title: Diallyl disulfide inhibits proliferation and transdifferentiation of lung fibroblasts through induction of cyclooxygenase and synthesis of prostaglandin E₂.
abstract: Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) are critically involved in idiopathic pulmonary fibrosis by inducing the proliferation and transdifferentiation of lung fibroblasts. In the present study, we examined the impact of diallyl disulfide (DADS), a garlic-derived compound, on such pathological conditions. DADS showed profound inhibitory effects on the PDGF-BB-induced proliferation of human and mouse lung fibroblasts. DADS also abrogated the TGF-β1-induced expression of α-smooth muscle actin, type I collagen and fibronectin. Following treatment with DADS, the expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E₂ (PGE₂) were found to be markedly enhanced, which in turn led to elevated cAMP levels in lung fibroblasts. Notably, the effect of DADS was largely abolished in the presence of either COX inhibitor indomethacin or siRNA-targeting COX-2, or in the absence of the PGE₂ receptor EP2, supporting an essential role for the COX-2-PGE₂-cAMP autocrine loop. Furthermore, we demonstrated that the upregulated expression of COX-2 was a result of increased level of histone 3 acetylation at COX-2 locus in DADS-treated cells. Together, these results suggest that DADS, by inducing COX-2 expression, may have therapeutic potential in treating lung fibrosis.
authors.affiliation: Department of Geriatrics, Peking University First Hospital, Xishiku Street No. 8, West District, Beijing, People's Republic of China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chai
authors.forename: Dan
authors.initials: D
authors.lastname: Sun
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
authors.forename: Xin-min
authors.initials: XM
authors.lastname: Liu
mesh_terms: D000498:Allyl Compounds / Q000008:administration & dosage*; D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D004220:Disulfides / Q000008:administration & dosage*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D005737:Garlic / Q000737:chemistry; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D016212:Transforming Growth Factor beta
chemical_list: D000498:Allyl Compounds; D004220:Disulfides; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D000077214:Becaplermin; C028009:diallyl disulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone
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