TY - JOUR
T1 - Cellular sources of IL-6 and associations with clinical phenotypes and outcomes in PAH
AU - Simpson, Catherine E.
AU - Chen, Jenny Y.
AU - Damico, Rachel L.
AU - Hassoun, Paul M.
AU - Martin, Lisa J.
AU - Yang, Jun
AU - Nies, Melanie
AU - Griffiths, Megan
AU - Dhananjay Vaidya, R.
AU - Brandal, Stephanie
AU - Pauciulo, Michael W.
AU - Lutz, Katie A.
AU - Coleman, Anna W.
AU - Austin, Eric D.
AU - Ivy, Dunbar D.
AU - Nichols, William C.
AU - Everett, Allen D.
N1 - Funding Information:
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. and E.D.A., M.W.P., 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).
Funding Information:
Pennsylvania) funded by the Cardiovascular Medical Research and Education Fund (CMREF). The cells
Publisher Copyright:
© 2020 European Respiratory Society. All rights reserved.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - The pro-inflammatory cytokine interleukin-6 (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 remodeling. We hypothesized 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-characterized PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analyzed with 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 modeling, serum IL-6 was associated with survival in the overall cohort (HR 1.22, 95% CI 1.08-1.38, p<0.01) and in IPAH, though 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.
AB - The pro-inflammatory cytokine interleukin-6 (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 remodeling. We hypothesized 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-characterized PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analyzed with 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 modeling, serum IL-6 was associated with survival in the overall cohort (HR 1.22, 95% CI 1.08-1.38, p<0.01) and in IPAH, though 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.
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U2 - 10.1183/13993003.01761-2019
DO - 10.1183/13993003.01761-2019
M3 - Article
C2 - 32029443
AN - SCOPUS:85083621608
SN - 0903-1936
VL - 55
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 4
ER -