title: Tight junction defects are seen in the buccal mucosa of patients receiving standard dose chemotherapy for cancer.
abstract: OBJECTIVE
  Oral mucositis is one of the most common and debilitating side effects of chemotherapy treatment. Patients are often unable to eat and drink, which can lead to poor clinical outcomes and extensive resource utilisation. The primary aim of this study was to determine the molecular integrity of oral epithelial tight junctions in patients undergoing chemotherapy. The secondary aim was to correlate these changes with proinflammatory cytokines and matrix metalloproteinase profiles.
  
  
  METHODS
  Patients (n = 23) were recruited from the Royal Adelaide Hospital between 2000 and 2003. Reach patient underwent two oral buccal mucosa biopsies (4 mm): one prior to chemotherapy treatment and a second one after chemotherapy treatment. Oral buccal mucosa biopsies were also taken from seven healthy volunteers with no history of cancer, chemo- or radiotherapy treatment or inflammatory disorders. Routine haematoxylin and eosin staining was performed to determine epithelial thickness. Immunohistochemical staining was performed for claudin-1, zonular occludens-1, occludin, interleukin-1β, tumour necrosis factor, interleukin-6, matrix metalloproteinase-2 and metalloproteinase-9.
  
  
  RESULTS
  Patients receiving standard dose chemotherapy had significant epithelial atrophy. Elevations in all cytokines and matrix metalloproteinases were seen, with significant lamina propria staining for interleukin-6 and tumour necrosis factor. Matrix metalloproteinase-2 appeared most upregulated within the oral epithelium. These changes coincided with altered tight junction staining properties. Changes in the staining intensity and localisation were both noted, with clear cytoplasmic staining for zonular occludens-1 and claudin-1 in patients treated with chemotherapy.
  
  
  CONCLUSIONS
  Chemotherapy causes defects in oral tight junctions, coupled with altered cytokine and matrix metalloproteinase profiles. Tight junction disruption in the epithelium may contribute to ulcer development or lead to poor tissue integrity, and the timing of these events may be a target for preventative treatment.
authors.affiliation: Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, North Terrace, Adelaide, South Australia, 5005, Australia. hannah.wardill@adelaide.edu.au.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Wardill
authors.affiliation: School of Dentistry, University of Adelaide, Adelaide, South Australia, Australia. richard.logan@adelaide.edu.au.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Logan
authors.affiliation: Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia. joanne.bowen@adelaide.edu.au.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.affiliation: Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia. ysabella.vansebille@adelaide.edu.au.
authors.forename: Ysabella Z A
authors.initials: YZ
authors.lastname: Van Sebille
authors.affiliation: Discipline of Anatomy and Pathology, School of Medicine, University of Adelaide, North Terrace, Adelaide, South Australia, 5005, Australia. rachel.gibson@adelaide.edu.au.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Gibson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001284:Atrophy / Q000139:chemically induced; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D062793:Occludin / Q000378:metabolism; D019226:Oral Ulcer / Q000139:chemically induced; D013021:South Australia; D019108:Tight Junctions / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D062793:Occludin; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2
keywords: Chemotherapy; Clinical; Mucositis; Oral mucosa; Oral toxicity; Tight junctions