Soluble CD163 in young sickle cell disease patients and their trait siblings

Tantawy, Azza Abdel Gawad; Adly, Amira Abdel Moneam; Ismail, Eman Abdel Rahman

doi:10.1097/mbc.0b013e3283573a42

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…Nakayama et al found that in patients with scleroderma and elevated serum soluble CD163 (sCD163) levels, 70% of patients had an elevated RVSP on echo versus 28% of patients with normal levels (54). In patients with sickle cell disease and PH, soluble sCD163 levels were over twice that of sickle cell patients without PH (55). …”

Section: Discussionmentioning

confidence: 99%

Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension

Kasmi

Pugliese

Riddle

et al. 2014

The Journal of Immunology

180

169

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Macrophage accumulation is not only a characteristic hallmark but also a critical component of pulmonary artery (PA) remodeling associated with pulmonary hypertension (PH). However, the cellular and molecular mechanisms that drive vascular macrophage activation and their functional phenotype remain poorly defined. Utilizing multiple levels of in vivo (bovine and rat models of hypoxia-induced PH, together with human tissue samples) and in vitro (primary mouse, rat, and bovine macrophages, human monocytes, as well as primary human and bovine fibroblasts) approaches, we observed that adventitial fibroblasts derived from hypertensive Pas (bovine and human) regulate macrophage activation. These fibroblasts activate macrophages through paracrine IL6 and STAT3, HIF1, and C/EBPβ signaling to drive expression of genes previously implicated in chronic inflammation, tissue remodeling, and PH. This distinct fibroblast-activated macrophage phenotype was independent of IL4/IL13-STAT6 and TLR-MyD88 signaling. We found that genetic STAT3 haplodeficiency in macrophages attenuated macrophage activation while complete STAT3 deficiency increased macrophage activation through compensatory upregulation of STAT1 signaling, while deficiency in C/EBPβ or HIF1 attenuated fibroblast driven macrophage activation. These findings challenge the current paradigm of IL4/IL13-STAT6 mediated alternative macrophage activation as the sole driver of vascular remodeling in PH and uncover a crosstalk between adventitial fibroblasts and macrophages in which paracrine IL6 activated STAT3, HIF1, and C/EBPβ signaling is critical for macrophage activation and polarization. Thus, targeting IL6 signaling in macrophages by completely inhibiting C/EBPβ, HIF1a or partially inhibiting STAT3 may hold therapeutic value for treatment of PH and other inflammatory conditions characterized by increased IL6 and absent IL4/IL13 signaling.

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Section: Discussionmentioning

confidence: 99%

Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension

Kasmi

Pugliese

Riddle

et al. 2014

The Journal of Immunology

180

169

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“…HIV-infected individuals also have elevated levels of inflammatory cytokines such as interleukin-1, interleukin-10, interleukin-12p40, interferon γ produced protein 10, interferon γ, as well as markers of cellular activation [soluble CD25 (sCD25) [8], soluble CD14 (sCD14), soluble tumor necrosis factor 2 (sTNFR-2), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble CD163 (sCD163)] [7,9,10]. …”

Section: Introductionmentioning

confidence: 99%

Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy

Ticona

Bull

Soria

et al. 2015

Aids

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Objective Inflammatory biomarkers associated with cardiovascular disease are elevated in HIV-infected persons. These biomarkers improve with antiretroviral therapy (ART) but do not normalize to values observed in HIV-uninfected adults. Little is known regarding biomarkers of inflammation in HIV-infected Peruvians, in whom an increased burden of infectious diseases may exacerbate inflammation, and women, in whom sex difference may alter inflammation compared with men. Methods Peruvians initiating first-line ART were enrolled in a prospective observational study. Individuals with suppression of HIV RNA plasma loads to less than 30 copies/ml when determined quarterly over 24 months of ART, had biomarkers of inflammation and cellular activation measured pre-ART and at 24-months of ART, and evaluated for associations with sex and clinical parameters. Results Pre-ART high-sensitivity C-reactive protein (hsCRP) values of men were in the high-risk cardiovascular disease category (>3.0mg/l) more frequently compared with women (P = 0.02); most women’s values were in the low/average-risk categories. At 24 months of suppressive ART, hsCRP concentrations decreased in men (P = 0.03), but tended to increase in women, such that the proportion with high-risk hsCRP did not differ by sex. Pre-ART, soluble CD163 concentrations were higher in women compared with men (P = 0.02), and remained higher after 24 months of suppressive ART (P = 0.02). All other inflammatory biomarkers (P < 0.03) decreased across sexes. Biomarker concentrations were not associated with BMI or coinfections. Conclusion Elevated inflammatory biomarkers persisted despite 24 months of suppressive ART in a subset of Peruvians, and to a greater extent in women compared with men. These findings suggest that lifestyle or pharmacologic interventions may be required to optimize the health of HIV-infected Peruvians, particularly women.

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“…Increased levels of circulating CFH have also been shown in the SU/hypoxia rat model of PAH and correlate with disease severity 33,34 . Moreover, populations at risk for developing pulmonary hypertension have abnormalities in hemoglobin processing proteins 17,18 . Hemoglobin infusion in animal models leads to pulmonary vascular injury which is mitigated by concomitant infusion of the CFH scavenger haptoglobin 13,15,16,35,36 .…”

Section: Discussionmentioning

confidence: 99%

“…33,34 Moreover, populations at risk for developing pulmonary hypertension have abnormalities in hemoglobin processing proteins. 17,18 Hemoglobin infusion in animal models leads to pulmonary vascular injury which is mitigated by concomitant infusion of the CFH scavenger haptoglobin. 13,15,16,35,36 Collectively, these studies suggest CFH generation and incomplete metabolism are common features of pulmonary vascular dysfunction that may be modifiable.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, previous studies have demonstrated that patients at risk for PAH may have abnormalities in hemoglobin-processing proteins. 17,18 Taken together, we hypothesized that both red blood cell lysis and dysregulated CFH processing contribute to elevated levels of CFH generated from the pulmonary circulation and contribute to PAH pathology.…”

Section: Introductionmentioning

confidence: 99%

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Transpulmonary generation of cell‐free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms

et al. 2023

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Circulating cell‐free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemoglobin α were analyzed in patients with PAH and healthy controls. Haptoglobin genotype and plasma hemoglobin processing proteins were analyzed in patients with PAH, unaffected bone morphogenetic protein receptor type II mutation carriers (UMCs), and control subjects. Transpulmonary CFH was increased in patients with PAH ( p = 0.04) and correlated with pulmonary vascular resistanc (PVR) ( r s = 0.75, p = 0.02) and mean pulmonary arterial pressure (mPAP) ( r s = 0.78, p = 0.02). Pulmonary vascular hemoglobin α protein was increased in patients with PAH ( p = 0.006), especially in occluded vessels ( p = 0.04). Haptoglobin genotype did not differ between groups. Plasma haptoglobin was higher in UMCs compared with both control subjects ( p = 0.03) and patients with HPAH ( p < 0.0001); patients with IPAH had higher circulating haptoglobin levels than patients with HPAH ( p = 0.006). Notably, circulating CFH to haptoglobin ratio was elevated in patients with HPAH compared to control subjects ( p = 0.02) and UMCs ( p = 0.006). Moreover, in patients with PAH, CFH: haptoglobin correlated with PVR ( r s = 0.37, p = 0.0004) and mPAP ( r s = 0.25, p = 0.02). Broad alterations in other plasma hemoglobin processing proteins (hemopexin, heme oxygenase‐1, and sCD163) were observed. In conclusion, pulmonary vascular CFH is associated with increased PVR and mPAP in PAH and dysregulated CFH clearance may contribute to PAH pathology. Further study is needed to determine whether targeting CFH is a viable therapeutic for pulmonary vascular dysfunction in PAH.

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Soluble CD163 in young sickle cell disease patients and their trait siblings

Cited by 16 publications

References 46 publications

Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension

Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension

Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy

Transpulmonary generation of cell‐free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms

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