title: Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis.
abstract: 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.
authors.affiliation: Departments of 1 Respiratory Medicine and Rheumatology, and.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.forename: Masami
authors.initials: M
authors.lastname: Kishi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yokota
authors.forename: Momoyo
authors.initials: M
authors.lastname: Azuma
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Akio
authors.initials: A
authors.lastname: Takezaki
authors.forename: Seidai
authors.initials: S
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawano
authors.forename: Jun
authors.initials: J
authors.lastname: Kishi
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D016022:Case-Control Studies; D002633:Chemotaxis; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007274:Injections, Intraperitoneal; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000008:administration & dosage; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001549:Benzamides; C527276:CXCR4 protein, human; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: fibrocyte; lung fibrosis; platelet-derived growth factor