Integrative blood profiling uncovers inflammatory network signatures in high-altitude pulmonary edema

Despite the well-known role of hypoxia-driven inflammatory mediators in the pathogenesis of hypoxic pulmonary hypertension, their involvement in high-altitude (HA) illnesses, particularly high-altitude pulmonary edema (HAPE), remains unclear. The present study uses an integrated clinical, transcriptomic, proteomic, and long noncoding RNA (lncRNA) profiling of 83 individuals, including HAPE patients segregated into mild, moderate, and severe categories, HAPE-free sojourners, and long-term HA residents, to highlight the molecular and immunological changes associated with HAPE and its severity. Clinical assessments revealed significantly reduced peripheral oxygen saturation and elevated respiratory parameters in HAPE patients. Differential gene expression and functional enrichment analyses identified 515 significantly differentially expressed genes, with marked enrichment of inflammatory and hypoxia-associated pathways. Protein-protein interaction network analysis revealed eighteen hub genes, including toll-like receptor (TLR) 2 and Forkhead box O3 (FOXO3), with strong diagnostic potential. Immune cell deconvolution analysis and hematological profiling indicated a prominent increase in neutrophil proportion. Interestingly, oncostatin M (OSM), a hypoxia-regulated predominant cytokine produced by neutrophils, was revealed in the cytokine and transcriptomic profiling, highlighting its role in inflammation and extracellular matrix degradation. Co-expression network analysis notably revealed significant alterations that formed a gene module exhibiting a strong correlation with immune response, leukocyte adhesion, and ncRNA processing pathways. Interestingly, these co-expressed partners, LINC01093 and immune-regulatory genes like interleukin-18 receptor 1 and TLR5, appear to regulate the NF-?B signaling pathway, one of the positively enriched pathways in our analysis. Overall, this multiomics approach highlighted a strong inflammatory signature and lncRNA-mRNA interactions associated with HAPE. Overall design: The study included 83 participants aged between 18 - 70 years and were classified into three distinct study groups: healthy HA sojourners or controls ( n=19), HAPE patients segregated into mild (n=15), moderate (n=13), and severe categories (n=14), and healthy highlanders (HLs, n=22). HAPE patients included sojourners from low-altitude regions (< 200 m) who traveled to Leh, Ladakh, and developed HAPE within 2 to 5 days of HA exposure. Healthy HA sojourners or controls included sojourners from low-altitude regions (< 200 m) who visited HA under similar conditions as the HAPE group but did not develop any HA related disorders. The HLs group comprised healthy individuals who are permanent residents of Leh, Ladakh, at the altitude of 3500m asl.