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Role of the Chemokine Receptors CXCR3 and CCR4 in Human Pulmonary Fibrosis

Allergy and Immunology Unit, Rehabilitative Pneumology Department, and Radiology Unit, Scientific Institute of Pavia; Pneumology Department, Scientific Institute of Gussago, Fondazione "Salvatore Maugeri"; and Clinic of Respiratory Diseases, University of Pavia, Policlinico San Matteo, IRCCS, Pavia, Italy

Correspondence and requests for reprints should be addressed to Giuseppe Brunetti, M.D., Rehabilitative Pneumology Department, Fondazione "Salvatore Maugeri," IRCCS, Pavia, Italy 27100. 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 with IPF, 17 with non-IPF (nIPF), 12 with sarcoidosis, and 10 healthy control subjects.

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: Patients with IPF had a significantly lower CXCR3 and a higher CCR4 expression on BAL CD4 T cells compared with the other groups. Among patients with IPF, those treated with corticosteroids exhibited higher CXCR3 and lower CCR4 expression compared with 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, whereas CCL17 was primarily detectable in patients with IPF. The percentage of BAL CCR4CD4 cells negatively correlated with DL_CO. The changes in the total lung capacity, VC, and of the alveolar–arterial PO₂ gradient in patients with IPF and those with nIPF 6 to 12 mo 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 patients with IPF, suggesting a pivotal role of these molecules in IPF.

Key Words: chemokines • CXCL10 • interstitial lung diseases

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