13 research outputs found
The Role of Fibrocytes in Sickle Cell Lung Disease
<div><h3>Background</h3><p>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.</p> <h3>Methodology/Principal Findings</h3><p>Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.</p> <h3>Conclusions</h3><p>These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.</p> </div
CXCR4, but not CXCR7, Discriminates Metastatic Behavior in Non–Small Cell Lung Cancer Cells
NY1DD SCD mice displayed increased numbers of fibrocytes in their bone marrow, circulation, and lungs under baseline conditions.
<p>A–C) demonstrates that fibrocytes are elevated in the bone marrow, circulation, and lungs of NY1DD SCD mice, as compared to strain and age-matched control mice. In addition, A–C) demonstrates that fibrocytes in the bone marrow, circulation, and lungs of NY1DD mice, as compared to strain and age-matched mice express a chemokine receptor hierarchy (i.e., CXCR4+≫CCR2+>CCR7+). D–F) demonstrates that elevated fibrocytes in the bone marrow, circulation, and lungs of NY1DD mice, as compared to appropriate strain and age-match mice express pro-collagens I and III (pro-collagen type I N and C-terminus = PINP and PICP, respectively; pro-collagen type III C-terminus = PIIICP). G–I) NY1DD SCD mice displayed increased numbers of fibrocytes (CD45+Col1+ cells) in their bone marrow, circulation, and lungs under baseline conditions that represent an activated phenotype (αSMA+ cells) compared to appropriate strain and age-match mice. N = six mice in each group. * p<0.05.</p
Fibrocytes are markedly elevated and activated in the circulation of patients with SCD at baseline compared to healthy African American controls.
<p>A) fibrocytes defined as CD45+Col1+ cells were elevated in number in the circulation of patients with SCD, as compared to control subjects. B–D) demonstrates that fibrocytes in the circulation of patients with SCD, as compared to control subjects express a chemokine receptor hierarchy (i.e., CXCR4+>CCR2+>CCR7+). E–F) demonstrates that fibrocytes in the circulation of patients with SCD, as compared to control subjects represent an activated phenotype of αSMA+ and pSmad2/3+ cells, respectively, compatible with fibrocytes pre-systemically activated by TGF-b.</p
Baseline demographics, SCD characteristics and fibrocyte levels in SCD subjects with severe SCD phenotypes (HbSS/Sβ-thalassemia<sup>0</sup>) compared to milder SCD phenotypes (HbSC/Sβ-thalassemia<sup>+</sup>).
<p>IQR, inter-quartile range; LDH, lactate dehydrogenase; SCD, sickle cell disease; SD, standard deviation; WBC, white blood cell.</p
NY1DD SCD mice displayed marked lung fibrosis and inflammation under conditions simulating VOC (hypoxia followed by reoxygenation) (B), as compared to NY1DD mice exposed to normoxic conditions alone (A).
<p>Photomicrographs are representative H&E of lungs from six mice in each group, under 400×. NY1DD SCD mice displayed increased numbers of fibrocytes in their bone marrow, circulation, and lungs under conditions simulating VOC (hypoxia followed by reoxygenation). C–E) demonstrates that fibrocytes are elevated in the bone marrow, circulation, and lungs of NY1DD SCD mice under conditions simulating VOC (hypoxia followed by reoxygenation), as compared to NY1DD mice exposed to normoxic conditions alone. In addition, C–E) demonstrates that fibrocytes in the bone marrow, circulation, and lungs of NY1DD SCD mice under conditions simulating VOC (hypoxia followed by reoxygenation), as compared to NY1DD mice exposed to normoxic conditions alone express a chemokine receptor hierarchy (i.e., CXCR4+≫CCR2+>CCR7+). N = six mice in each group. * p = <0.05.</p
NY1DD SCD mice have increased lung levels of CXCL12 and other cytokines that are relevant to fibrocyte biology.
<p>A) demonstrates that the ligand to CXCR4, CXCL12, is markedly elevated in the lungs of NY1DD mice under baseline conditions compared to appropriate strain and age-match mice. B) demonstrates that the growth factor (PDGF) and colony stimulating factor (M-CSF) are significantly elevated in the lungs of NY1DD mice under baseline conditions compared to appropriate strain and age-match mice. N = six mice lungs in each group. * p = <0.05.</p
NY1DD SCD mice demonstrated increased deposition of extracellular matrix in their lungs under baseline conditions.
<p>A) NY1DD SCD mice, as compared to appropriate strain (C57Bl/6) and age-matched mice, demonstrate elevated levels of total collagen in their lungs under baseline (normoxia) conditions. The levels of total collagen in the lungs of NY1DD mice at baseline are equivalent to C57Bl/6 mice exposed to the pulmonary fibrotic agent, bleomycin, at day 16. B) NY1DD mice, as compared to appropriate strain and age-matched mice demonstrate elevated levels of collagen, as assessed by morphometric analysis of picrosirius red staining of lung tissue. N = six mice in each group. * p<0.05.</p