TY - JOUR
T1 - Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension
AU - Vu, Luan D.
AU - Saravia, Jordy
AU - Jaligama, Sridhar
AU - Panday, Rajshri V.Baboeram
AU - Sullivan, Ryan D.
AU - Mancarella, Salvatore
AU - Cormier, Stephania A.
AU - Kimura, Dai
N1 - Funding Information:
This study was funded by National Institute of Allergy and Infectious Diseases Grant AI090059 (to S. A. Cormier) and a Le Bonheur Foundation Award (to D. Kimura).
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/8
Y1 - 2021/8
N2 - Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH. NEW & NOTEWORTHY We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.
AB - Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH. NEW & NOTEWORTHY We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.
KW - Arginase
KW - Periostin
KW - Pulmonary hypertension
KW - Respiratory syncytial virus
KW - ST2
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U2 - 10.1152/ajpheart.00018.2021
DO - 10.1152/ajpheart.00018.2021
M3 - Article
C2 - 34170196
AN - SCOPUS:85112238181
VL - 321
SP - H309-H317
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6135
IS - 2
ER -