Published ahead of print on October 20, 2005, doi:10.1164/rccm.200502-244OC Am. J. Respir. Crit. Care Med., Volume 173, Number 3, February 2006, 310-317 A more recent version of this article appeared on February 1, 2006
Submitted on February 15, 2005 Role of the Chemokine Receptors CXCR3 and CCR4 in Human Pulmonary FibrosisPatrizia Pignatti1,1 Allergy and Immunology Unit, Scientific Institute of Pavia, Pavia, Italy, 2 Rehabilitative Pneumology, Scientific Institute of Pavia, Pavia, Italy, 3 Radiology Unit, Scientific Institute of Pavia, Pavia, Italy, 4 Pneumology Department Scientific Institute of Gussago, Fondazione "Salvatore Maugeri" IRCCS, Gussago, Italy, 5 Clinic of Respiratory Diseases, University of Pavia - Policlinico, San Matteo, IRCCS, Pavia, Italy * To whom correspondence should be addressed. E-mail: gbrunetti{at}fsm.it.
Rationale: The chemokine receptors CXCR3 and CCR4 have recently been described as playing a pivotal role in the mouse model of bleomycin induced fibrosis. Objectives: to evaluate the role of these receptors in human idiopathic pulmonary fibrosis (IPF). Methods: We studied 57 patients: 18 IPF, 17 non idiopathic pulmonary fibrosis (nIPF), 12 sarcoidosis and 10 healthy controls. Measurements: We evaluated the expression of CXCR3 and CCR4 in blood and bronchoalveolar lavage (BAL) T lymphocytes by flow cytometry and the chemokine CXCL10, CXCL11 and CCL17 BAL concentration by singular immunoassay. Main Results: IPF patients had a significantly lower CXCR3 and a higher CCR4 expression on BAL CD4 T cells compared with the other groups. Among IPF patients, the corticosteroid treated ones exhibited higher CXCR3 and lower CCR4 expression compared to untreated patients. CXCR3 expression correlated with BAL lymphocytes and CCR4 with BAL neutrophils and eosinophils. CXCL10 levels correlated with the expression of CXCR3 on BAL CD4 cells CXCL11 was undetectable in almost all patients, while CCL17 was above all detectable in IPF patients. The percentage of BAL CCR4CD4 cells negatively correlated with DLCO. The changes in the total lung capacity, vital capacity and of the alveolar-arterial PO2 gradient in IPF and nIPF patients 6-12 months after the first evaluation were associated with CD4CXCR3 percentage on BAL cells. Conclusions: We found an imbalance in CXCR3/CCR4 expression on BAL CD4 lymphocytes and reduced CXCL10 BAL levels in IPF patients suggesting a pivotal role of these molecules in IPF. Key words: chemokines, interstitial lung diseases, CXCL10
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