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Involvement of Discoidin Domain Receptor 1 in the Deterioration of Pulmonary Sarcoidosis

Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Kagoshima, Japan

Correspondence and requests for reprints should be addressed to Wataru Matsuyama, M.D., Ph.D., Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan. E-mail: vega{at}xa2.so-net.ne.jp

The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase–dependent manner from CD14-positive BALF cells of patients with deteriorated sarcoidosis. DDR1 activation also induced NF-B nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-B inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.

Key Words: chemokines • lung • NF-B • monocyte chemoattractant protein-1 • matrix metalloproteinase-9

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