Genome wide expression analysis suggests perturbation of vascular homeostasis during high altitude pulmonary edema.
BACKGROUND
High 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.


RESULTS
We 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
Our 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.
Molecular Biology Division, Defence Institute of Physiology And Allied Sciences (DIPAS), DRDO, Delhi, India.
Manish
M
Sharma
Molecular Biology Division, Defence Institute of Physiology And Allied Sciences (DIPAS), DRDO, Delhi, India.
Shashi Bala
SB
Singh
Molecular Biology Division, Defence Institute of Physiology And Allied Sciences (DIPAS), DRDO, Delhi, India.
Soma
S
Sarkar
D000064:Acclimatization / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000532:Altitude Sickness / Q000235:genetics* / Q000503:physiopathology; D002319:Cardiovascular System / Q000378:metabolism* / Q000503:physiopathology; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011654:Pulmonary Edema / Q000235:genetics* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult