The 7th International Leh Symposium: Lungs at High Altitude: Molecular Mechanisms and Therapeutics of Hypoxic Lung

The 7th International Leh Symposium on “Molecular Mechanisms and Therapeutics of Hypoxic Lung” from August 4 to 9, 2024, organized at the Mahabodhi International Meditation Centre in Saboo, Leh, Ladakh, India (Pictures 1), ensured the participation of a galaxy of national and international researchers, who explored the complex clinico-physiological processes associated with high-altitude adaptive and maladaptive mechanisms. The symposium provided a platform for sharing ideas and advancing knowledge to improve the quality of life and develop effective treatments for high-altitude complications. Whereas, high-altitude exposure is unavoidable for several reasons, such as over-whelming tourism, endurance training, the presence of native high-altitude populations, and military deployments. The inaugural session began with Nobel Laureate Professor Ratcliffe, who emphasized the role of HIF-mediated pathways in adapting to high altitude and managing related vascular complications. He highlighted the critical role of genetic regulation in maintaining normal physiology under hypoxic conditions. The discussion on human metabolic adaptation to high-altitude hypoxia concluded that metabolic responses to tissue hypoxia have important implications for health, both at altitude and in broader contexts like critically ill patients and pregnancy complications. Hypoxia triggers increased erythropoiesis through hypoxia-inducible factors (HIFs), which regulate erythropoietin transcription. Evolutionary adaptations in high-altitude populations—Tibetans, Ethiopians, and Andeans—reveal that Tibetans and Ethiopians maintain normal hemoglobin levels, while many Aymara and Quechua from the Andean highlands exhibit polycythemia. It was noted that NF-κB interacts with HIFs to regulate erythropoiesis. The Aymara population expresses a distinct NFKB1 variant, which modulates inflammation by producing a truncated, nonfunctional NF-κB peptide. This variant is associated with higher hemoglobin levels, lower leukocytes, and suppressed inflammation, marking a key genetic adaptation to high altitude in the Aymara people. Immune Cell-Mediated Inflammation and PH. “Immune Cell-Mediated Inflammation play a significant role in the pathogenesis of and pulmonary hypertension (PH), with evidence linking autoimmune and infectious diseases to the development of PH. Inflammation can induce experimental PH, and perivascular inflammation is observed in human pulmonary arterial hypertension (PAH) and animal models. In both, inflammatory cell infiltrates—including mast cells, dendritic cells, fibroblasts, macrophages, B cells, and CD4/CD8 T cells. Experimental models have shown that anti-inflammatory treatments, such as glucocorticoids and inhibitors of TGF-β, IL-6, IL-21, SDF-1, and macrophages, can reduce inflammation and PH symptoms. However, these results have not yet translated into clinical benefits for patients with PH, except in rare cases like lupus-associated disease. Studies using Schistosoma and hypoxia-induced PH models have provided valuable insights into immune cell involvement, but the causal relationship between inflammation and PH remains unclear. Whether inflammation is a trigger, amplifier, or merely an epiphenomenon of the disease is still under investigation. Systematic studies using hypoxia and Schistosoma or a combination of models could shed light on innate-adaptive immunity crosstalk contributing to vascular disease. Presenters also drew parallels between PH and cancer, highlighting shared hypoxia-related mechanisms. This ‘cancer hypothesis’ of PAH stems from the observation that PH involves an imbalance of cell proliferation and death, similar to neoplastic processes. Investigators have expanded this hypothesis to include the role of Hypoxia Inducible Factor (HIF-1α), a key regulator of anaerobic glycolysis in both normal and cancer cells. Tumor microenvironments, such as those in hepatocellular carcinoma, show immune cells with metabolic changes that promote survival under hypoxic conditions. A new mechanism for lung cancer-associated pulmonary hypertension (LC-PH) was proposed, involving tumor-associated macrophages and vascular remodeling.” The Leh Symposium underscored the inseparable link between genetics, epigenetics, and high-altitude adaptation, with experts focusing on the relevance of EPAS1 and EGLN1 variants. These genetic markers, identified in high-altitude populations such as Tibetans, Ethiopians, and Andeans, enhance survival in hypoxic conditions. Unique adaptations, like those in the Aymara people, highlight the role of erythropoiesis and inflammation in high-altitude survival. The discussion also extended to circulating cell-free DNA (cfDNA) as a promising noninvasive biomarker for high-altitude disorders. Elevated cfDNA levels were observed in severe cases of high-altitude pulmonary edema (HAPE), suggesting its potential in diagnosis and monitoring. Similarly, exploring telomere system dynamics was presented as a new frontier in understanding and managing high-altitude health challenges. Presentations further delved into how epigenetic regulation and genetic changes observed in highlanders support physiological and metabolic adaptations to hypoxia, crucial for maintaining oxygen delivery and overall health. However, these adaptations can impact cellular energetics, with broader implications for human health. The roles of telomeres, telomerase, and tankyrase (TNKS)—crucial in cancer, ageing, endurance, and respiratory diseases—were emphasized as equally significant in high-altitude contexts, offering new approaches to managing health challenges in such environments. Among other pulmonary diseases, Chronic obstructive pulmonary disease (COPD) and respiratory conditions like silicosis/anthracosis are significant health challenges, particularly in regions such as Ladakh, where environmental and socioeconomic factors exacerbate their prevalence. COPD, affecting millions globally, is fueled by smoking, biomass fuel exposure, and limited diagnostic access. In Ladakh, the high altitude, coupled with dust and biomass fuel use, contributes to a high prevalence of anthracosis, a condition often mistaken for COPD due to its similar clinical presentation and needs serious targeted attention and interventions. In parallel, anemia remains a critical concern in high-altitude populations, with recent data suggesting that hypoxia-related correction factors might lead to inflated prevalence estimates. Localized research highlights a discrepancy between anemia prevalence before and after applying such adjustment factors, indicating the need for tailored population-specific diagnostic approaches for newborns in these regions.”. Apart from the pulmonary, the neurological system is equally relevant. The illnesses include acute mountain sickness (AMS), high altitude cerebral edema (HACE), and insignificantly stroke. Experts highlighted the evolution of oxygen-dependent organisms and how rising atmospheric oxygen led to the human brain's reliance on it for continuous activity. Despite oxygen's essential role in the CNS, its paradoxical nature—both vital and harmful—was emphasized, with its quantum properties offering new insights into brain disease pathophysiology. Regional variations in HA-related conditions were influenced by factors like geographic location, altitude, and exposure duration. Hypoxia-induced hypercoagulability and other unique risk factors like thrombosis/thromboembolism (Choose the correct term) highlight the need for tailored preventive strategies, especially in younger people and those with cardiovascular issues. Enhancing High-Altitude Healthcare with artificial intelligence (AI) was another relevant topic. Its role in today's scientific world is impeccable, as in Advanced Imaging. This session explored the transformative potential of AI in high-altitude healthcare. AI tools are expected to significantly improve disease diagnosis and understanding of high-altitude conditions, offering timely clinical decision support and enhanced detection. 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