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

ABSTRACT: 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. METHODS:By using fluorescence-activated cell sorting analysis, fibrocytes (CD45(+) and collagen 1 [Col1](+)) were enumerated and characterized in the buffy coats of fresh peripheral blood samples from 15 control subjects and 40 asthmatic patients. RESULTS:Concentrations of peripheral blood total (CD45(+)Col1(+)), activated (the TGF-? transducing protein phosphorylated SMAD2/3 [p-SMAD2/3](+) or phosphorylated AKT [p-AKT](+)), and differentiated (?-smooth muscle actin [?-SMA](+)) fibrocytes were increased in asthmatic patients compared with control subjects. The increase in total and CD45(+)Col1(+)CXCR4(+) fibrocytes was primarily seen in patients with severe asthma (Global Initiative for Asthma steps 4-5) as opposed to those with milder asthma (Global Initiative for Asthma steps 1-3). In addition, numbers of circulating ?-SMA(+) and ?-SMA(+)CXCR4(+) fibrocytes were increased in asthmatic patients experiencing an asthma exacerbation in the preceding 12 months. A significant correlation (P < .05) was observed between CD45(+)Col1(+)CXCR4(+) fibrocytes and the activation phenotypes CD45(+)Col1(+)p-SMAD2/3(+) and CD45(+)Col1(+)p-AKT(+). CONCLUSION:There was correlation between circulating fibrocyte subsets and asthma severity, and there was an increased number of activated/differentiated fibrocytes in circulating blood of asthmatic patients experiencing an exacerbation in the preceding 12 months.

SUBMITTER: Shipe R

PROVIDER: S-EPMC4836439 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Shipe Ryan R Burdick Marie D MD Strieter Brett A BA Liu Ling L Shim Yun Michael YM Sung Sun-sang SS Teague W Gerald WG Mehrad Borna B Strieter Robert M RM Rose C Edward CE

The Journal of allergy and clinical immunology 20150912 3

<h4>Background</h4>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.<h4>Objective</h4>We sought to test the hypothesis that the concentration and activation state of peripheral blood fibrocytes correlates with asthma severity.<h4>Methods</h4>By using fluorescence-activated cell sorting analysis, fibrocytes (CD45(+) and col ...[more]

PMID: 26371837

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Project description:BackgroundAirway remodeling is a poorly reversible feature of asthma which lacks effective therapeutic interventions. CD147 can regulate extracellular matrix (ECM) remodeling and tissue fibrosis, and participate in the pathogenesis of asthma. In this study, the role of CD147 in airway remodeling and activation of circulating fibrocytes was investigated in asthmatic mice.MethodsAsthmatic mouse model was established by sensitizing and challenging mice with ovalbumin (OVA), and treated with anti-CD147 or Isotype antibody. The number of eosinophils in bronchoalveolar lavage fluid (BALF) was examined by microscope, and the levels of interleukin-4 (IL-4), IL-5 and IL-13 in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The number of CD45+ and collagen I (COL-I)+ circulating fibrocytes in BALF was detected by flow cytometry. Lung tissue sections were respectively stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS) or Masson trichrome staining, or used for immunohistochemistry of CD31 and immunohistofluorescence of α-smooth muscle actin (α-SMA), CD45 and COL-I. The protein expression of α-SMA, vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), Fibronectin, and COL-I was determined by western blotting.ResultsAnti-CD147 treatment significantly reduced the number of eosinophils and the levels of IL-4, IL-13, and IL-5 in BALF, and repressed airway inflammatory infiltration and airway wall thickening in asthmatic mice. Anti-CD147 treatment also reduced airway goblet cell metaplasia, collagen deposition, and angiogenesis in asthmatic mice, accompanied by inhibition of VEGF and α-SMA expression. The number of CD45+COL-I+ circulating fibrocytes was increased in BALF and lung tissues of OVA-induced asthmatic mice, but was decreased by anti-CD147 treatment. In addition, anti-CD147 treatment also reduced the protein expression of COL-I, fibronectin, and TGF-β1 in lung tissues of asthmatic mice.ConclusionOVA-triggered airway inflammation and airway remodeling in asthmatic mice can be repressed by anti-CD147 treatment, along with inhibiting the accumulation and activation of circulating fibrocytes.

Project description:Asthma encompasses a spectrum of heterogenous immune-mediated respiratory disorders sharing a similar clinical pattern characterized by cough, wheeze and exercise intolerance. In horses, equine asthma can be subdivided into severe or moderate asthma according to clinical symptoms and the extent of airway neutrophilic inflammation. While severe asthmatic horses are characterized by an elevated neutrophilic inflammation of the lower airways, cough, dyspnea at rest and high mucus secretion, horses with moderate asthma show a milder neutrophilic inflammation, exhibit intolerance to exercise but no labored breathing at rest. Yet, the physiopathology of different phenotypes of equine asthma remains poorly understood and there is a need to elucidate the underlying mechanisms tailoring those phenotypes in order to improve clinical management and elaborate novel therapeutic strategies. In this study, we sought to quantify the presence of neutrophil extracellular traps (NETs) in bronchoalveolar lavage fluids (BALF) of moderate or severe asthmatic horses and healthy controls, and assessed whether NETs correlated with disease severity. To this end, we evaluated the amounts of NETs by measuring cell-free DNA and MPO-DNA complexes in BALF supernatants or by quantifying NETs release by BALF cells by confocal microscopy. We were able to unequivocally identify elevated NETs levels in BALF of severe asthmatic horses as compared to healthy controls or moderate asthmatic horses. Moreover, we provided evidence that BALF NETs release was a specific feature seen in severe equine asthma, as opposed to moderate asthma, and correlated with disease severity. Finally, we showed that NETs could act as a predictive factor for severe equine asthma. Our study thus uniquely identifies NETs in BALF of severe asthmatic horses using three distinct methods and supports the idea that moderate and severe equine asthma do not rely on strictly similar pathophysiological mechanisms. Our data also suggest that NETs represent a relevant biomarker, a putative driver and a potential therapeutic target in severe asthma disease.

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Dataset Information

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

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

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