PMID- 37949331
OWN - NLM
STAT- MEDLINE
DCOM- 20231121
LR  - 20231121
IS  - 1096-1186 (Electronic)
IS  - 1043-6618 (Linking)
VI  - 197
DP  - 2023 Nov
TI  - Targeting IL-11 system as a treatment of pulmonary arterial hypertension.
PG  - 106985
LID - S1043-6618(23)00341-9 [pii]
LID - 10.1016/j.phrs.2023.106985 [doi]
AB  - 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-11Ralpha 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-11Ralpha 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-11Ralpha 
      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-11Ralpha induce HPASMC proliferation and HPAEC to 
      monocyte interactions, mesenchymal transition, and tube formation. Neutralizing 
      monoclonal IL-11 and IL-11Ralpha antibodies inhibited TGFbeta1 and EDN-1 induced HPAEC 
      to mesenchymal transition and HPASMC proliferation. In 3D PCLS, rhIL-11 and 
      soluble rhIL-11Ralpha do not promote pulmonary artery contraction but sensitize PCLS 
      pulmonary artery contraction induced by EDN-1. In summary, IL-11 and IL-11Ralpha are 
      more highly expressed in the pulmonary arteries of iPAH patients and contribute 
      to pulmonary artery remodeling and the development of PH.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Milara, Javier
AU  - Milara J
AD  - 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.
FAU - Roger, Ines
AU  - Roger I
AD  - CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, 
      Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, 
      Spain.
FAU - Montero, Paula
AU  - Montero P
AD  - Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
FAU - Artigues, Enrique
AU  - Artigues E
AD  - Surgery Unit, University General Hospital Consortium, Valencia, Spain.
FAU - Escriva, Juan
AU  - Escriva J
AD  - Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, 
      Spain.
FAU - Perez-Vizcaino, Francisco
AU  - Perez-Vizcaino F
AD  - CIBER de enfermedades respiratorias, Health Institute Carlos III, Valencia, 
      Spain; Dept of Pharmacology and Toxicology, School of Medicine, Universidad 
      Complutense de Madrid, Madrid, Spain.
FAU - Cortijo, Julio
AU  - Cortijo J
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20231109
PL  - Netherlands
TA  - Pharmacol Res
JT  - Pharmacological research
JID - 8907422
RN  - 0 (Interleukin-11)
RN  - 73077K8HYV (Monocrotaline)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Rats
MH  - *Pulmonary Arterial Hypertension
MH  - Familial Primary Pulmonary Hypertension
MH  - Interleukin-11
MH  - *Hypertension, Pulmonary/chemically induced/drug therapy
MH  - Monocrotaline
MH  - Pulmonary Artery
MH  - RNA, Small Interfering/genetics
OTO - NOTNLM
OT  - IL-11
OT  - IL-11Ralpha
OT  - Monocrotaline
OT  - Pulmonary arterial hypertension
OT  - Pulmonary artery endothelial cells
OT  - Pulmonary artery smooth muscle cells
COIS- Declaration of Competing Interest The authors declare that they have no conflict 
      of interest.
EDAT- 2023/11/11 11:43
MHDA- 2023/11/21 06:42
CRDT- 2023/11/10 19:16
PHST- 2023/09/07 00:00 [received]
PHST- 2023/11/02 00:00 [revised]
PHST- 2023/11/06 00:00 [accepted]
PHST- 2023/11/21 06:42 [medline]
PHST- 2023/11/11 11:43 [pubmed]
PHST- 2023/11/10 19:16 [entrez]
AID - S1043-6618(23)00341-9 [pii]
AID - 10.1016/j.phrs.2023.106985 [doi]
PST - ppublish
SO  - Pharmacol Res. 2023 Nov;197:106985. doi: 10.1016/j.phrs.2023.106985. Epub 2023 
      Nov 9.