title: Exacerbation of bleomycin-induced injury by lipopolysaccharide in mice: establishment of a mouse model for acute exacerbation of interstitial lung diseases.
abstract: OBJECTIVE
  Interstitial lung disease (ILD) is sometimes seen in patients with primary lung cancer. Therapeutic interventions for lung cancer patients with ILD sometimes provoke acute exacerbation (AE) of pre-existing lung disease. Although postoperative AE after lung resection is a potentially fatal complication, prophylactic treatments have yet to be established. Prophylaxis for postoperative AE is imperative for thoracic surgeons. However, no animal models for preclinical research into postoperative management and prophylactic interventions for AE of ILD have been developed. The objective of this study was to establish a new mouse model of AE of ILD, for further investigation of prophylactic interventions.
  
  
  METHODS
  C57BL/6 mice were intratracheally administered bleomycin (BLM, 1 mg/kg) or saline on Day 0 to induce pulmonary fibrosis, and lipopolysaccharide (LPS, 0.5 mg/kg) or saline to induce inflammatory stimulation on Day 7. Mice were divided into four groups: control group; LPS group; BLM group and BLM + LPS group. Histological changes and computed tomography (CT) images of the lung, lung water content, oxygen partial pressure (pO2) of arterial blood and cell counts and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were assessed on Day 8. Survival rates were also determined.
  
  
  RESULTS
  In the BLM + LPS group, chest CT showed diffuse ground-glass opacities, and pO2 was significantly decreased. The most severe inflammatory reaction was evident in the BLM + LPS group, with increased infiltrating cells on histopathology and increased lung water content. Total cell and neutrophil counts and levels of cytokines such as monocyte chemoattractant protein-1, interleukin-6 and keratinocyte chemoattractant in the BALF were significantly elevated in the BLM + LPS group. These findings mimic human AE of ILD. Furthermore, survival curves demonstrated that the BLM + LPS group had the lowest survival rate among all groups.
  
  
  CONCLUSIONS
  A new mouse model of AE of ILD was developed. This model represents an attractive experimental method for preclinical research of postoperative management and prophylactic interventions for AE of ILD in lung cancer patients.
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan kimura@thoracic.med.osaka-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nojiri
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita-City, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.affiliation: Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
authors.forename: Meinoshin
authors.initials: M
authors.lastname: Okumura
authors.affiliation: Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita-City, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D001761:Bleomycin / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011654:Pulmonary Edema / Q000473:pathology / Q000503:physiopathology; D011897:Random Allocation; D015996:Survival Rate; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D008070:Lipopolysaccharides; D001761:Bleomycin
keywords: Acute exacerbation; Bleomycin; Interstitial lung disease; Lipopolysaccharide; Lung cancer; Lung resection