title: Inhibition of pulmonary eosinophilia does not necessarily prevent the airway hyperresponsiveness induced by Sephadex beads.
abstract: BACKGROUND
  The Lewis rat among highly inbred strains exhibits significant airway hyperresponsiveness (AHR) following intravenous administration of Sephadex G-200 (Sephadex). The aim of this study was to investigate the association of Sephadex-induced AHR with changes in airway inflammation in Lewis rats.
  
  
  METHODS
  A suspension (0.5 mg/ml/rat) of Sephadex was intravenously administered to male Lewis rats on days 0, 2 and 5. Measurement of airway responsiveness to serotonin, bronchoalveolar lavage (BAL) and histological study were performed on day 2-11.
  
  
  RESULTS
  Significant AHR induced by Sephadex was recognized on day2 (p < 0.05), and AHR reached a maximum on day 7 (p < 0.001). In the BAL study, eosinophils increased on day2 (p < 0.01) with a peak on day 5 (p < 0.05). In the histological study, we found Sephadex beads trapped in small arteries of the lung and granulomatous arteritis on day 2 or later. Pulmonary granulomas, horseshoe-shaped multinuclear giant cells, eosinophils and goblet cell hyperplasia were observed on day 2, and the degree became intense on day 5-7. GCC-AP0341 (10 mg/kg, i.p. x 3) inhibited the recruitment of eosinophils in BAL fluid and in lung tissue, but it did not inhibit AHR. The compound also inhibited pulmonary granulomas and goblet cell hyperplasia.
  
  
  CONCLUSIONS
  The mechanism of Sephadex-induced AHR may not be directly associated with inflammatory changes such as recruitment of eosinophils, pulmonary granulomas and hyperplasia of goblet cells in rats.
authors.affiliation: Lead Optimization Research Laboratory, Tanabe Seiyaku, Toda, Saitama, Japan. s-matsu@tanabe.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Matsubara
authors.forename: K
authors.initials: K
authors.lastname: Fushimi
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: H
authors.initials: H
authors.lastname: Kikkawa
authors.forename: A
authors.initials: A
authors.lastname: Nakata
authors.forename: R
authors.initials: R
authors.lastname: Kameda
authors.forename: M
authors.initials: M
authors.lastname: Kikuchi
authors.forename: K
authors.initials: K
authors.lastname: Naito
authors.forename: K
authors.initials: K
authors.lastname: Ikezawa
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003911:Dextrans / Q000008:administration & dosage / Q000009:adverse effects*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000009:adverse effects*; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D003911:Dextrans; C100738:GCC-AP 0341; D007202:Indicators and Reagents; D011506:Proteins; D014230:Triazoles; C025614:sephadex