parameters are not sensitive enough to detect small changes in interstitial fl uid and may require highresolution tissue density measurements by CT or MR imaging. Reentry HAPE occurs when longterm high-altitude residents return to high altitude following a brief low-altitude sojourn. It has a strong familial basis and affl icts children more than adults [ 17 ], perhaps due to a twofold greater magnitude of HPV in preteen children (age 6-9) compared to teenagers (age 14-16) when tested 40 h after ascent to high altitude [ 18 ]. PathophysiologyFrom its fi rst modern descriptions, pulmonary hypertension and HAPE have been inex...

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Section: Neuro-humoral Responsesmentioning

confidence: 98%

Section: Neuro-humoral Responsesmentioning

confidence: 99%

Section: Neuro-humoral Responsesmentioning

confidence: 99%

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High-Altitude Pulmonary Edema (HAPE)

Schoene

Swenson

2013

High Altitude

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“…31,32 The ensuing oxidative stress primarily contributes to endothelial damage and vascular wall remodeling, which are potentially involved in the development of HA-related disorders in sojourners. 1,13 Thus, we can say that harsh climatic conditions at HA initiate a series of events in which there is an increased production of reactive intermediates, 29,30,32,33 vasoconstrictors such as endothelin 1 (ET-1), 32,34-36 5-hydroxytryptamine (5-HT), 8-iso-prostaglandin F2α (8-iso-PGF2α), 34 and various other proinflammatory cytokines. 29,35,[37][38][39] In contrast, there is a decrease in the production of vasodilators such as NO, 32,34,40,41 prostacyclins, 38 antioxidants, 29,30,38 and anti-inflammatory cytokines.…”

Section: Hypobaric Hypoxia-induced Oxidative Stressmentioning

confidence: 99%

“…The selection of genetic variants from such HA. 56 This may well be the case for the genes associated with the major physiological pathways that play crucial roles under the hypobaric hypoxic environment of HA, such as vascular homeostasis, 34,46 oxygen sensing, 57,58 and inflammatory pathways. 40,42,59,60 The genes that majorly associate with these pathways can easily be recognized as ET-1, 35 …”

Section: Notesmentioning

confidence: 99%

Oxidative stress at high altitude: genotype–phenotype correlations

Pandey¹,

Pasha²

2014

AGG

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It has been well-documented that the hypobaric hypoxic environment at high altitude (HA) causes stress to both the permanent residents of HA and the sojourners. This oxidative stress primarily disturbs the oxygen-sensing and vascular homeostasis pathways, thereby upsetting normal human physiology, especially in sojourners. These environmental challenges have caused dynamic evolutionary changes within natives of HA, allowing them to develop adaptive plasticity. This review focuses on the genomic and biochemical features of the molecules involved in the oxygen-sensing and vascular homeostasis pathways with respect to HA pulmonary edema (HAPE) and adaptation. We review the role of genetic markers such as HIF-prolyl hydroxylase 2, endothelial PAS domain-containing protein 1, endothelial nitric oxide synthase, endothelin 1, cytochrome b-245 alpha polypeptide, and glutathione S-transferase pi 1, as well as three circulatory biomarkers (nitric oxide, endothelin 1, and 8-iso-prostaglandin F2α), by highlighting approaches such as candidate gene and genome-wide, adopted in deciphering the pathways. A disagreement between the two approaches has also been highlighted. In addition, we discuss that an overrepresentation of wild-type alleles in HA natives and mutant alleles of same polymorphisms in HAPE patients implies that the allelic variants at the same locus are involved in adaptation and HAPE, respectively. Moreover, healthy sojourners present a number of genomic features similar to HA natives, further strengthening the concept of genetic predisposition. A trend in correlation between protective and risk alleles and altered levels of circulatory markers clearly documents the phenomenon of genotype-phenotype correlations. We conclude that the genetic and biochemical markers discussed here both could prove to be potential targets for future diagnostic and therapeutic interventions.

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Hematologic and spirometric characteristics of Tajik and Kyrgyz highlanders in the Pamir Mountains

Sulaiman

Cai³

et al. 2020

American J Hum Biol

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Objectives In this study, we measured the hematologic and spirometric parameters of native Tajik and Kyrgyz highlanders in the Pamir Mountains to investigate adaptations to high altitude stressors. Methods Hematological parameters including arterial oxygen saturation (SaO2), red blood cell (RBC) counts, and hemoglobin (Hb) concentration were measured on Sarikoli Tajik (n = 80; 3100 m), Wakhi Tajik (n = 48; 3500 m), and Kyrgyz (n = 64; 3250 m) in comparison to lowland Uyghurs (n = 50; 1300 m). Spirometric parameters including forced vital capacity (FVC), the first second of forced expiration (FEV1), and forced expiratory flow between 25% and 75% (FEF25‐75) were measured. We also reported mountain sickness symptoms in these highlanders and conducted a multivariate regression analysis to analyze the association between these symptoms and the measured parameters. Results SaO2 of Sarikoli Tajik, Wakhi Tajik, and Kyrgyz (91%‐93.5%) are significantly lower than lowland Uyghurs, yet are comparable to other native highlanders at a similar altitude. RBC counts and Hb concentrations of all three highland populations are significantly increased compared to Uyghurs. FVC is lower in Sarikoli Tajik, Wakhi Tajik, and Kyrgyz (male: 3.48‐3.86 L, female: 2.47‐2.78 L) compared to Uyghurs. Combined with normal FEV1, elevated FEV1/FVC ratio, and FEF25‐75, the spirometric patterns of these highlanders indicate restrictive lung disease. A high prevalence of mountain sickness symptoms such as headache and nausea was found in all three highland populations, and are attributed to low FVC and aging by regression analysis. Conclusion Tajik and Kyrgyz highlanders showed adaptation in SaO2, RBC, and Hb level, but poor performance in spirometry, which causes mountain sickness.

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Interactions among Vascular-Tone Modulators Contribute to High Altitude Pulmonary Edema and Augmented Vasoreactivity in Highlanders

Cited by 40 publications

References 45 publications

High-Altitude Pulmonary Edema (HAPE)

High-Altitude Pulmonary Edema (HAPE)

Oxidative stress at high altitude: genotype–phenotype correlations

Hematologic and spirometric characteristics of Tajik and Kyrgyz highlanders in the Pamir Mountains

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Interactions among Vascular-Tone Modulators Contribute to High Altitude Pulmonary Edema and Augmented Vasoreactivity in Highlanders

Cited by 40 publications

References 45 publications

High-Altitude Pulmonary Edema (HAPE)

High-Altitude Pulmonary Edema (HAPE)

Oxidative stress at high altitude: genotype&ndash;phenotype correlations

Hematologic and spirometric characteristics of Tajik and Kyrgyz highlanders in the Pamir Mountains

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Oxidative stress at high altitude: genotype–phenotype correlations