Macrophages Contribute to Pulmonary Hypertension Associated With Sickle Cell Disease

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.