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Arterioscler Thromb Vasc Biol ; 41(1): 430-445, 2021 01.
Article in English | MEDLINE | ID: mdl-33147993

ABSTRACT

OBJECTIVE: To determine whether global reduction of CD68 (cluster of differentiation) macrophages impacts the development of experimental pulmonary arterial hypertension (PAH) and whether this reduction affects the balance of pro- and anti-inflammatory macrophages within the lung. Additionally, to determine whether there is evidence of an altered macrophage polarization in patients with PAH. Approach and Results: Macrophage reduction was induced in mice via doxycycline-induced CD68-driven cytotoxic diphtheria toxin A chain expression (macrophage low [MacLow] mice). Chimeric mice were generated using bone marrow transplant. Mice were phenotyped for PAH by echocardiography and closed chest cardiac catheterization. Murine macrophage phenotyping was performed on lungs, bone marrow-derived macrophages, and alveolar macrophages using immunohistochemical and flow cytometry. Monocyte-derived macrophages were isolated from PAH patients and healthy volunteers and polarization capacity assessed morphologically and by flow cytometry. After 6 weeks of macrophage depletion, male but not female MacLow mice developed PAH. Chimeric mice demonstrated a requirement for both MacLow bone marrow and MacLow recipient mice to cause PAH. Immunohistochemical analysis of lung sections demonstrated imbalance in M1/M2 ratio in male MacLow mice only, suggesting that this imbalance may drive the PAH phenotype. M1/M2 imbalance was also seen in male MacLow bone marrow-derived macrophages and PAH patient monocyte-derived macrophages following stimulation with doxycycline and IL (interleukin)-4, respectively. Furthermore, MacLow-derived alveolar macrophages showed characteristic differences in terms of their polarization and expression of diphtheria toxin A chain following stimulation with doxycycline. CONCLUSIONS: These data further highlight a sex imbalance in PAH and further implicate immune cells into this paradigm. Targeting imbalance of macrophage population may offer a future therapeutic option.


Subject(s)
Macrophage Activation , Macrophages, Alveolar/pathology , Muscle, Smooth, Vascular/pathology , Pulmonary Arterial Hypertension/pathology , Vascular Remodeling , Adult , Aged , Animals , Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Case-Control Studies , Cell Proliferation , Diphtheria Toxin/genetics , Disease Models, Animal , Female , Humans , Hypoxia/complications , Macrophages, Alveolar/metabolism , Male , Mice, Transgenic , Middle Aged , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Paracrine Communication , Peptide Fragments/genetics , Phenotype , Pulmonary Arterial Hypertension/etiology , Pulmonary Arterial Hypertension/metabolism , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Sex Factors
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