Sunitha Konatham

Introduction: Pulmonary hypertension (PH) is a rare and uncurable^1,2 condition characterized by increased mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest^1,3. The 5‐year survival rate is low at 50%³, as the lack of symptom specificity delays diagnosis^1,3. Serum levels of interleukin-6 (IL-6) are higher in subjects with PH compared to healthy patients⁴, but the use of IL-6 as a biomarker is currently for research and not clinical contexts⁴, so studies explored mechanisms by which IL-6 contributes to PH. Methods: In one study,  mice were treated with chronic hypoxia or normoxia, then sIL-6R, sgp130, and IL-6 plasma levels were investigated⁵. In another, the lungs and blood of both PH and control mice were processed into a single cell suspension to compare neutrophil levels by flow analysis, and measured inflammatory cytokines and chemokines (CX3CR1 and IL-6)⁶. In a third study, mice with smooth muscle cell–specific deletion of the IL-6 receptor were subjected to hypoxia for 3 weeks to produce PH, and pulmonary artery smooth muscle cells (PA-SMCs) were harvested⁷. IL-6, sIL6R, and sgp130 concentrations were measured with ELISA, and lung paraffin slices were immunocytofluorescence-labeled for IL6R and other inflammatory markers⁷. In another mouse study, Tamoxifen was given to transgenic animals to generate an IL-6Ra deletion confirmed by qPCR⁸. After being challenged with hypoxia or normoxia, pulmonary vessel wall thickness was measured using immunostaining for -smooth muscle actin (-SMA) or smooth muscle myosin heavy chain⁸. In a clinical study, 338 PH patients and 352 controls were genotyped using PCR amplification and gene sequencing to investigate connections between PH and two promoter-area polymorphisms (IL-6-572C/G and IL-6-174C/G) and blood IL-6 levels were measured using ELISA². Results: IL-6 trans-signaling is elevated after chronic hypoxia and promoted pulmonary arterial cell migration and CH-induced pulmonary hypertension⁵. Il-6 overexpression increased neutrophil influx and worsened PH pathogenesis⁶. Deletion of IL6R in the smooth muscle layer prevented the development of PH, and ectopic IL6R upregulation contributed to PA-SMC survival in iPAH, contributing to PA-SMC accumulation⁷. Loss of IL-6 receptor antagonists enhanced vascular remodeling⁸. When IL-6 promoter transcriptional activity was decreased, there was a decreased risk of developing pulmonary hypertension². Conclusions: The proposed mechanism of IL-6 in PH pathogenesis starts with chronic hypoxia, which induces IL-6 trans-signaling (promoter, gene transcription, production, receptor binding). This promotes neutrophil infiltration, causing vascular remodeling that decreases vessel diameter, increasing arterial pressure.

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