title: Radiation-Induced Microvascular Injury as a Mechanism of Salivary Gland Hypofunction and Potential Target for Radioprotectors.
abstract: Radiation therapy is commonly used to treat patients with head and neck squamous cell carcinoma (HNSCC). One of the major side effects of radiotherapy is injury to the salivary glands (SG), which is thought to be mediated by microvascular dysfunction leading to permanent xerostomia. The goal of this study was to elucidate the mechanism of radiation-induced microvasculature damage and its impact on SG function. We measured bovine aortic endothelial cell (BAEC) apoptosis and ceramide production in response to 5 Gy irradiation, either alone or with reactive oxygen species (ROS) scavengers. We then investigated the effect of a single 15 Gy radiation dose on murine SG function. BAECs exposed to 5 Gy underwent apoptosis with increased ceramide production, both prevented by ROS scavengers. Among the 15 Gy irradiated mice, there was considerable weight loss, alopecia and SG hypofunction manifested by reduced saliva production and lower lysozyme levels. All of these effects, except for the lysozyme levels, were prevented by pretreatment with ROS scavengers. Microvessel density was significantly lower in the SG of irradiated mice compared to the control group, and this effect was significantly attenuated by pretreatment with Tempol. This study demonstrates that radiation-induced SG hypofunction is to a large extent mediated by microvascular dysfunction involving ceramide and ROS generation. These findings strongly suggest that ROS scavengers may serve as potential radioprotectors of SG function in patients undergoing radiotherapy for HNSCC.
authors.affiliation: Departments of a Surgery, Head and Neck Service.
authors.forename: Aviram
authors.initials: A
authors.lastname: Mizrachi
authors.affiliation: d Radiation Biology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland; and.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Cotrim
authors.affiliation: b Pathology and.
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.affiliation: d Radiation Biology Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland; and.
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.affiliation: e Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: c Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York;
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002417:Cattle; D002518:Ceramides / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D051379:Mice; D055806:Microvessels / Q000166:cytology / Q000187:drug effects / Q000293:injuries* / Q000528:radiation effects*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012469:Salivary Glands / Q000098:blood supply / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D013997:Time Factors
chemical_list: D002518:Ceramides; D016166:Free Radical Scavengers; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species