Pathophysiology Of High Altitude Pulmonary Edema Research Articles

High-altitude pulmonary edema: the intercellular network hypothesis

The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3) triggering the inflammation mainly led by alveolar macrophages, 4) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.

Patchy Vasoconstriction Versus Inflammation: A Debate in the Pathogenesis of High Altitude Pulmonary Edema.

High altitude pulmonary edema (HAPE) occurs in individuals rapidly ascending at altitudes greater than 2,500 m within one week of arrival. HAPE is characterized by orthopnea, breathlessness at rest, cough, and pink frothy sputum. Several mechanisms to describe the pathophysiology of HAPE have been proposed in different kinds of literature where most of the mechanisms are reported to be activated before a drop in oxygen saturation levels. The majority of the current studies favor diffuse hypoxic pulmonary vasoconstriction (HPV) as a pathophysiological basis for HAPE. However, some of the studies described inflammation in the lungs and genetic basis as the pathophysiology of HAPE. So, there is a major disagreement regarding the exact pathophysiology of HAPE in the current literature, which raises a question as to what is the exact pathophysiology of HAPE. So, we reviewed 23 different articles which include clinical trials, review articles, randomized controlled trials (RCTs), and original research published from 2010 to 2020 to find out widely accepted pathophysiology of HAPE. In our study, we found out sympathetic stimulation, reduced nitric oxide (NO) bioavailability, increased endothelin, increased pulmonary artery systolic pressure (PASP) resulting in diffuse HPV, and reduced reabsorption of interstitial fluid to be the most important determinants for the development of HAPE. Similarly, with the evaluation of the role of inflammatory mediators like C-reactive protein (CRP) and interleukin (IL-6), we found out that inflammation in the lungs seems to modulate but not cause the process of development of HAPE. Genetic basis as evidenced by increased transcription of certain gene products seems to be another promising hypoxic change leading to HAPE. However, comprehensive studies are still needed to decipher the pathophysiology of HAPE in greater detail.

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

ContextFew potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension (PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude. AimsWe hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules. Methods and materialsIn a case–control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses. ResultsThe genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P≤0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P≤0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P≤0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P≤0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P≤0.05).The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P≤0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P≤0.01). ConclusionsThe genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology.

241 Echocardiographic Assessment of Myocardial Performance in Response to High Altitude and Development of Subclinical Pulmonary Edema in Healthy Climbers

Despite a known association with increased pulmonary artery pressure (PAP), the pathophysiology of high-altitude pulmonary edema (HAPE) remains incompletely understood. Data regarding the impact of high altitude on left and right heart functions are sparse and conflicting. No single parameter has been validated to predict the development of HAPE among recreational climbers. We aimed to assess, by echocardiography, the right and left ventricular responses to high-altitude-induced hypoxia and to detect the occurrence of subclinical pulmonary edema. This observational study included 14 healthy subjects (8 men ; ages 27-65 years old) participating in a trekking expedition in the Everest Valley, Nepal. Echocardiography, using a portable unltrasound system (Vivid I, GE Healthcare), including the assessment of right ventricular performance parameters, was performed in Montréal (30 meters above sea level), Namche Bazar, Nepal (3450m) and Chhukkung (4730m). Lung ultrasound was performed to detect the appearance of ultrasound lung comets (ULCs) suggestive of subclinical pulmonary edema, quantified by a previously validated ULC score integrating the extent and severity of lung comets. Symptoms of high altitude sickness were assessed via the validated Lake Louise Questionnaire (LLQ). At high altitude, ULCs were seen in all except one of the subjects, with ULC scores ranging from 0 to 18 at 4730m (Fig. 1). None of the subjects had clinical criteria for HAPE. Systolic PAP increased in all subjects between Montréal and Chhukkung (mean PAP 27.4 +/− 5.4 mmHg vs. 39.3 +/− 7.7 mmHg respectively; p<0.001). Right ventricular myocardial performance index (MPI; Tei index), assessed by the pulsed-wave doppler method, increased with rising altitude (0.32 +/− 0.08 at 30m vs. 0.41 +/− 0.10 at 4730m; p=0.046). The right ventricular parameters S' and Tricuspid Annular Plane Systolic Excursion (TAPSE) remained unchanged, as did the left ventricular E/A ratio suggesting no significant change in left ventricular diastolic function. Heart rate and cardiac output increased in every subject at high altitude. No correlation could be drawn between PAP increment and MPI, MPI and ULC score, and MPI and LLQ score. Subclinical high-altitude pulmonary edema is frequent in healthy climbers living at low altitude. Right ventricular MPI increases at high altitude, and does not seem to be correlated to the magnitude of PAP increment. Whether rising MPI is a physiologic adaptive mechanism to high-altitude hypoxia or a pathologic response identifying HAPE-susceptible subjects needs to be further determined.

Volatile organic compounds (VOCs) in exhaled breath condensate (EBC) as a biomarker of high altitude pulmonary edema (HAPE)

HAPE is the most common cause of death at high altitude. The underlying pathophysiology of HAPE is not well understood. While certain individuals are more susceptible to developing HAPE, the ability to identify these individuals prior to ascent has yet to be determined. The present study was designed to determine if a difference exists between the profile of VOCs in EBC, hypoxic ventilatory response (HVR) and pulmonary artery systolic pressures (PASP) in healthy males with (HAPE, n=5) and without (control, n=11) a history of HAPE. On the first day of the protocol, subjects performed pulmonary function, VO2 max, and HVR tests. On the second day of the study, the subjects completed a pre and post hypoxic exposure 20 minute EBC collection, supine exercise test with Doppler Echocardiography measurement of PASP and a ninety minute hypoxic exposure (12% O2) with measurement of PASP. The main results of the study showed that the EBC profile of VOCs was significantly different between groups. In addition, this profile was strongly correlated with HVR. These results indicate that EBC analysis can be used to identify individuals who have had a previous episode of HAPE, as well as physiological responses to hypoxia. In the future, this technique could be used in the field to determine HAPE sensitivity prior to altitude exposure.

Identification of haptoglobin and apolipoprotein A-I as biomarkers for high altitude pulmonary edema

We have investigated the plasma proteome using 2D gel electrophoresis and matrix-assisted laser desorption/ionization tandem time of flight from patients with high altitude pulmonary edema (HAPE). A complete proteomic analysis was performed on 20 patients with HAPE and ten healthy sea level controls. In total, we have identified 25 protein spots in human plasma and found that 14 of them showed altered changes in HAPE patients, which mainly were acute phase proteins (APPs), compliment components, and apolipoproteins among others. Among the APPs, haptoglobin α2 chain, haptoglobin β chain, transthyretin, and plasma retinol binding precursor showed overexpression in HAPE patients as compared to controls. To validate the result of proteomic analysis, two proteins were selected for enzyme-linked immunosorbent assay and Western blotting analysis. Our data conclusively shows that two proteins, haptoglobin and apolipoprotein A-I are upregulated in plasma of HAPE patients. These proteins may provide a fast and effective control of inflammatory damage until the subsequent mechanisms can begin to operate. Taken together, our findings further support the hypothesis that inflammatory response system is linked to the pathophysiology of HAPE.

High-altitude pulmonary edema in Japan

To understand the pathophysiology of high-altitude pulmonary edema (HAPE), we examined the pathway of adaptation to high altitude in lifelong of Tibet. The Tibetan natives had higher exercise performance, but lower maximal oxygen uptake and lower blood lactate concentrations than did acclimatized Han newcomers. Clinical and basic studies done to determine the pathophysiologic characteristics of 47 patients with HAPE and of subjects susceptible to HAPE. The altitude of onset was 2,680 m to 3,190 m above sea level. Results of hemodynamic studies and the presence of protein-rich edema fluid indicated that HAPE is noncardiogenic and is a type of increased permeability edema. The levels of IL-1 beta, IL-6, IL-8, and TNF-alpha in bronchoalveolar lavage fluid from subjects with HAPE were high on admission. The subjects susceptible to HAPE had much greater increases in an index of pulmonary vascular resistance than did the controls, which resulted in much higher levels of pulmonary arterial pressure during both acute hypoxia and hypobaria. The subjects susceptible to HAPE also has blunted hypoxic ventilatory drives. We studied whether human leukocyte antigen DR-6 functions as a genetic predisposition to HAPE. The frequency of DR-6 was increased in the subjects susceptible to HAPE, which suggests that they have a constitutional abnormality in the pulmonary circulatory, and ventilatory responses to hypoxia and hypobaria, and that genetic factors may be involved in the development of HAPE.

Altered ion transporter expression in bronchial epithelium in mountaineers with high-altitude pulmonary edema.

Hypoxia inhibits activity and expression of transport proteins of cultured lung alveolar epithelial cells. Here we tested whether hypoxia at high altitude affected the expression of ion transport proteins in tissues obtained from controls and mountaineers with high-altitude pulmonary edema (HAPE) at the Capanna Margherita (4,559 m). Expression was determined by RT-PCR and Western blots from brush biopsies of bronchial epithelium and from leukocytes obtained before and during the stay at high altitude. At low altitude, amounts of mRNAs were not different between control and HAPE-susceptible subjects. At high altitude, the amount of mRNA of Na-K-ATPase, CFTR, and beta-actin of brush biopsies did not change in controls but decreased significantly (-60%) in HAPE-susceptible subjects. There was no change in Na channel mRNAs at high altitude in controls and HAPE. No statistically significant correlation was found between the expression of Na transporters and PO2 and O2 saturation. In leukocytes, 28S-rRNA and Na-K-ATPase decreased at altitude in control and HAPE-susceptible subjects, but no significant change in Na-K-ATPase protein was found. Hypoxia-inducible factor-1alpha mRNA and GAPDH mRNA tended to increase in leukocytes obtained from HAPE-susceptible subjects at high altitude but did not change in controls. These results show that hypoxia induces differences in mRNA expression of ion transport-related proteins between HAPE-susceptible and control subjects but that these changes may not necessarily predict differences in protein concentration or activity. It is therefore unclear whether these differences are related to the pathophysiology of HAPE.

Update: High altitude pulmonary edema.

Recent high altitude studies with pulmonary artery (PA) catheterization and broncho-alveolar lavage (BAL) in early high altitude pulmonary edema(HAPE) have increased our understanding of the pathogenetic sequence in HAPE. High preceding PA and pulmonary capillary pressures lead to a non-inflammatory leak of the alveolar-capillary barrier with egress of red cells, plasma proteins and fluid into the alveolar space. The mechanisms accounting for an increased capillary pressure remain speculative. The concept that hypoxic pulmonary vasoconstriction (HPV) is uneven so that regions with less vasoconstriction are over-perfused and become edematous remains compelling but unproved. Also uncertain is the role and extent of pulmonary venoconstriction. With disruption of the normal alveolar-capillary barrier, some individuals may later develop a secondary inflammatory reaction. A high incidence of preceding or concurrent respiratory infection in children with HAPE has been used to support a causative role of inflammation in HAPE. However, alternatively even mild HPV may simply lower the threshold at which inflammation-mediated increases in alveolar capillary permeability cause significant fluid flux into the lung. Other major questions to be addressed in future research are: 1.) What is the mechanism of exaggerated hypoxic pulmonary vasoconstriction? Is there a link to primary pulmonary hypertension? Several observations suggest that susceptibility to HAPE is associated with endothelial dysfunction in pulmonary vessels. This has not yet been studied adequately. 2.) What is the nature of the leak? Is there structural damage, i. e. stress failure, or does stretch cause opening of pores? 3.) What is the pathophysiologic significance of a decreased sodium and water clearance across alveolar epithelial cells in hypoxia? 4.) What is the role of exercise? Do HAPE-susceptible individuals develop pulmonary edema when exposed to hypoxia without exercise? Answers to these questions will increase our understanding of the pathophysiology of HAPE and also better focus research on the genetic basis of susceptibility to HAPE.

High-altitude Pulmonary Edema with Pulmonary Thromboembolism

High-altitude pulmonary edema (HAPE) is a form of noncardiogenic pulmonary edema. The pathophysiology of HAPE remains unclear. A case of HAPE was associated with pulmonary thromboembolism of a left upper pulmonary artery. Pulmonary thromboembolism was an important factor in development of HAPE in this case.

New developments in the pathophysiology of high-altitude pulmonary edema

New developments in the pathophysiology of high-altitude pulmonary edema