title: Amelioration of radiation-induced pulmonary fibrosis by a water-soluble bifunctional sulfoxide radiation mitigator (MMS350).
abstract: A water-soluble ionizing radiation mitigator would have considerable advantages for the management of acute and chronic effects of ionizing radiation. We report that a novel oxetanyl sulfoxide (MMS350) is effective both as a protector and a mitigator of clonal mouse bone marrow stromal cell lines in vitro, and is an effective in vivo mitigator when administered 24 h after 9.5 Gy (LD100/30) total-body irradiation of C57BL/6NHsd mice, significantly improving survival (P = 0.0097). Furthermore, MMS350 (400 μM) added weekly to drinking water after 20 Gy thoracic irradiation significantly decreased: expression of pulmonary inflammatory and profibrotic gene transcripts and proteins; migration into the lungs of bone marrow origin luciferase+/GFP+ (luc+/GFP+) fibroblast progenitors (in both luc+ marrow chimeric and luc+ stromal cell line injected mouse models) and decreased radiation-induced pulmonary fibrosis (P < 0.0001). This nontoxic and orally administered small molecule may be an effective therapeutic in clinical radiotherapy and as a counter measure against the acute and chronic effects of ionizing radiation.
authors.affiliation: a Radiation Oncology Department, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and.
authors.forename: Ronny
authors.initials: R
authors.lastname: Kalash
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Julie
authors.initials: J
authors.lastname: Goff
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Sprachman
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.forename: Donna
authors.initials: D
authors.lastname: Shields
authors.forename: Shaonan
authors.initials: S
authors.lastname: Cao
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Hebist
authors.initials: H
authors.lastname: Berhane
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Au
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D004988:Ethers, Cyclic / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000473:pathology; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D012451:Safrole / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013454:Sulfoxides / Q000494:pharmacology*; D014867:Water / Q000737:chemistry; D014916:Whole-Body Irradiation
chemical_list: D004988:Ethers, Cyclic; C586473:MMS350; D011837:Radiation-Protective Agents; D013454:Sulfoxides; D014867:Water; D012451:Safrole; C005746:sulfoxide