title: Leukotriene C4 aggravates bleomycin-induced pulmonary fibrosis in mice.
abstract: OBJECTIVE
  Synthesis of cysteinyl leukotrienes (cys-LT) is thought to cause inflammatory disorders such as bronchial asthma and allergic rhinitis. Recent reports have suggested that leukotriene C4 (LTC4 ) is an important regulator of pulmonary fibrosis. This study examined the effect of LTC4 in LTC4 synthase-overexpressed transgenic mice with bleomycin-induced pulmonary fibrosis. The function of lung-derived fibroblasts from transgenic mice was also investigated.
  
  
  METHODS
  Bleomycin was administrated to transgenic mice and wild-type (WT) mice by intratracheal instillation. Concentrations of interleukin (IL)-4 and -13, interferon-γ, and transforming growth factor (TGF)-β1 in bronchoalveolar lavage fluid were measured 1, 3, 7 and 14 days after the administration of bleomycin. Lung tissue was examined histopathologically on day 14. In addition, lung-derived fibroblasts from transgenic and WT mice were cultured for 7 days. Expression of TGF-β1 mRNA was measured by real-time polymerase chain reaction.
  
  
  RESULTS
  Both the pathological scores for pulmonary fibrosis (3.8 ± 0.4 vs 2.0 ± 0.1, P < 0.05) and the levels of IL-4 (12.1 ± 2.3 vs <7.8 pg/mL, P < 0.05), IL-13 (26.5 ± 5.2 vs <7.8 pg/mL, P < 0.01) and TGF-β1 (211.1 ± 30.2 vs 21.3 ± 1.2 pg/mL, P < 0.01) on day 14 were significantly greater in transgenic than in WT mice. Furthermore, the reduction of LTC4 by pranlukast hydrate, a cys-LT1 receptor antagonist, in fibroblasts from transgenic significantly (P < 0.05) decreased the expression of TGF-β1 mRNA (by ∼50%) compared with those from WT mice.
  
  
  CONCLUSIONS
  Overexpression of LTC4 , amplifies bleomycin-induced pulmonary fibrosis in mice. Our findings suggest a role for LTC4 in lung fibrosis.
authors: Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan. hirokuni@dokkyomed.ac.jp
authors: Hirokuni
authors: H
authors: Hirata
authors: Masafumi
authors: M
authors: Arima
authors: Yasutsugu
authors: Y
authors: Fukushima
authors: Kumiya
authors: K
authors: Sugiyama
authors: Takeshi
authors: T
authors: Tokuhisa
authors: Takeshi
authors: T
authors: Fukuda
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000009:adverse effects* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
chemical_list: D018793:Interleukin-13; D001761:Bleomycin; D015847:Interleukin-4; D017997:Leukotriene C4; D007371:Interferon-gamma; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase