Role of Platelet-Derived Growth Factor/Platelet-Derived Growth Factor Receptor Axis in the Trafficking of Circulating Fibrocytes in Pulmonary Fibrosis

• DOI: 10.1165/rcmb.2013-0455oc
• Publication Date: 2014-06-02T15:49:02Z
• Authors: Yoshinori Aono; Masami Kishi; Yuki Yokota; Momoyo Azuma; Katsuhiro Kinoshita; Akio Takezaki; Seidai Sato; Hiroshi Kawano; Jun Kishi; Hisatsugu Goto; Hisanori Uehara; Keisuke Izumi; Yasuhiko Nishioka
• Keywords: Platelet-Derived Growth Factor; 0301 basic medicine; Receptors, CXCR4; Chemotaxis; Pulmonary Fibrosis; Drug Evaluation, Preclinical; Piperazines; 3. Good health; Mice, Inbred C57BL; Receptor, Platelet-Derived Growth Factor beta; 03 medical and health sciences; Pyrimidines; Case-Control Studies; Benzamides; Imatinib Mesylate; Animals; Humans; Female; Injections, Intraperitoneal; Signal Transduction

Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.