Abstract
The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.
IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.
Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08–1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.
IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.
Abstract
Circulating IL-6, a pro-inflammatory cytokine produced by pulmonary arterial smooth muscle cells, is significantly associated with clinical phenotypes and survival in pulmonary arterial hypertension, which may guide individualised disease management https://bit.ly/3awkkSz
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.00314-2020
This article has supplementary material available from erj.ersjournals.com
Conflict of interest: Catherine E. Simpson has nothing to disclose.
Conflict of interest: Jenny Y. Chen has nothing to disclose.
Conflict of interest: Rachel L. Damico has nothing to disclose.
Conflict of interest: Paul M. Hassoun has nothing to disclose.
Conflict of interest: Lisa J. Martin has nothing to disclose.
Conflict of interest: Jun Yang has nothing to disclose.
Conflict of interest: Melanie Nies has nothing to disclose.
Conflict of interest: Megan Griffiths has nothing to disclose.
Conflict of interest: R. Dhananjay Vaidya has nothing to disclose.
Conflict of interest: Stephanie Brandal has nothing to disclose.
Conflict of interest: Michael W. Pauciulo has nothing to disclose.
Conflict of interest: Katie A. Lutz has nothing to disclose.
Conflict of interest: Anna W. Coleman has nothing to disclose.
Conflict of interest: Eric D. Austin has nothing to disclose.
Conflict of interest: Dunbar D. Ivy has nothing to disclose.
Conflict of interest: William C. Nichols has nothing to disclose.
Conflict of interest: Allen D. Everett has nothing to disclose.
Support statement: This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute awards R01HL135114 (A.D.E., J.Y., R.D., D.V., W.C.N., D.D.I and E.D.A.), R24 HL105333 (W.C.N., D.D.I., E.D.A., M.W.P. and L.J.M.), and T32HL007534 (C.E.S.).
Serum/tissue samples were provided by the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under an NHLBI R24 grant, R24HL123767, and by the Cardiovascular Medical Research and Education Fund (CMREF). National Heart, Lung, and Blood Institute; DOI: http://dx.doi.org/10.13039/100000050; Grant: R01HL135114, R24 HL105333, T32HL007534.
- Received September 6, 2019.
- Accepted January 18, 2020.
- Copyright ©ERS 2020