Genome Wide Expression Analysis Suggests Perturbation of Vascular Homeostasis during High Altitude Pulmonary Edema

Abstract

BackgroundHigh altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic edema which occurs in unacclimatized but otherwise normal individuals within two to four days after rapid ascent to altitude beyond 3000 m. The precise pathoetiology and inciting mechanisms regulating HAPE remain unclear.Methodology/Principle findingsWe performed global gene expression profiling in individuals with established HAPE compared to acclimatized individuals. Our data suggests concurrent modulation of multiple pathways which regulate vascular homeostasis and consequently lung fluid dynamics. These pathways included those which regulate vasoconstriction through smooth muscle contraction, cellular actin cytoskeleton rearrangements and endothelial permeability/dysfunction. Some notable genes within these pathways included MYLK; rho family members ARGEF11, ARHGAP24; cell adhesion molecules such as CLDN6, CLDN23, PXN and VCAM1 besides other signaling intermediates. Further, several important regulators of systemic/pulmonary hypertension including ADRA1D, ECE1, and EDNRA were upregulated in HAPE. We also observed significant upregulation of genes involved in paracrine signaling through chemokines and lymphocyte activation pathways during HAPE represented by transcripts of TNF, JAK2, MAP2K2, MAP2K7, MAPK10, PLCB1, ARAF, SOS1, PAK3 and RELA amongst others. Perturbation of such pathways can potentially skew vascular homeostatic equilibrium towards altered vascular permeability. Additionally, differential regulation of hypoxia-sensing, hypoxia-response and OXPHOS pathway genes in individuals with HAPE were also observed.Conclusions/SignificanceOur data reveals specific components of the complex molecular circuitry underlying HAPE. We show concurrent perturbation of multiple pathways regulating vascular homeostasis and suggest multi-genic nature of regulation of HAPE.

High Altitude Pulmonary Edema: An Update on Omics Data and Redefining Susceptibility

“…It contributes to HIF-2A stability and regulation. EGLN-3 inhibits HIF-2α modulated hypoxia responsive elements [34]. As evident from previous studies that mitochondria plays a role in HAPE susceptibility the mitochondrial haplotype has also been found associated with susceptibility.…”

“…Recently a study at by Sharma et al [34] showed differential expression of a large clad of genes associated with energy metabolism were altered during hypoxia and may therefore be associated to the susceptibility. Genome wide profiling associated differential regulation of OXPHOS (oxidative phosphorylation) pathways to HAPEsusceptibility.…”

“…Endothelin converting enzyme-1 transcripts and Endothelin receptor type A regulated genes are upregulated in HAPE. Both can serve as possible biomarkers for HAPE [34]. She J et al [32] observed that at simulated altitude of 5000 m, aquaporin 5(AQP5) knockout (AQP5-/-) mice had increased lung wet:dry weight ratio and higher protein concentrations in broncheoalveolar lavage fluid.…”

“…Involvement of genetic, epigenetic, physiological and other associated factors in deciding the HAPE susceptibility poses a major challenge for the scientific resolution of the problem. With the advancement and accessibility to high throughput omics technologies, genome-wide data sets and description of susceptibility architecture, translational research in high altitude medicine will be an important aspect of medical progress [34]. Global metabolite profiling combined with a systems biology approach (i.e., integrating genomics, epigenomics, and proteomics) is an exciting upcoming approach for improving our understanding of HAPE and evaluating various potential biomarkers for the same.…”

Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation

“…Leukocytic invasion into other ischemic or hypoxic tissues has also been reported [50,51,52,53,54,55,56,57]. However, the triggers for these specific inflammatory responses of the pulmonary vascular system are still unidentified [58,59,60,61]. Recent progress on this issue will be discussed further.…”