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Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1α, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-β in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.

Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-B activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-B nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-B inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well. (Am J Pathol

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-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-kappaB inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.