title: Botulinum Toxin Confers Radioprotection in Murine Salivary Glands.
abstract: OBJECTIVE
  Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.
  
  
  METHODS
  We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.
  
  
  RESULTS
  Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.
  
  
  CONCLUSIONS
  These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.
authors.affiliation: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: zeidan@miami.edu.
authors.forename: Youssef H
authors.initials: YH
authors.lastname: Zeidan
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Nan
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California; Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Kong
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
authors.forename: Davud
authors.initials: D
authors.lastname: Sirjani
mesh_terms: D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D016923:Cell Death; D054365:Chemokine CXCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012463:Saliva / Q000378:metabolism; D012472:Salivation / Q000528:radiation effects; D013363:Submandibular Gland / Q000166:cytology / Q000528:radiation effects*; D013997:Time Factors
chemical_list: D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D011837:Radiation-Protective Agents; D001905:Botulinum Toxins