Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis.

RATIONALE The clinical management of idiopathic pulmonary fibrosis (IPF) remains a major challenge due to lack of effective drug therapy or accurate indicators for disease progression. Fibrocytes are circulating mesenchymal cell progenitors that are involved in tissue repair and fibrosis. OBJECTIVES To test the hypothesis that assay of these cells may provide a biomarker for activity and progression of IPF. METHODS Fibrocytes were defined as cells positive for CD45 and collagen-1 by flow cytometry and quantified in patients with stable IPF and during acute exacerbation of the disease. We investigated the clinical and prognostic value of fibrocyte counts by comparison with standard clinical parameters and survival. We used healthy age-matched volunteers and patients with acute respiratory distress syndrome as control subjects. MEASUREMENTS AND MAIN RESULTS Fibrocytes were significantly elevated in patients with stable IPF (n = 51), with a further increase during acute disease exacerbation (n = 7; P < 0.001 vs. control subjects). Patients with acute respiratory distress syndrome (n = 10) were not different from healthy control subjects or stable patients with IPF. Fibrocyte numbers were not correlated with lung function or radiologic severity scores, but they were an independent predictor of early mortality. The mean survival of patients with fibrocytes higher than 5% of total blood leukocytes was 7.5 months compared with 27 months for patients with less than 5% (P < 0.0001). CONCLUSIONS Fibrocytes are an indicator for disease activity of IPF and might be useful as a clinical marker for disease progression. This study suggests that quantification of circulating fibrocytes may allow prediction of early mortality in patients with IPF.

[1]  R. Agarwal,et al.  Acute exacerbation of idiopathic pulmonary fibrosis: a systematic review. , 2008, European journal of internal medicine.

[2]  S. Phan,et al.  Biology of fibroblasts and myofibroblasts. , 2008, Proceedings of the American Thoracic Society.

[3]  R. Strieter What differentiates normal lung repair and fibrosis? Inflammation, resolution of repair, and fibrosis. , 2008, Proceedings of the American Thoracic Society.

[4]  E. B. Meltzer,et al.  Idiopathic pulmonary fibrosis , 2008, Orphanet journal of rare diseases.

[5]  M. Selman,et al.  Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. , 2008, The international journal of biochemistry & cell biology.

[6]  K. Brown,et al.  Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. , 2008, Chest.

[7]  R. Hyzy,et al.  Acute exacerbation of idiopathic pulmonary fibrosis. , 2007, Chest.

[8]  L. Ortiz,et al.  Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury , 2007, Proceedings of the National Academy of Sciences.

[9]  N. Kaminski,et al.  Accelerated Variant of Idiopathic Pulmonary Fibrosis: Clinical Behavior and Gene Expression Pattern , 2007, PloS one.

[10]  M. Gotway,et al.  Challenges in pulmonary fibrosis · 1: Use of high resolution CT scanning of the lung for the evaluation of patients with idiopathic interstitial pneumonias , 2007, Thorax.

[11]  M. Burdick,et al.  Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. , 2007, Biochemical and biophysical research communications.

[12]  H. Collard,et al.  Acute exacerbations of idiopathic pulmonary fibrosis. , 2007, American journal of respiratory and critical care medicine.

[13]  O. Meyer Prognostic markers for systemic sclerosis. , 2006, Joint, bone, spine : revue du rhumatisme.

[14]  R. Bucala,et al.  The role of circulating fibrocytes in fibrosis , 2006, Current rheumatology reports.

[15]  A. Malmström,et al.  Tissue fibrocytes in patients with mild asthma: A possible link to thickness of reticular basement membrane? , 2006, Respiratory research.

[16]  L. Murray,et al.  The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. , 2006, American journal of respiratory cell and molecular biology.

[17]  A. Nicholson,et al.  Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features , 2006, European Respiratory Journal.

[18]  J. Myers,et al.  Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. , 2005, Chest.

[19]  David A Lynch,et al.  High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. , 2005, American journal of respiratory and critical care medicine.

[20]  F. Martinez,et al.  The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis , 2005, Annals of Internal Medicine.

[21]  A. Wells,et al.  Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia. , 2005, American journal of respiratory and critical care medicine.

[22]  A. Nicholson,et al.  Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. , 2005, The American journal of pathology.

[23]  W. Travis,et al.  Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. , 2005, American journal of respiratory and critical care medicine.

[24]  M. Stacey,et al.  Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. , 2005, Experimental cell research.

[25]  G. Raghu,et al.  Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. , 2005, Chest.

[26]  S. Rennard,et al.  Cells derived from the circulation contribute to the repair of lung injury. , 2004, American journal of respiratory and critical care medicine.

[27]  D. Lipsker,et al.  Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis , 2004, The British journal of dermatology.

[28]  S. Phan,et al.  Bone marrow-derived progenitor cells in pulmonary fibrosis. , 2004, The Journal of clinical investigation.

[29]  F. Martinez,et al.  Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. , 2003, American journal of respiratory and critical care medicine.

[30]  C. Metz Fibrocytes: a unique cell population implicated in wound healing , 2003, Cellular and Molecular Life Sciences CMLS.

[31]  D. A. Schwartz,et al.  Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group. , 2002, American journal of respiratory and critical care medicine.

[32]  Paul J. Friedman,et al.  American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors , 2002, American journal of respiratory and critical care medicine.

[33]  J. Tooze,et al.  Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. , 2001, American journal of respiratory and critical care medicine.

[34]  R. Bucala,et al.  Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  T. Ochi,et al.  Induction of fibroblast‐like cells from CD34+ progenitor cells of the bone marrow in rheumatoid arthritis , 2001, Journal of leukocyte biology.

[36]  G. Raghu,et al.  Usual Interstitial Pneumonia , 2001, Seminars in respiratory and critical care medicine.

[37]  F. Martinez,et al.  The role of pulmonary function testing in pulmonary fibrosis , 2000, Current opinion in pulmonary medicine.

[38]  M A Schork,et al.  Idiopathic pulmonary fibrosis: predicting response to therapy and survival. , 1998, American journal of respiratory and critical care medicine.

[39]  H. Tagami,et al.  Inverse correlation between CD34 expression and proline‐4‐hydroxyase immunoreactivity on spindle cells noted in hypertrophic scars and keloids , 1997 .

[40]  R. Bucala,et al.  Circulating Fibrocytes Define a New Leukocyte Subpopulation That Mediates Tissue Repair , 1994, Molecular medicine.

[41]  Y. Kawabata,et al.  Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. , 1993, Chest.