Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Abstract

With rising altitude the partial pressure of oxygen falls. This phenomenon leads to hypobaric hypoxia at high altitude. Since more than 140 million people permanently live at heights above 2500 m and more than 35 million travel to these heights each year, understanding the mechanisms resulting in acute or chronic maladaptation of the human body to these circumstances is crucial. This review summarizes current knowledge of the body's acute response to these circumstances, possible complications and their treatment, and health care issues resulting from long-term exposure to high altitude. It furthermore describes the characteristic mechanisms of adaptation to life in hypobaric hypoxia expressed by the three major ethnic groups permanently dwelling at high altitude. We additionally summarize current knowledge regarding possible treatment options for hypoxia-induced pulmonary hypertension by reviewing in vitro, rodent, and human studies in this area of research.

Figure 1

Mechanisms of vascular remodeling in chronic hypoxia (from [16], permission granted). AEC: alveolar epithelial cell; CCL: C-C motif chemokine ligand; CD40L: CD40 ligand; CXCL: C-X-C motif chemokine ligand; ECAM: endothelial cell adhesion molecule; FGF: fibroblast growth factor; HDAC: histone deacetylase; GM-CSF: granulocyte macrophage colony stimulating factor; HIF: hypoxia-inducible factor; ICAM: intercellular adhesion molecule; IL: interleukin; NO-sGC-cGMP: nitric oxide-soluble guanylate cyclase-cyclic GMP; MCP: monocyte chemoattractant protein; PDGF: platelet-derived growth factor; PGI₂: prostacyclin; RANTES: regulated upon activation, normally T-expressed, and presumably secreted; ROS: reactive oxygen species; SDF: stromal cell-derived factor; TRPC6: transient receptor potential cation channel 6; VCAM: vascular cell adhesion molecule.

Figure 2

Map showing populated regions at altitudes of 2500 m or higher (from [17], permission granted), and characteristics of three major high-altitude populations. ^∗Compared with sea-level populations at low altitude (see [18, 19]). EGLN1: hypoxia-inducible factor prolyl 4-hydroxylase 2; EPAS1: hypoxia-inducible factor-2α; hb: hemoglobin. †: [20, 21], ††: [–24], †††: [25].