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Tytuł pozycji:

Altered Macrophage Polarization Induces Experimental Pulmonary Hypertension and Is Observed in Patients With Pulmonary Arterial Hypertension.

Tytuł :
Altered Macrophage Polarization Induces Experimental Pulmonary Hypertension and Is Observed in Patients With Pulmonary Arterial Hypertension.
Autorzy :
Zawia A; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Arnold ND; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
West L; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Pickworth JA; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Turton H; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Iremonger J; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Braithwaite AT; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Cañedo J; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Johnston SA; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Thompson AAR; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
Miller G; Department of Oncology and Metabolism (G.M.), University of Sheffield, United Kingdom.; College of Medical and Dental Science, University of Birmingham, United Kingdom (G.M.).
Lawrie A; Department of Infection, Immunity and Cardiovascular Disease (A.Z., N.D.A., L.W., J.A.P., H.T., J.I., A.T.B., J.C., S.A.J., A.A.R.T., A.L.), University of Sheffield, United Kingdom.
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Źródło :
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2021 Jan; Vol. 41 (1), pp. 430-445. Date of Electronic Publication: 2020 Nov 05.
Typ publikacji :
Journal Article; Observational Study; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
MeSH Terms :
Macrophage Activation*
Vascular Remodeling*
Macrophages, Alveolar/*pathology
Muscle, Smooth, Vascular/*pathology
Pulmonary Arterial Hypertension/*pathology
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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Grant Information :
FS/18/52/33808 United Kingdom BHF_ British Heart Foundation
Contributed Indexing :
Keywords: heart failure, right*; humans*; macrophages*; models, animal*; pulmonary hypertension*
Substance Nomenclature :
0 (Antigens, CD)
0 (Antigens, Differentiation, Myelomonocytic)
0 (CD68 antigen, human)
0 (Diphtheria Toxin)
0 (Peptide Fragments)
0 (diphtheria toxin fragment A)
Entry Date(s) :
Date Created: 20201105 Date Completed: 20210201 Latest Revision: 20210310
Update Code :
20210310
PubMed Central ID :
PMC7752239
DOI :
10.1161/ATVBAHA.120.314639
PMID :
33147993
Czasopismo naukowe
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.

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