Systemic Fibrocyte Levels and Keloid Expression of the Chemoattractant CXCL12 Are Upregulated Compared With Patients With Normal Scar.

Background: Fibrocytes are bone marrow mesenchymal precursors with a surface phenotype compatible with leukocytes, fibroblasts, and hematopoietic progenitors that have been shown to traffic to wound healing sites in response to described chemokine pathways. Keloids are focal fibrotic responses to cutaneous trauma characterized by disordered collagen, which may be associated with elevated systemic fibrocyte levels and/or wound bed chemokine expression.

Methods: Blood specimens from patients with longstanding keloids and those who form grossly normal scars were assayed by fluorescence activated cell sorting analysis for fibrocytes (CD45+, Col I+).

Increased type 2 inflammation post rhinovirus infection in patients with moderate asthma.

Rhinovirus (RV) infections are a major cause of exacerbations in patients with asthma. Experimental RV challenges can provide insight into the pathophysiology of viral exacerbations. Previous reports, investigating mild or moderate asthma patients, have shown an upregulation in type 2 inflammation post RV infection, however, studies specifically involving asthma patients taking inhaled corticosteroids have concentrated on symptoms and lung function, rather than the inflammatory response.

Circulating fibrocytes as biomarkers of impaired lung function in adults with sickle cell disease.

Lung injury and fibrosis are common in patients with sickle cell disease (SCD). Fibrocytes, a population of circulating, bone marrow-derived cells, have been linked to development and progression of tissue fibrogenesis and have been implicated in the development of lung fibrosis in preclinical models of SCD. We tested the hypothesis that the levels and activation state of circulating fibrocytes during steady state are associated with abnormal pulmonary function in adults with SCD.

Circulating fibrocytes as predictors of adverse events in unstable angina.

Half of the patients who present with unstable angina (UA) develop recurrent symptoms over the subsequent year. Identification of patients destined to develop such adverse events would be clinically valuable, but current tools do not allow for this discrimination. Fibrocytes are bone marrow-derived progenitor cells that co-express markers of leukocytes and fibroblasts and are released into the circulation in the context of tissue injury.

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity.

Background: A biomarker that predicts poor asthma control would be clinically useful. Fibrocytes are bone marrow-derived circulating progenitor cells that have been implicated in tissue fibrosis and T(H)2 responses in asthmatic patients.

Objective: We sought to test the hypothesis that the concentration and activation state of peripheral blood fibrocytes correlates with asthma severity.

GITR agonist enhances vaccination responses in lung cancer.

An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens.

Increased circulating fibrocytes are associated with higher reticulocyte percent in children with sickle cell anemia.

Background: Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease.

Drug development for airway diseases: looking forward.

Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics.

A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to growth factors, cytokines, and chemokines. Chemokine receptor CXCR2 and its cognate ligands are reported to mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif which has been reported to modulate cellular signaling and functions.

Circulating fibrocytes as biomarker of prognosis in Hermansky-Pudlak syndrome.

Rationale: The rate of progression of most interstitial lung diseases (ILD) is unpredictable. Fibrocytes are circulating bone marrow-derived cells that have been implicated in the pathogenesis of lung fibrosis. Hermansky-Pudlak syndrome (HPS), a genetic cause of ILD in early adulthood, allows for study of biomarkers of ILD in a homogeneous population at near-certain risk of developing fibrotic lung disease.

Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis.

Background: Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options.

Objective: We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE.

Methods: Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months.

CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells.

Unlabelled: Chemokines have been implicated as key contributors of non-small cell lung cancer (NSCLC) metastasis. However, the role of CXCR7, a recently discovered receptor for CXCL12 ligand, in the pathogenesis of NSCLC is unknown. To define the relative contribution of chemokine receptors to migration and metastasis, we generated human lung A549 and H157 cell lines with stable knockdown of CXCR4, CXCR7, or both.

Dose-dependent Effect of Statin Therapy on Circulating CXCL12 Levels in Patients with Hyperlipidemia.

Background: HMG-CoA reductase inhibitors (statins) have pleiotropic effects that are independent of cholesterol-lowering, including a dose-dependent effect on angiogenesis. Angiogenesis plays a critical role both in vascularization of the chronically ischemic myocardium and in stabilization of atherosclerotic plaques. Chemokines, a family of structurally-related cytokine molecules, exert diverse biological functions including control of angiogenesis.

Fibrocytes and the pathogenesis of diffuse parenchymal lung disease.

Fibrosis is fundamental to the pathogenesis of many chronic lung diseases, including some lung infections, airway diseases such as bronchiectasis and asthma, and most of the diffuse parenchymal lung diseases. Idiopathic pulmonary fibrosis, the prototypical fibrotic lung disease, is amongst the most common diffuse parenchymal lung diseases and is characterized by progressive decline in lung function and premature death from respiratory failure. The clinical management of patients with this illness is hampered by our current inability to predict clinical deterioration and lack of an effective therapy.

Plasma CXCL12 levels as a predictor of future stroke.

Background And Purpose: The chemokine ligand CXCL12 is constitutively expressed in the bone marrow and other tissues including the brain endothelium and is responsible for regulating the trafficking of bone marrow progenitor cells. CXCL12 has been shown to play a significant role in animal models of ischemic stroke but its role in human stroke is unclear. The aim of this study was to test the hypothesis that elevated circulating baseline CXCL12 levels are associated with subsequent stroke.

Liver inflammation in a mouse model of Th1 hepatitis despite the absence of invariant NKT cells or the Th1 chemokine receptors CXCR3 and CCR5.

The specific mechanisms that mediate CD4(+) T-cell-mediated liver injury have not been fully elucidated. CD4(+) invariant natural killer T (iNKT) cells are required for liver damage in some mouse models of hepatitis, while the chemokine receptors CXCR3 and CCR5 are considered dominant Th1 chemokine receptors involved in Th1 trafficking in inflammatory conditions. BALB/c-Tgfb1(-/-) mice spontaneously develop Th1 hepatitis.

Elevated circulating fibrocyte levels in patients with hypertensive heart disease.

Objective: Autopsy and biopsy studies have shown that there is significantly more fibrosis in hearts of patients with hypertensive heart disease compared to normal hearts. Fibrocytes, a population of circulating bone marrow-derived cells, have been shown to home to tissues and promote scar formation in several diseases, but their role in human hypertensive heart disease has not been investigated to date. Our objective was to determine whether fibrocyte levels are elevated in individuals with hypertensive heart disease.

Type I immune response cytokine-chemokine cascade is associated with pulmonary arterial hypertension.

Background: Perivascular infiltrating mononuclear cells have been described in the vasculopathy found in multiple types of pulmonary arterial hypertension (PAH). We determined the expression of a specific type 1 immune response cytokine-chemokine cascade-interleukin (IL)-18 → (monokine induced by γ-interferon [MIG]/chemokine [C-X-C motif] ligand [CXCL] 9, interferon γ-induced protein [IP]-10/CXCL10 and interferon-inducible T-cell α chemoattractant [ITAC]/CXCL11)-in plasma samples from individuals with World Health Organization (WHO) Group 1 PAH.

Methods: We analyzed cytokine and chemokine protein levels in plasma from 43 individuals with WHO Group 1 PAH by enzyme-linked immunosorbent assay compared with 35 healthy individuals.

The role of fibrocytes in sickle cell lung disease.

Background: Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.

Adenosine A2B receptor blockade slows growth of bladder and breast tumors.

The accumulation of high levels of adenosine in tumors activates A(2A) and A(2B) receptors on immune cells and inhibits their ability to suppress tumor growth. Deletion of adenosine A(2A) receptors (A(2A)ARs) has been reported to activate antitumor T cells, stimulate dendritic cell (DC) function, and inhibit angiogenesis. In this study, we evaluated the effects of intermittent intratumor injection of a nonselective adenosine receptor antagonist, aminophylline (AMO; theophylline ethylenediamine) and, for the first time to our knowledge, a selective A(2B)AR antagonist, ATL801.

Circulating fibrocytes correlate with bronchiolitis obliterans syndrome development after lung transplantation: a novel clinical biomarker.

Background: Development of bronchiolitis obliterans syndrome (BOS) after lung transplantation confers increased patient morbidity and mortality. Fibrocytes are circulating bone marrow-derived mesenchymal cell progenitors that influence tissue repair and fibrosis. Fibrocytes have been implicated in chronic pulmonary inflammatory processes.

Plasma chemokine levels are associated with the presence and extent of angiographic coronary collaterals in chronic ischemic heart disease.

Background: In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings.

Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling.

Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few studies have investigated the mechanisms responsible for neutrophil mobilization from the bone marrow during polymicrobial sepsis.