title: Combined Tlr2 and Tlr4 deficiency increases radiation-induced pulmonary fibrosis in mice.
abstract: OBJECTIVE
  To determine whether Toll-like receptor 2 or 4 genotype alters the lung response to irradiation in C57BL/6 mice using a model developing a phenotype that resembles radiotherapy-induced fibrosis in both histological characteristics and onset post-treatment.
  
  
  METHODS
  The pulmonary phenotype of C57BL/6 mice deficient in each or both of these genes was assessed after an 18-Gy single dose to the thoracic cavity by survival time postirradiation, bronchoalveolar lavage cell differential, histological evidence of alveolitis and fibrosis, and gene expression levels, and compared with that of wild-type mice.
  
  
  RESULTS
  The lung phenotype of Tlr4-deficient and Tlr2-deficient mice did not differ from that of wild-type mice in terms of survival time postirradiation, or by histological evidence of alveolitis or fibrosis. In contrast, mice deficient in both receptors developed respiratory distress at an earlier time than did wild-type mice and presented an enhanced fibrotic response (13.5% vs. 5.8% of the lung by image analysis of histological sections, p < 0.001). No differences in bronchoalveolar cell differential counts, nor in numbers of apoptotic cells in the lung as detected through active caspase-3 staining, were evident among the irradiated mice grouped by Tlr genotype. Gene expression analysis of lung tissue revealed that Tlr2,4-deficient mice have increased levels of hyaluronidase 2 compared with both wild-type mice and mice lacking either Tlr2 or Tlr4.
  
  
  CONCLUSIONS
  We conclude that a combined deficiency in both Tlr2 and Tlr4, but not Tlr2 or Tlr4 alone, leads to enhanced radiation-induced fibrosis in the C57BL/6 mouse model.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paun
authors.forename: Jessica
authors.initials: J
authors.lastname: Fox
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
authors.forename: Christina K
authors.initials: CK
authors.lastname: Haston
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000032:analysis; D002452:Cell Count; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000528:radiation effects; D008407:Mast Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000473:pathology; D017564:Radiation Pneumonitis / Q000235:genetics* / Q000473:pathology; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics*
chemical_list: D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase; C505409:Casp3 protein, mouse; D053148:Caspase 3