Lungs at high-altitude: genomic insights into hypoxic responses.
Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K(+)- and Ca(2+)-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs.
Department of Genomics and Molecular Medicine, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; Department of Biotechnology, University of Pune, Pune, India;
Aastha
A
Mishra
Department of Medicine, SNM Hospital, Leh, Ladakh, J&K, India;
Ghulam
G
Mohammad
Ladakh Institute of Prevention, Leh, Ladakh, J&K, India; and.
Tsering
T
Norboo
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
John H
JH
Newman
Department of Genomics and Molecular Medicine, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India; qpasha@igib.res.in.
M A Qadar
MA
Pasha
D000222:Adaptation, Physiological / Q000235:genetics; D000531:Altitude; D000532:Altitude Sickness / Q000503:physiopathology*; D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics* / Q000503:physiopathology*; D008168:Lung / Q000503:physiopathology*
acute hypoxic ventilatory response; acute mountain sickness; asymmetric dimethyl arginine; high altitude; high-altitude pulmonary edema; hypobaric hypoxia; hypoxia-inducible factor; hypoxic pulmonary vasoconstriction response; vascular remodeling