Levels Of Fibrocytes Research Articles

Circulating fibrocyte levels correlate with left ventricular mass in middle-aged healthy adults without hypertension

BackgroundFibrocytes, circulating bone-marrow derived cells that differentiate into fibroblasts and myofibroblasts, are a major source of hypertensive arterial fibrosis and correlate with left ventricular (LV) mass in subjects with hypertension. We tested whether circulating fibrocytes levels correlate with LV mass in middle-aged adults without hypertension. MethodsWe measured peripheral blood fibrocyte levels and their activated phenotypes in 13 middle-aged, non-hypertensive adults and performed cardiac magnetic resonance imaging to assess LV mass. ResultsThere was a strong correlation between total fibrocyte levels (CD45 + Col1+) and LV mass index (r = 0.71, p = 0.006), as well as fibrocyte subsets expressing the chemokine markers CCR2 (r = 0.60, p = 0.032), CCR5 (r = 0.62, p = 0.029), CCR7 (r = 0.60, p = 0.034), co-expression of CXCR4 and CCR2 (r = 0.62, p = 0.029), α-SMA+ (r = 0.57, p = 0.044), CD133 (r = 0.59, p = 0.036), and pSTAT6 (r = 0.64, p = 0.032). ConclusionsCirculating fibrocytes are associated with LV mass index in middle-aged, non-hypertensive adults and may be a harbinger for the development of hypertension.

Characterization of Circulating Fibrocytes in People Living with HIV on Stable Antiretroviral Therapy.

Highly effective combination antiretroviral therapy has reduced HIV infection to a manageable chronic disease, shifting the clinical landscape toward management of noninfectious comorbidities in people living with HIV (PLWH). These comorbidities are diverse, generally associated with accelerated aging, and present within multiple organ systems. Mechanistically, immune dysregulation and chronic inflammation, both of which persist in PLWH with well-controlled virally suppressive HIV infection, are suggested to create and exacerbate noninfectious comorbidity development. Persistent inflammation often leads to fibrosis, which is the common end point pathologic feature associated with most comorbidities. Fibrocytes are bone marrow-derived fibroblast-like cells, which emerged as key effector cells in tissue repair and pathologic fibrotic diseases. Despite their relevance to fibrosis, the circulating fibrocyte concentration in PLWH remains poorly characterized, and an understanding of their functional role in chronic HIV is limited. In this study, utilizing PBMCs from a cross-sectional adult HIV cohort study with matched uninfected controls (HIV-), we aimed to identify and compare circulating fibrocytes in blood. Both the percentage and number of fibrocytes and α-smooth muscle actin+ fibrocytes in circulation did not differ between the HIV+ and HIV- groups. However, circulating fibrocyte levels were significantly associated with increasing age in both the HIV+ and HIV- groups (the percentage and number; r = 0.575, p ≤ 0.0001 and r = 0.558, p ≤ 0.0001, respectively). Our study demonstrates that circulating fibrocyte levels and their fibroblast-like phenotype defined as collagen I and α-smooth muscle actin+ expression are comparable between, and strongly associated with, age irrespective of HIV status.

Circulating and renal fibrocytes are associated with interstitial fibrosis in lupus nephritis.

Fibrocytes, the extracellular matrix-producing cells derived from bone marrow progenitors, contribute to organ fibrosis. We investigated the presence and characteristics of fibrocytes in the peripheral blood and kidney of patients with lupus nephritis (LN), and the association of the abundance of fibrocytes with renal tubular epithelial cells (RTECs) in LN fibrogenesis. Fibrocytes were identified with type I collagen (colI), α-smooth muscle actin (α-SMA), CD34 and CD45 using flow cytometry and confocal imaging. The associations between the levels of fibrocytes and pathological features of patients with LN were analysed. The contribution of RTECs to fibrocyte generation was determined using LN sera-treated HK-2 cells. Spindle-shaped fibrocytes (colI+α-SMA+CD34+CD45+ cells) were present in the peripheral blood and their abundance was especially high in LN patients with interstitial fibrosis compared with healthy control. Renal fibrocytes (colI+α-SMA+CD45+ cells) were found in the tubulointerstitium in patients with LN, and their numbers were significantly associated with the degrees of chronicity indices including interstitial fibrosis and renal dysfunction. Stimulation of peripheral blood mononuclear cells with supernatants from LN serum-treated HK-2 cells led to a significant generation of fibrocytes, which was abrogated by the addition of IL-6 neutralizing antibody. Fibrocytes were significantly increased in the blood and kidney tissue of patients with LN, especially those with interstitial fibrosis. Fibrocytes could be differentiated from blood cells, with an active contribution from RTECs. Our results show a possible link between fibrocytes and tubulointerstitial fibrosis, which may serve as a novel therapeutic target for LN fibrogenesis.

Circulating fibrocyte level in children with cystic fibrosis.

This study aimed to evaluate circulating fibrocyte levels in cystic fibrosis (CF) patients during stable and exacerbation periods of the condition. The study group consisted of 39 patients diagnosed with CF and 20 healthy controls. Individuals included in the study were divided into three groups: CF, CF exacerbated, and a healthy control group. Their circulating fibrocyte levels were compared. Findings from a pulmonary function test and high-resolution computed tomography of the lung were evaluated and compared. The circulating fibrocyte count was found to be significantly higher in patients with CF compared with the exacerbated and control groups. No correlation was found between the forced expiratory volume in 1 s and forced vital capacity values in the pulmonary function test and the circulating fibrocyte count. The circulating fibrocyte count in patients (in the CF group) with positive findings in the high-resolution computed tomography was statistically significantly lower. The circulating fibrocyte level in the peripheral blood of the patients with CF was increased.

Circulating fibrocyte levels correlate with infarct size in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention

Study objectiveInfarct size is a strong predictor of outcomes after ST elevation myocardial infarction (STEMI). Circulating fibrocytes are bone marrow-derived progenitor cells associated with fibrotic processes. We tested whether fibrocytes correlate with infarct size in STEMI patients treated with primary percutaneous coronary intervention (PCI). DesignProspective observational study. SettingAcademic medical center. ParticipantsSubjects with STEMI treated with primary PCI. InterventionsPeripheral blood draw and cardiac magnetic resonance imaging (CMR). Main outcome measureCorrelation of fibrocyte levels with infarct size. MethodsPeripheral blood fibrocytes were quantified at discharge from STEMI hospitalization and at 6 months follow-up using flow cytometry. Infarct size was determined within 2 weeks of discharge and at 6 months follow-up using late gadolinium enhancement on CMR. ResultsAmong 14 patients (median age 54 years, 79% men) with STEMI, there was a statistically significant positive correlation between fibrocyte levels at 6 months and 6-month infarct size on CMR (r = 0.58, p = 0.031). In addition, there was positive correlation between peak troponin I level (r = 0.85, p < 0.001), and white blood cell count (r = 0.55, p = 0.042) during the hospital stay and 6-month infarct size on CMR. ConclusionsCirculating fibrocytes measured 6 months after STEMI positively correlate with 6-month infarct size assessed by CMR.

In vitro effect of biological and conventional disease-modifying antirheumatic drugs on fibrocyte differentiation in patients with rheumatoid arthritis and healthy controls.

Fibrocytes are circulating bone-marrow-derived cells that migrate to organs with ongoing repair or inflammation. In the target organ, the cells differentiate, become long and spindle-shaped, and are able to produce extracellular matrix components. In fibrotic diseases, the levels of fibrocytes are increased, both in circulation and the diseased tissue. In rheumatoid arthritis (RA), fibrocytes have been proposed to be involved in the spread of the disease and possibly in RA fibrotic manifestations, as can be seen in RA interstitial lung disease (RA-ILD). Therefore, we aimed to investigate a range of current RA treatment modalities (corticosteroids and conventional and biological disease-modifying antirheumatic drugs (DMARDs)) regarding their effect on in vitro fibrocyte differentiation. A total of 10 participants were included (5 patients with RA and 5 healthy controls). Peripheral blood mononuclear cells (PBMCs) were isolated and cultured for 5 days with prednisolone, conventional DMARDs (methotrexate, sulfasalazine, and hydroxychloroquine), and biological DMARDs (etanercept, tocilizumab, adalimumab, abatacept, and rituximab). The numbers of fibrocytes were counted. Dose-response data for abatacept and tocilizumab were collected. Abatacept and prednisolone significantly suppressed differentiation of PBMC into fibrocytes compared with control (p=0.02 and p<0.01, respectively) (n=10). In overall analysis (n=10), abatacept reduced fibrocyte levels with an average of 44% overall and 71% in the RA group compared with the control wells. Tocilizumab reduced the fibrocyte count by 63% overall and 45% in the RA group, although it was not significant (p=0.07 and p=0.06, respectively). Both tocilizumab and abatacept display a dose-response relationship. Abatacept and prednisolone suppress the differentiation of mononuclear cells to mature fibrocytes in vitro in patients with RA, and data indicate a similar effect of tocilizumab; this was further supported by the observed dose-response relationship. Clinical trials are needed to compare the effect of these drugs on fibrotic RA manifestations, for example, RA-ILD.

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

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. 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+). The expression of the fibrocyte chemotactic cell surface marker CXCR4, intracellular markers of fibroblast differentiation (pSMAD2/3), and plasma levels of the CXCR4 cognate CXCL12 were compared. Keloid specimens and grossly normal scars were excised, and local expression of CXCL12 was assayed. Keloid-forming patients demonstrated a significantly greater number of circulating fibrocytes (17.4 × 105 cells/mL) than control patients (1.01 × 105 cells/mL, P = 0.004). The absolute number of fibrocytes expressing CXCR4 was significantly greater (P = 0.012) in keloid-forming patients. Systemic CXCL12 levels were insignificantly greater in keloid-forming patients than controls. Keloid specimens had significantly greater CXCL12 expression (529.3 pg/mL) than normal scar (undetectable). Systemic fibrocyte levels and the CXCR4/CXCL12 biologic axis responsible for fibrocyte trafficking to areas of regional fibrosis were both upregulated in patients who form keloids compared with controls. Keloids persistently expressed CXLC12, which serves both as the main chemoattractant for fibrocytes and a downstream mediator for local inflammation, suggesting a role for this biologic axis in keloid formation and possibly recurrence.

Elevated circulating fibrocyte levels in hemodialysis-dependent end-stage renal disease patients.

Numerous studies have demonstrated that end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) have high myocardial fibrosis (MF) levels. Circulating fibrocytes are bone marrow-derived circulating mesenchymal progenitors, and new evidence suggests a vital role for fibrocytes in the development of MF. This study aimed to investigate whether fibrocyte levels are elevated in patients undergoing HD and its influence factors. We carried out a flow cytometry analysis to measure the proportion of peripheral blood circulating fibrocytes in a cohort of 126 healthy control individuals and 161 subjects with HD. Cardiac function and morphology were assessed by electrocardiogram and transthoracic echocardiogram. Compared to healthy controls, individuals with ESRD had significantly higher levels of circulating fibrocytes. There was a strong correlation between the frequency of fragmented QRS (fQRS) and circulating fibrocytes in HD patients. Furthermore, higher fibrocytes correlated to increasing age, dialysis age, left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and hypertension complication. On multivariate analysis, the dialysis age [odds ratio (OR) 1.011, 95% confidence interval (CI) 1.003-1.019, p=0.006], LVMI (OR 1.012, 95% CI 1.002-1.022, p=0.016), hypertension (OR 4.303, 95% CI 1.129-16.406, p=0.033), and fQRS (OR 2.439, 95% CI 1.049-5.262, p=0.038) were significant independent predictors of fibrocytes percentage. We concluded that bone marrow-derived circulating fibrocytes were significantly increased in ESRD patients with HD compared with controls. Our data suggested that these cells might play essential roles during MF in HD patients.

Fibrocytes in early and long-standing rheumatoid arthritis: a 6-month trial with repeated synovial biopsy, imaging and lung function test

ObjectivesTo correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function.MethodsTwenty patients with...

P039 &lt;break /&gt; Modulation of Fibrocyte and Chemokine levels in Balb/C Mouse Lung upon Transient Pulmonary Over-expression of Oncostatin M

P039 &lt;break /&gt; Modulation of Fibrocyte and Chemokine levels in Balb/C Mouse Lung upon Transient Pulmonary Over-expression of Oncostatin M

Circulating fibrocytes correlate with the asthma control test score

BackgroundBronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting β2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. MethodsThere were 20 patients with asthma and seven healthy controls. The number of CD45+Collagen I+ circulating fibrocytes was assessed in the peripheral blood by flow cytometry. ResultsThe number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short-acting β2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. ConclusionThe results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma.

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

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. Cross-sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study. Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated α-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels. Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction.

Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects.

Hypersensitivity pneumonitis (HP) represents a lung inflammation provoked by exposure to a variety of antigens. Chronic HP may evolve to lung fibrosis. Bone marrow-derived fibrocytes migrate to injured tissues and contribute to fibrogenesis, but their role in HP is unknown. To assess the possible participation of fibrocytes in chronic HP. CD45(+)/CXCR4(+)/Col-I(+) circulating fibrocytes were evaluated by flow cytometry, and the presence of fibrocytes in HP and normal lungs by confocal microscopy. The concentration of CXCL12 in plasma and bronchoalveolar lavage fluids was quantified by ELISA. The effect of fibrocytes on lung fibroblasts and T lymphocytes was examined in co-cultures. The percentage of circulating fibrocytes was significantly increased in patients with HP compared with healthy individuals (5.3 ± 3.4% vs. 0.8 ± 0.7%; P = 0.00004). Numerous fibrocytes were found infiltrating the HP lungs near fibroblasts and lymphocytes. Plasma CXCL12 concentration was significantly increased in patients with HP (2,303.3 ± 813.7 vs. 1,385.6 ± 318.5 pg/ml; P = 0.00003), and similar results were found in bronchoalveolar lavage fluids. The chemokine was primarily expressed by epithelial cells. In co-cultures, fibrocytes induced on lung fibroblasts a significant increase in the expression of α1 type I collagen, matrix metalloprotease-1, and platelet-derived growth factor-β. Likewise, fibrocytes induced the up-regulation of CCL2 in HP lymphocytes and fibroblasts. These findings demonstrate that high levels of fibrocytes are present in the peripheral blood of patients with chronic HP and that these cells infiltrate the HP lungs. Fibrocytes may participate in the pathogenesis of HP, amplifying the inflammatory and fibrotic response by paracrine signaling inducing the secretion of a variety of proinflammatory and profibrotic molecules.

Higher Levels of Circulating Fibrocytes Are Associated with Lower Oxygen Saturation in Adults with Sickle Cell Disease

Background: In patients with sickle cell disease (SCD), tissue injury due to vaso-occlusion can result in fibrosis and organ dysfunction. Fibrocytes are circulating bone marrow-derived cells that can home to damaged organs, differentiate into fibroblasts and myofibroblasts and contribute to scarring. Fibrocytes have been implicated in the pathogenesis of pulmonary fibrosis in several animal models, including a mouse model of SCD. A preliminary study of patients with SCD suggests that the concentration of circulating fibrocytes is increased compared to controls. To build upon these findings, we tested the hypothesis that in adults with SCD higher levels of fibrocytes are associated with measures of lung disease.Methods: In a prospective cohort study of steady state adults with SCD, peripheral blood fibrocytes were measured and subjects underwent a pulmonary assessment that included pulmonary function tests, resting pulse oximetry, a 6-minute walk test, 2-D echocardiography, and high-resolution chest CT. A control group of healthy, African Americans also provided fibrocyte measurements and had pulmonary function testing. Fibrocytes were identified as collagen-1+ CD45+ cells using quantitative flow cytometry. For statistical analyses, fibrocyte values were log-transformed. Continuous and dichotomous variables were tested with Pearson’s correlation and Mann-Whitney U, respectively.Results: The cohort was comprised of 47 adults with SCD and 19 healthy African American controls. Sixty percent of the SCD subjects were HbSS or HbS-β-thalassemia0. Mean age (SD) of SCD cases was 35 years (±11) and 70% were female. Twenty-seven percent of SCD cases had asthma and 41% had a significant smoking history. Sixty-four percent of SCD cases had ground glass opacities on CT of the lung, 34% had bronchiectasis and 20% had evidence of pulmonary fibrosis. Compared to controls, patients with SCD had lower forced expiratory volume in 1 second (p<0.001), forced vital capacity (p<0.001), and pre- and post-bronchodilator 25-75% forced expiratory flow (FEF25-75%) (p=0.006). Fibrocyte levels also trended higher in patients with SCD compared to controls (median 1.2 x 106 vs. 8.5 x 105, p=0.07). Within patients with SCD, most fibrocytes expressed the chemokine receptor CXCR4 and smaller subsets expressed CCR2 or CCR7. Increased levels of fibrocytes in patients with SCD were associated with lower oxygen saturation (p=0.01) and higher reticulocyte counts (p=0.01). Lower oxygen saturation and higher reticulocyte counts were also associated with each other, independent of fibrocytes (p=0.007). Fibrocytes expressing CXCR4, a chemokine that mediates homing to the lungs, were associated with lower post-bronchodilator FEF25-75% (p=0.04). There was no association between fibrocyte levels and other measures of pulmonary function testing, degree of fibrosis on high-resolution CT, or abnormalities on 2-D echocardiogram or 6-minute walk.Conclusion: In adults with SCD, higher fibrocyte levels were associated with lower resting oxygen saturation and FEF25-75%, a measure of lung obstruction. Significant lung pathology was observed in a high percentage of SCD patients. The associations between fibrocyte levels, hypoxia and a measure of pulmonary dysfunction suggest that fibrocytes contribute to this lung disease. Higher reticulocyte counts in patients with increased fibrocytes may be due to the association of both reticulocyte count and fibrocyte level with hypoxia. Ongoing longitudinal studies may better define the relationship between fibrocytes and evolving lung disease. If additional evidence is found in these longitudinal studies, fibrocytes could be a therapeutic target to prevent chronic pulmonary disease in adults with SCD. DisclosuresField:NKTT: Consultancy, Research Funding. Strieter:Novartis: Employment.

New Light Is Shed on the Enigmatic Origin of the Lung Myofibroblast

New Light Is Shed on the Enigmatic Origin of the Lung Myofibroblast

Rapamycin Blocks Fibrocyte Migration and Attenuates Bronchiolitis Obliterans in a Murine Model

Fibrocytes are integral in the development of fibroproliferative disease. The CXCL12/CXCR4 chemokine axis has been shown to play a central role in fibrocyte migration and the development of bronchiolitis obliterans (BO) after lung transplantation. Inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin has been shown to decrease expression of both CXCR4 and its receptor agonist CXCL12. Thus, we hypothesized that rapamycin treatment would decrease fibrocyte trafficking into tracheal allografts and prevent BO. A total alloantigenic mismatch murine heterotopic tracheal transplant (HTT) model of BO was used. Animals were either treated with rapamycin or dimethyl sulfoxide (DMSO) for 14 days after tracheal transplantation. Fibrocyte levels were assessed by flow cytometry, and allograft neutrophil, CD3(+) T-cell, macrophage, and smooth muscle actin (SMA) levels were assessed by immunohistochemistry. Tracheal luminal obliteration was assessed on hematoxylin and eosin (H&E) stains. Compared with DMSO-treated controls, rapamycin-treated mice showed a significant decrease in fibrocyte levels in tracheal allografts. Fibrocyte levels in recipient blood showed a similar pattern, although it was not statistically significant. Furthermore, animals treated with rapamycin showed a significant decrease in tracheal allograft luminal obliteration compared with controls. Based on immunohistochemical analyses, populations of α-SMA-positive (α-SMA(+)) cells, neutrophils, CD3(+) T cells, and macrophages were all decreased in rapamycin-treated allografts versus DMSO controls. Rapamycin effectively reduces recruitment of fibrocytes into tracheal allografts and mitigates development of tracheal luminal fibrosis. Further studies are needed to determine the cellular and molecular mechanisms that mediate the protective effect of rapamycin against BO.

Elevated circulating fibrocyte levels in patients with hypertensive heart disease

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. We measured peripheral blood fibrocyte levels and their activated phenotypes in 12 individuals with hypertensive heart disease as determined by increased left ventricular mass on noninvasive imaging and compared them to fibrocyte levels from 19 healthy normal controls and correlated them to cardiac MRI findings. Compared to normal controls, individuals with hypertensive heart disease had significantly higher circulating levels of total fibrocytes [median (interquartile range); 149000 (62200-220000) vs. 564500 (321000-1.2900e(+006)), P < 0.0001, respectively] as well as activated fibrocytes [15700 (6380-19800) vs. 478500 (116500-1.2360e(+006)) P < 0.0001]. Moreover, the fibrocyte subsets expressing the chemokine markers CXCR4 (P < 0.0001), CCR2 (P < 0.0001), CCR7 (P < 0.0001) and coexpression of both CXCR4 and CCR2 (P < 0.0001) were significantly elevated in patients with hypertensive heart disease compared to controls. Lastly, in patients with hypertensive heart disease there was a strong correlation between left ventricular mass index and total fibrocytes (r = 0.65, P = 0.037) and activated fibrocytes (r = 0.70, P = 0.016). Our data suggest that bone marrow-derived circulating fibrocytes are associated with the presence and extent of left ventricular hypertrophy in patients with hypertensive heart disease.

Hypertensive heart disease

Hypertensive heart disease

Increased Expression of TSH Receptor by Fibrocytes in Thyroid-Associated Ophthalmopathy Leads to Chemokine Production

The molecular basis for anatomically dispersed clinical manifestations in Graves' disease (GD) eludes our understanding. Bone marrow-derived, pluripotent fibrocytes represent a subset of peripheral blood mononuclear cells and infiltrate the orbital and thyroid tissues in GD. These cells may be involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO). The objective of the study was to quantify fibrocyte display of functional cell surface TSH receptor (TSHR), identify the profile of chemokines they express after TSHR activation, and determine whether circulating TSHR(+) peripheral blood fibrocytes are more frequent in situ in patients with TAO. Using a newly developed technique, fibrocytes were directly identified in peripheral blood from 31 patients with TAO and 19 healthy subjects receiving care at a multidisciplinary academic center. The frequency in situ of fibrocytes (collagen 1(+), CD45(+), CD34(+), CD14(+), CD86(+) peripheral blood mononuclear cells) was assessed by multiparameter flow cytometry and correlated to clinical disease activity and smoking status. Levels of TSHR-displaying fibrocytes and their response to TSH and TSHR-activating antibody, M22, were measured by flow cytometry, Luminex, and real-time PCR. The levels of TSHR expression by fibrocytes are substantially higher than those found in orbital fibroblasts. Moreover, the frequency of TSHR(+) fibrocytes in patients with TAO was greater than that in healthy subjects in situ. Their abundance is not influenced by disease activity or smoking history. These cells produce high levels of several cytokines and chemokines including IL-8, regulated upon activation, normal T cell expressed and secreted, and monocyte chemoattractant protein-1 when treated with TSH or M22. TSH induces IL-8 production at the pretranslational level. This induced cytokine can be detected in intact fibrocytes ex vivo. Frequency of circulating TSHR(+) fibrocytes is markedly increased in patients with TAO, and they express proinflammatory chemokines in response to TSH. Because they infiltrate both orbit and thyroid in GD, they may represent the link between systemic immunoreactivity and organ-specific autoimmunity.

Fibrocytes in chronic lung disease – Facts and controversies

Fibrocytes are bone marrow-derived mesenchymal cell precursors, defined primarily by their ability to co-express markers of both haematopoietic (e.g. CD45 or CXCR4) and stromal (e.g. collagen) lineages. Fibrocytes in culture also have ultrastructural cell surface features that distinguish them from other leukocytes. Extensive efforts have helped to characterise fibrocytes phenotypically and functionally, but it is still unclear exactly how these cells contribute to tissue repair and/or pathologic fibrosis. Nevertheless, the varied levels of fibrocytes in blood have raised considerable interest as a biomarker of disease activity, such as chronic lung diseases, including pulmonary fibrosis, asthma and pulmonary hypertension. These cells also may become a novel therapeutic target for these difficult to treat disorders. This review will briefly summarize the current knowledge about fibrocytes in human lung disease and in animal disease models and highlight areas of consensus as well as issues that remain controversial to date.