title: Effect of roflumilast, novel phosphodiesterase-4 inhibitor, on lung chronic graft-versus-host disease in mice.
abstract: Chronic graft-versus-host disease (CGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Roflumilast has anti-inflammatory effects and has been used in the treatment of inflammatory airway diseases. It is at present unclear whether roflumilast may have a therapeutic role in CGVHD. To test this, we used the B10.D2 → BALB/c model of CGVHD to address the therapeutic effect of roflumilast on the development of CGVHD. Lungs of animals treated with roflumilast exhibited less chronic inflammatory cell infiltration and fibrosis in the peribronchial and perivascular area versus allogeneic controls. To define the mechanism, we examined the expression of pro-inflammatory and profibrotic cytokines in the lung. Messenger RNA expression of interleukin-6 and interleukin-1β in the lungs was significantly reduced in recipients treated with roflumilast. Similar changes were observed in profibrotic cytokines and chemokines. In addition, the percentage of Foxp3(+) regulatory T cells (Tregs), which have the potential to attenuate GVHD, increased significantly within the CD4(+) T cells with roflumilast in the lungs. In conclusion, roflumilast treatment attenuated murine lung CGVHD by blocking T-cell activation mediated by Tregs and downregulating pro-inflammatory and profibrotic cytokines, resulting in the reduction of lung inflammation and fibrosis.
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sei Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chin Kook
authors.initials: CK
authors.lastname: Rhee
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Park
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chul Soo
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chang Ki
authors.initials: CK
authors.lastname: Min
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: cmcyhg@catholic.ac.kr.
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Yoon
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods; D017690:Cell Transplantation / Q000009:adverse effects / Q000379:methods; D018932:Chemokine CCL2 / Q000235:genetics; D054405:Chemokine CCL3 / Q000235:genetics; D003521:Cyclopropanes / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008807:Mice, Inbred BALB C; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D000631:Aminopyridines; D001549:Benzamides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D003521:Cyclopropanes; D053583:Interleukin-1beta; D015850:Interleukin-6; D058988:Phosphodiesterase 4 Inhibitors; D053773:Transforming Growth Factor beta1; C424423:Roflumilast