Placenta growth factor mediated gene regulation in sickle cell disease

Kalra, Vijay K.; Zhang, Shuxiao; Tahara, Stanley M.

doi:10.1016/j.blre.2017.08.008

Cited by 9 publications

(7 citation statements)

References 100 publications

(172 reference statements)

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“…One of the least appreciated roles of PlGF is the one that it has in hematopoiesis ( 311 , 312 ) and in hemoglobinopathies ( 313 ) ( Figure 2 ). Plasma PlGF is elevated in SCD patients and the increase correlates with the severity of hemolysis, endothelin 1 (ET-1) expression, the occurrence of pulmonary hypertension ( 167 , 280 , 314 , 315 ) and VOC ( 316 , 317 ).…”

Section: Hemolysis Plgf and Complications Of Sickle Cell Diseasementioning

confidence: 99%

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Gbotosho¹,

Kapetanaki

Kato

2021

Front. Immunol.

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Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.

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Section: Hemolysis Plgf and Complications Of Sickle Cell Diseasementioning

confidence: 99%

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Gbotosho¹,

Kapetanaki

Kato

2021

Front. Immunol.

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“…Our results showing a reduction in LAM and AT-2 cells PPAR-γ at baseline in SS mice support and extend previous publications on PPAR-γ expression in SCD. 86 –90 However, it differs from these publications by documenting PPAR-γ expression in non-endothelial cells in the lung, suggesting that derangement of PPAR-γ in other alveolar cell types may contribute to pulmonary dysfunction in SCD. Peroxisome Proliferator Activated Receptors (PPARs) belong to the nuclear hormone receptor superfamily with three isoforms encoded by separate genes: PPAR-γ, PPARα, and PPARδ.…”

Section: Discussionmentioning

confidence: 83%

The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD

Gbotosho

Joiner

et al. 2023

Exp Biol Med (Maywood)

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The lung microenvironment plays a crucial role in maintaining lung homeostasis as well as the initiation and resolution of both acute and chronic lung injury. Acute chest syndrome (ACS) is a complication of sickle cell disease (SCD) like acute lung injury. Both the endothelial cells and peripheral blood mononuclear cells are known to secrete proinflammatory cytokines elevated during ACS episodes. However, in SCD, the lung microenvironment that may favor excessive production of proinflammatory cytokines and the contribution of other lung resident cells, such as alveolar macrophages and alveolar type 2 epithelial (AT-2) cells, to ACS pathogenesis is not completely understood. Here, we sought to understand the pulmonary microenvironment and the proinflammatory profile of lung alveolar macrophages (LAMs) and AT-2 cells at steady state in Townes sickle cell (SS) mice compared to control mice (AA). In addition, we examined lung function and micromechanics molecules essential for pulmonary epithelial barrier function in these mice. Our results showed that bronchoalveolar lavage (BAL) fluid in SS mice had elevated protein levels of pro-inflammatory cytokines interleukin (IL)-1β and IL-12 (p ⩽ 0.05) compared to AA controls. We showed for the first time, significantly increased protein levels of inflammatory mediators (Human antigen R (HuR), Toll-like receptor 4 (TLR4), MyD88, and PU.1) in AT-2 cells (1.4 to 2.2-fold) and LAM (17-21%) isolated from SS mice compared to AA control mice at steady state. There were also low levels of anti-inflammatory transcription factors (Nrf2 and PPARy) in SS mice compared to AA controls (p ⩽ 0.05). Finally, we found impaired lung function and a dysregulated composition of surfactant proteins (B and C). Our results demonstrate that SS mice at steady state had a compromised lung microenvironment with elevated expression of proinflammatory cytokines by AT-2 cells and LAM, as well as dysregulated expression of surfactant proteins necessary for maintaining the alveolar barrier integrity and lung function.

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“…Exposure to heme also results in increased production of placenta growth factor (PIGF) by erythroid cells via the erythroid Krüppel-like factor (EKLF) 61 and NRF2antioxidant response signaling 62 . PIGF is an angiogenic factor that activates endothelial cells to secrete ET-1 63 . In an elegant study, overexpression of erythroid-specific PIGF in normal mice up to the levels seen in sickle cell mice resulted in an increase in the production of ET-1, which correlated with increased right ventricular pressure and pulmonary arteriolar thickening 64 .…”

Section: Inflammation and Acute Chest Syndromementioning

confidence: 99%

“…Elevated ET-1 and PlGF levels also correlate with severity of PH in patients with SCD 64 . PIGF was shown to activate expression of hypoxia-inducible factor 1α (HIF-1α), independently of hypoxia, which in turn can stimulate expression of ET-1, which is involved with the development and severity of PH in SCD 63 .…”

Section: Inflammation and Acute Chest Syndromementioning

confidence: 99%

The Role of Inflammation in the Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

Gbotosho¹,

Gollamudi²,

Hyacinth³

2023

Preprint

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Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD associated cardiopulmonary complications in recent mechanistic and observational studies. In this review, we discuss recent cellular and molecular mechanisms of cardiopulmonary complications in SCD and summarize the most recent evidence from clinical and laboratory studies. We emphasize the role of inflammation in the onset and progression of these complications to better understand the underlying pathobiological processes. We also discuss future basic and translational research in addressing questions about the complex role of inflammation in the development of SCD cardiopulmonary complications, which may lead to promising therapies and reduce morbidity and mortality in this vulnerable population.

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Placenta growth factor mediated gene regulation in sickle cell disease

Cited by 9 publications

References 100 publications

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD

The Role of Inflammation in the Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

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