title: Therapeutic effects of C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me; bardoxolone methyl) on radiation-induced lung inflammation and fibrosis in mice.
abstract: The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), one of the synthetic triterpenoids, has been found to have potent anti-inflammatory and anticancer properties in vitro and in vivo. However, its usefulness in mitigating radiation-induced lung injury (RILI), including radiation-induced lung inflammation and fibrosis, has not been tested. The aim of this study was to explore the therapeutic effect of CDDO-Me on RILI in mice and the underlying mechanisms. Herein, we found that administration of CDDO-Me improved the histopathological score, reduced the number of inflammatory cells and concentrations of total protein in bronchoalveolar lavage fluid, suppressed secretion and expression of proinflammatory cytokines, including transforming growth factor-β and interleukin-6, elevated expression of the anti-inflammatory cytokine interleukin-10, and downregulated the mRNA level of profibrotic genes, including for fibronectin, α-smooth muscle actin, and collagen I. CDDO-Me attenuated radiation-induced lung inflammation. CDDO-Me also decreased the Masson's trichrome stain score, hydroxyproline content, and mRNA level of profibrotic genes, and blocked radiation-induced collagen accumulation and fibrosis. Collectively, these findings suggest that CDDO-Me ameliorates radiation-induced lung inflammation and fibrosis, and this synthetic triterpenoid is a promising novel therapeutic agent for RILI. Further mechanistic, efficacy, and safety studies are warranted to elucidate the role of CDDO-Me in the management of RILI.
authors.affiliation: Department of Radiation Oncology, General Hospital of Ningxia Medical University, Guiyang, People's Republic of China.
authors.forename: Yan-Yang
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Graduate School, Ningxia Medical University, Guiyang, People's Republic of China.
authors.forename: Cui-Ying
authors.initials: CY
authors.lastname: Zhang
authors.affiliation: Department of Pathology, General Hospital of Ningxia Medical University, Guiyang, People's Republic of China.
authors.forename: Ya-Qiong
authors.initials: YQ
authors.lastname: Ma
authors.affiliation: Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, People's Republic of China.
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, General Hospital of Ningxia Medical University, Guiyang, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhe
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D055370:Lung Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D017564:Radiation Pneumonitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D009828:Oleanolic Acid; D003094:Collagen; C445068:bardoxolone methyl; D006909:Hydroxyproline
keywords: CDDO-Me; cytokine; fibrosis; inflammation; mouse; radiation-induced lung injury; radiotherapy; transforming growth factor-β