Emmanouil Mavrogiannis, Rebeca Weldeghebreal, Iris R. Schilthuis, Zain K. Fal, Niels J. Kloosterhuis, Mirjam H. Koster, Wim Timens, Johannes M. Douwes, Rolf M. F. Berger, Marit Westerterp
Beatrix Children’s Hospital, University Medical Center Groningen and University of Groningen.
Netherlands
Pulmonary Circulation
Pulm Circ 2026; 16:
DOI: 10.1002/pul2.70354
Abstract
Pulmonary arterial hypertension (PAH) is a progressive vasculopathy leading to right-sided heart failure. We have shown previously that the (NOD-like-receptor-3) NLRP3 inflammasome is activated in end-stage disease of the monocrotaline and aortocaval shunt (MCT/ACS) neointimal PAH rat model. The NLRP3 and absent-in-melanoma 2 (AIM2) inflammasomes mediate the secretion of interleukin (IL)-1β and IL-18. We investigated the role of the NLRP3 inflammasome in PAH rats and the presence of NLRP3 and AIM2 in PAH rat and pediatric patient lungs. For a natural history study, we assessed inflammasome activation by Western blot at different disease stages in the MCT/ACS neointimal PAH rat model. To assess the role of the inflammasome in PAH, we treated PAH rats with or without the NLRP3 inflammasome inhibitor MCC950 and assessed vascular remodeling employing hematoxylin and eosin staining on rat lungs. Lung sections from patients who had undergone lung transplantation were stained for NLRP3 and AIM2 using immunofluorescence. We found that inflammasome activation in lungs of PAH rats, reflected by cleaved caspase-1, IL-1β, and IL-18, increased over time, reaching significance for cleaved caspase-1 and IL-18 in end-stage PAH. The NLRP3 inflammasome inhibitor MCC950 suppressed vascular remodeling but not hemodynamic variables compared to control PAH rats. We detected NLRP3+ and AIM2+ cells in end-stage pediatric PAH lungs. In conclusion, inflammasome activation increases over time in the MCT/ACS neointimal PAH rat model, and NLRP3 inflammasome activation increases vascular remodeling. NLRP3 and AIM2 positive cells are present in end-stage pediatric patient PAH lungs, suggesting human relevance.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes