Targeting IL-11 system as a treatment of pulmonary arterial hypertension

Javier Milara; Inés Roger; Paula Montero; Enrique Artigues; Juan Escrivá; Francisco Perez-Vizcaino; Julio Cortijo

doi:10.1016/j.phrs.2023.106985

Targeting IL-11 system as a treatment of pulmonary arterial hypertension

Pharmacol Res. 2023 Nov:197:106985. doi: 10.1016/j.phrs.2023.106985. Epub 2023 Nov 9.

Authors

Javier Milara¹, Inés Roger², Paula Montero³, Enrique Artigues⁴, Juan Escrivá⁵, Francisco Perez-Vizcaino⁶, Julio Cortijo⁷

Affiliations

¹ CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain; Pharmacy Unit, University General Hospital Consortium of Valencia, Spain. Electronic address: javier.milara-paya@uv.es.
² CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
³ Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
⁴ Surgery Unit, University General Hospital Consortium, Valencia, Spain.
⁵ Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
⁶ CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, Spain; Dept of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
⁷ CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain; Research and Teaching Unit, University General Hospital Consortium, Valencia, Spain.

PMID: 37949331
DOI: 10.1016/j.phrs.2023.106985

Abstract

IL-11 is linked to fibrotic diseases, but its role in pulmonary hypertension is unclear. We examined IL-11's involvement in idiopathic pulmonary arterial hypertension (iPAH). Using samples from control (n = 20) and iPAH (n = 6) subjects, we assessed IL-11 and IL-11Rα expression and localization through RT-qPCR, ELISA, immunohistochemistry, and immunofluorescence. A monocrotaline-induced PAH model helped evaluate the impact of siRNA-IL-11 on pulmonary artery remodeling and PH. The effects of recombinant human IL-11 and IL-11Rα on human pulmonary artery smooth muscle cell (HPASMC) proliferation, pulmonary artery endothelial cell (HPAEC) mesenchymal transition, monocyte interactions, endothelial tube formation, and precision cut lung slice (PCLS) pulmonary artery remodeling and contraction were evaluated. IL-11 and IL-11Rα were over-expressed in pulmonary arteries (3.2-fold and 75-fold respectively) and serum (1.5-fold and 2-fold respectively) of patients with iPAH. Therapeutic transient transfection with siRNA targeting IL-11 resulted in a significant reduction in pulmonary artery remodeling (by 98%), right heart hypertrophy (by 66%), and pulmonary hypertension (by 58%) in rats exposed to monocrotaline treatment. rhIL-11 and soluble rhIL-11Rα induce HPASMC proliferation and HPAEC to monocyte interactions, mesenchymal transition, and tube formation. Neutralizing monoclonal IL-11 and IL-11Rα antibodies inhibited TGFβ1 and EDN-1 induced HPAEC to mesenchymal transition and HPASMC proliferation. In 3D PCLS, rhIL-11 and soluble rhIL-11Rα do not promote pulmonary artery contraction but sensitize PCLS pulmonary artery contraction induced by EDN-1. In summary, IL-11 and IL-11Rα are more highly expressed in the pulmonary arteries of iPAH patients and contribute to pulmonary artery remodeling and the development of PH.

Keywords: IL-11; IL-11Rα; Monocrotaline; Pulmonary arterial hypertension; Pulmonary artery endothelial cells; Pulmonary artery smooth muscle cells.

MeSH terms

Animals
Familial Primary Pulmonary Hypertension
Humans
Hypertension, Pulmonary* / chemically induced
Hypertension, Pulmonary* / drug therapy
Interleukin-11
Monocrotaline
Pulmonary Arterial Hypertension*
Pulmonary Artery
RNA, Small Interfering / genetics
Rats

Substances

Interleukin-11
Monocrotaline
RNA, Small Interfering