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Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients.MethodsWe examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL) fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization.ResultsBAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients.ConclusionWe speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology
Belperio et al demonstrated that CCL17, CCL22 and CCR4 were overexpressed in a mice model of bleomycin-induced pulmonary fibrosis [9], and Pignatti et al showed that CCR4 expression on bronchoalveolar lavage (BAL) fluid CD4 T cells were significantly elevated in IPF patients [10]
The percentage of BAL fluid macrophages was significantly lower in IPF, collagen vascular diseases associated with interstitial pneumonia (CVD-IP) and sarcoidosis patients than in healthy volunteers, and it was significantly lower in CVD-IP patients than in IPF patients
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. We have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients. Belperio et al demonstrated that CCL17, CCL22 and CCR4 were overexpressed in a mice model of bleomycin-induced pulmonary fibrosis [9], and Pignatti et al showed that CCR4 expression on bronchoalveolar lavage (BAL) fluid CD4 T cells were significantly elevated in IPF patients [10]. We have previously demonstrated the selective upregulation of CCL22 and CCL17 in a rat model of radiation pneumonitis/pulmonary fibrosis [11]. We analyzed CCR4 expression on BAL fluid cells and obtained supportive results that CCL22 and CCR4 contribute to the pathophysiology of IPF
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