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

Redinus, Katherine; Baek, Jin Hyen; Yalamanoglu, Ayla; Shin, Hyun Soo; Moldova, Radu; Harral, Julie W.; Swindle, Delaney; Pak, David; Ferguson, Scott K.; Nuss, Rachelle; Hassell, Kathryn L.; Nozik‐Grayck, Eva; Palmer, Andre F.; Fini, Mehdi A.; Karoor, Vijaya; Stenmark, Kurt R.; Buehler, Paul W.; Irwin, David

doi:10.1172/jci.insight.127860

Cited by 23 publications

(48 citation statements)

References 36 publications

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“…Based on our reported observations in human SCA PH that demonstrate pulmonary vascular iron macrophage accumulation 4 and the results presented in Figure 1, we next stained lung tissue to assess for pulmonary vascular iron accumulation. Lung tissue sections stained with Perls DAB are shown (Figure 1G).…”

Section: Discussionmentioning

confidence: 99%

“…These contributors to the pathophysiology of PH development likely become more pronounced with age concomitant with a lifetime of exposure to hemolysis, endothelial dysfunction and anemia in murine models. Molecular contributors that include, decreased nitric oxide bioavailability that occurs after Hb consumption and/or arginase elevation, heme/iron induced oxidative processes and intermittent bouts of hypoxia that occur with RBC clearance are expected to contribute as underlying mechanisms 4,55,56 . Interestingly, functional and tissue metabolic differences are observed in the two murine models evaluated here.…”

Section: Discussionmentioning

confidence: 99%

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Murine models of sickle cell disease and beta‐thalassemia demonstrate pulmonary hypertension with distinctive features

et al. 2021

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Sickle cell anemia (SCA) and Î²-thalassemia intermedia are very different genetically determined hemoglobinopathies predisposing to pulmonary hypertension (PH). The etiologies responsible for the associated development of PH in both diseases are multi-factorial with extensive mechanistic contributors described. Both SCA and Î²-thalassemia intermedia present with intra and extravascular hemolysis, and because SCA and Î²-thalassemia intermedia share features of extravascular hemolysis, macrophage iron excess and anemia we sought to characterize the common features of the PH phenotype, cardiac mechanics, and function as well as lung and right ventricular metabolism. Within the concept of iron, we have defined a unique pulmonary vascular iron accumulation in lungs of SCA PH patients at autopsy. This observation is unlike findings in idiopathic or other forms of pulmonary arterial hypertension. In this study we hypothesized that a common pathophysiology would characterize the PH phenotype in SCA and Î²-thalassemia intermedia murine models, but because unlike SCA, Î²-thalassemia is also a disease of dyserythropoiesis, with increased iron absorption and cellular iron extrusion mediated by high erythroferrone and low hepcidin levels as well as dysregulated iron transport due transferrin saturation, there may be differences as well. Herein we describe common and divergent features of PH in aged Berk-ss (SCA) and Hbbth/3+ (intermediate Î²-thalassemia) mice and suggest translational utility as proof-of-concept models to study PH therapeutics specific to genetic anemias.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Murine models of sickle cell disease and beta‐thalassemia demonstrate pulmonary hypertension with distinctive features

et al. 2021

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“…In our PH model, we have observed a macrophage phenotype characterized by intracellular accumulation of iron, robust expression of heme oxygenase 1 (HO-1), and mediators of hypoxia (HX) induced PH such as endothelin-1 (ET-1) and interleukin 6 (IL-6). Furthermore, by depleting circulating macrophages with gadolinium trichloride (GdCl3), we observed a significant attenuation of the PH response, suggesting a critical role for macrophages in the development and progression of PH during exposures to Hb and HX 7 . Macrophages are essential in the resolution of inflammation and tissue repair after injury.…”

Section: Introductionmentioning

confidence: 87%

“…In SCD patients, pre or post-capillary driven PH processes are causally linked to the pulmonary vasculopathy caused by free hemoglobin (Hb) and its degradation products, heme, and iron, resulting in nitric oxide depletion hypoxia, and macrophage reprogramming 3,4 . We have developed an animal model that combines chronic Hb infusion and hypoxia (HX) to mimic intravascular hemolysis and impaired tissue oxygenation to approximate PH in the SCD population [5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Evidence supporting a role for circulating macrophages in the regression of vascular remodeling following sub‐chronic exposure to hemoglobin plus hypoxia

et al. 2021

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Macrophages are a heterogeneous population with both pro, and anti-inflammatory functions play an essential role in maintaining tissue homeostasis, promoting inflammation under pathological conditions, and tissue repair after injury. In pulmonary hypertension (PH), the M1 phenotype is more pro-inflammatory compared to the M2 phenotype, which is involved in tissue repair. The role of macrophages in the initiation and progression of PH is well studied. However, their role in the regression of established PH is not well known. Rats chronically exposed to hemoglobin (Hb) plus hypoxia (HX) share similarities to humans with PH associated with hemolytic disease, including the presence of a unique macrophage phenotype surrounding distal vessels that are associated with vascular remodeling. These lung macrophages are characterized by high iron content, HO-1, ET-1, and IL-6 and are recruited from the circulation. Depletion of macrophages in this model prevents the development of PH and vascular remodeling. In this study, we specifically investigate the regression of PH over a four-week duration after rats were removed from Hb+HX exposure with and without gadolinium chloride administration. Withdrawal of Hb+HX reversed systolic pressures and right ventricular function after Hb+Hx exposure in 4 weeks. Our data show that depleting circulating monocytes/macrophages during reversal prevents complete recovery of right ventricular systolic pressure and vascular remodeling in this rat model of PH at 4 weeks post exposure. The data presented offer a novel insight into the role of macrophages in the processes of PH regression in a rodent model of Hb+Hx-driven disease

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“…Similarly, haptoglobin dosing in subchronic settings suggests reduction of renal tubule Hb accumulation [109], with no demonstrable improvement in overall kidney function [110]. Human SCD with pulmonary hypertension and lung injury appears to be influenced by Hb, hypoxia, and, subsequently, macrophage reprogramming consistent with both stressors [111]. A rat model designed to mimic the effects of hypoxia and Hb on pulmonary hypertension and right heart failure suggests that progression of pulmonary vascular remodeling and right heart dysfunction are attenuated by haptoglobin dosing, administered multiple times per week [76].…”

Section: Trends In Molecular Medicinementioning

confidence: 99%

Haptoglobin Therapeutics and Compartmentalization of Cell-Free Hemoglobin Toxicity

Buehler

Humar

Schaer

2020

Trends in Molecular Medicine

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

Cited by 23 publications

References 36 publications

Murine models of sickle cell disease and beta‐thalassemia demonstrate pulmonary hypertension with distinctive features

Murine models of sickle cell disease and beta‐thalassemia demonstrate pulmonary hypertension with distinctive features

Evidence supporting a role for circulating macrophages in the regression of vascular remodeling following sub‐chronic exposure to hemoglobin plus hypoxia

Haptoglobin Therapeutics and Compartmentalization of Cell-Free Hemoglobin Toxicity

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