THU0056 EFFECTS OF CX3CL1 INHIBITION ON MURINE BLEOMYCIN-INDUCED INTERSTITIAL PNEUMONIA

Abstract

Background Pathological findings of interstitial pneumonia (IP) reveal the accumulation of inflammatory cells and proliferation of fibroblasts in lung tissue. Although a treatment has not yet been established for IP, particularly for IP with collagen diseases, chemokines may play a role in the pathogenesis of IP for inflammatory cell infiltration. We previously reported that chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) has potential as a therapeutic target for rheumatoid arthritis (RA).1,2,3Humanized anti-human CX3CL1 monoclonal antibody (mAb) is currently undergoing clinical trials for RA.4 Objectives In the present study, we examined the therapeutic effects of CX3CL1 blockade in a murine model of IP. Methods Bleomycin (BLM)-induced IP was developed by the intratracheal administration of BLM to C57BL/6 mice. The murine lung was stained with hematoxylin and eosin, and the expression of CX3CL1 and CX3CR1, a receptor for CX3CL1, was analyzed by immunohistochemistry. Mice were treated with anti-CX3CL1 mAb for 2 weeks. Collagen eluted from the lung was quantified using the SircolTM Collagen Assay. The expression of CX3CL1 and CX3CR1 by mouse lung fibroblasts (MLFs) was examined with quantitative RT-PCR and Western blotting, respectively. Cell movement was investigated using the scrape motility assay. Results The expression of CX3CL1 and CX3CR1 was upregulated in BLM-induced IP. The treatment with anti-CX3CL1 mAb did not significantly alter inflammatory cell infiltration. However, collagen in the lung was decreased by the treatment with anti-CX3CL1 mAb. Stimulation with CX3CL1 did not alter the in vitro production of collagen by MLFs, but significantly enhanced cell movement. Conclusion CX3CL1 may be involved in increasing collagen in IP and the cell movement of MLFs. The present results suggest that CX3CL1 plays an important role in fibrosis in IP.