An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease.

Autor: Redinus K; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Baek JH; Division of Blood Components and Devices, Office of Blood Research and Review, The Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA., Yalamanoglu A; Division of Blood Components and Devices, Office of Blood Research and Review, The Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA., Shin HKH; Division of Blood Components and Devices, Office of Blood Research and Review, The Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA., Moldova R; Advanced Light Microscopy Core Facility and., Harral JW; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Swindle D; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Pak D; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Ferguson SK; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Nuss R; Division of Hematology and Colorado Sickle Cell Treatment and Research Center, School of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Hassell K; Division of Hematology and Colorado Sickle Cell Treatment and Research Center, School of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Nozik-Grayck E; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Palmer AF; William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA., Fini MA; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Karoor V; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Stenmark KR; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA., Buehler PW; Division of Blood Components and Devices, Office of Blood Research and Review, The Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA., Irwin DC; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, Anschutz Medical Campus, University of Colorado-Denver School of Medicine, Aurora, Colorado, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2019 Aug 08; Vol. 4 (15). Date of Electronic Publication: 2019 Aug 08 (Print Publication: 2019).
DOI: 10.1172/jci.insight.127860
Abstrakt: Circulating macrophages recruited to the lung contribute to pulmonary vascular remodeling in various forms of pulmonary hypertension (PH). In this study we investigated a macrophage phenotype characterized by intracellular iron accumulation and expression of antioxidant (HO-1), vasoactive (ET-1), and proinflammatory (IL-6) mediators observed in the lung tissue of deceased sickle cell disease (SCD) patients with diagnosed PH. To this end, we evaluated an established rat model of group 5 PH that is simultaneously exposed to free hemoglobin (Hb) and hypobaric hypoxia (HX). Here, we tested the hypothesis that pulmonary vascular remodeling observed in human SCD with concomitant PH could be replicated and mechanistically driven in our rat model by a similar macrophage phenotype with iron accumulation and expression of a similar mixture of antioxidant (HO-1), vasoactive (ET-1), and inflammatory (IL-6) proteins. Our data suggest phenotypic similarities between pulmonary perivascular macrophages in our rat model and human SCD with PH, indicating a potentially novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating macrophages with gadolinium trichloride (GdCl3), the response to combined Hb and hypobaric HX was significantly attenuated in rats, suggesting a critical role for macrophages in the exacerbation of SCD PH.
Databáze: MEDLINE