Jason C. Lao, Christine B. Bui, Merrin A. Pang, Steven X. Cho, Ina Rudloff, Kirstin Elgass, Jan Schroder, Anton Maksimenko, Niamh E. Mangan, Malcolm R. Starkey, Elisabeth M. Skuza, Yu B. Y. Sun, Friederike Beker, Clare L. Collins, Omar F. Kamlin, Kai Konig, Atul Malhotra, Kenneth Tan, Chritiane Theda, Morag J. Young, Catriona A. McLean, Nicholas J. Wilson, Arvind Sehgal, Philip M. Hansbro, James T. Pearson, Jose M. Polo, Alex Veldman, Philip J. Berger, Claudia A. Nold-Petry, Marcel F. Nold
Monash University. Hudson Institute of Medical Research. Monash Biomedicine Discovery Institute. Australian Synchrotron. Hunter Medical Research Institute and University of Newcastle. University of Queensland. Royal Women’s Hospital. University of Melbourne. Murdoch Children’s Research Institute. Medicum Wesemlin. Monash Children’s Hospital. Baker Heart and Diabetes Institute. Alfred Health. Bio21 Institute. Centenary Institute and University of Technology Sydney. National Cerebral and Cardiovascular Center Research Institute. Victorian Heart Institute. University of Adelaide. Helios HSK. J. Liebig University.
Australia and Germany
Science Translational Medicine
Sci Transl Med 2022; 14:
DOI: 10.1126/scitranslmed.aaz8454
Abstract
Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Pulmonary Hypertension Associated with Inflammation
Class III. Pulmonary Hypertension Associated with Lung Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
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