Christina Lisk, Francesca Cendali, Natalie Westover, Delaney Swindle, Daniel Colon Hidalgo, Caitlin Lewis, Melissa J. Lucero, Nishant K. Rana, Gemlyn George, Saini Setua, Monika Dzieciatkowska, Kathryn Hassel, Christy S. Niemeyer, Kurt Stenmark, Eva Nozik, Angelo D’Alessandro, Paul W. Buehler, David C. Irwin
University of Colorado Denver – Anschutz Medical Campus. Children’s Hospital Colorado. University of Maryland School of Medicine.
United States
Pulmonary Circulation
Pulm Circ 2026; 16:
DOI: 10.1002/pul2.70413
Abstract
Pulmonary hypertension (PH) is a fatal sequela in sickle cell disease (SCD) patients and occurs with greater prevalence compared to the general population. Macrophages (Mϕ) are one of the first immune cells to be recruited to the lungs in mouse models of PH, including SCD-PH, and a key cell type that contribute toward disease progression. Here, we first determined if phenotypic difference exist between control (C57BL/6) and Berkeley-SS (Berk-SS, SCD) mouse pulmonary Mϕs and, if so, how chronic moderate hypoxic exposure (~8,000 ft, Pb ~568 mmHg for 10 weeks) altered molecular and metabolic pathways. Next, we aimed to determine if the microenvironment of the Berk-SS lung is primed for Mϕs recruitment compared to the C57BL/6 lung. Using precision cut lung slice (PCLS), we determined PCLS from Berk-SS mice have significant increases in adhesion molecules associate with Mϕ recruitment and recruit splenic Mϕs at a greater rate compared to control mice. We confirmed these results in an acute hypoxic exposure (18,000 ft for 3 days) experiment and our results suggest that Berk-SS mice recruit more interstitial Mϕ with a pro-inflammatory phenotype when compared to C57BL/6 mice. Lastly, the depletion of Mϕ in our Berk-SS PH model improved right ventricular function, decreased pulmonary vascular muscularization, and improved exercise tolerance. Together, these data emphasize a critical role of Mϕ pulmonary recruitment in SCD-PH pathophysiology that is driven by inflammation.
Category
Class I. Pulmonary Hypertension Associated with Inflammation
Class V. Pulmonary Hypertension Associated with Hematological, Systemic, Metabolic, Nutritional and Other Disorders
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
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