Leukotriene <scp>C₄</scp> aggravates bleomycin‐induced pulmonary fibrosis in mice

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background and objective</jats:title><jats:p>Synthesis of cysteinyl leukotrienes (cys‐<jats:styled-content style="fixed-case">LT</jats:styled-content>) is thought to cause inflammatory disorders such as bronchial asthma and allergic rhinitis. Recent reports have suggested that leukotriene <jats:styled-content style="fixed-case">C<jats:sub>4</jats:sub></jats:styled-content> (<jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content>) is an important regulator of pulmonary fibrosis. This study examined the effect of <jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content> in <jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content> synthase‐overexpressed transgenic mice with bleomycin‐induced pulmonary fibrosis. The function of lung‐derived fibroblasts from transgenic mice was also investigated.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Bleomycin was administrated to transgenic mice and wild‐type (<jats:styled-content style="fixed-case">WT</jats:styled-content>) mice by intratracheal instillation. Concentrations of interleukin (<jats:styled-content style="fixed-case">IL</jats:styled-content>)‐4 and ‐13, interferon‐γ, and transforming growth factor (<jats:styled-content style="fixed-case">TGF</jats:styled-content>)‐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 <jats:styled-content style="fixed-case">WT</jats:styled-content> mice were cultured for 7 days. Expression of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 <jats:styled-content style="fixed-case">mRNA</jats:styled-content> was measured by real‐time polymerase chain reaction.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Both the pathological scores for pulmonary fibrosis (3.8 ± 0.4 vs 2.0 ± 0.1, <jats:italic><jats:styled-content style="fixed-case">P</jats:styled-content></jats:italic> < 0.05) and the levels of <jats:styled-content style="fixed-case">IL</jats:styled-content>‐4 (12.1 ± 2.3 vs <7.8 pg/mL, <jats:italic><jats:styled-content style="fixed-case">P</jats:styled-content></jats:italic> < 0.05), <jats:styled-content style="fixed-case">IL</jats:styled-content>‐13 (26.5 ± 5.2 vs <7.8 pg/mL, <jats:italic><jats:styled-content style="fixed-case">P</jats:styled-content></jats:italic> < 0.01) and <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 (211.1 ± 30.2 vs 21.3 ± 1.2 pg/mL, <jats:italic><jats:styled-content style="fixed-case">P</jats:styled-content></jats:italic> < 0.01) on day 14 were significantly greater in transgenic than in <jats:styled-content style="fixed-case">WT</jats:styled-content> mice. Furthermore, the reduction of <jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content> by pranlukast hydrate, a cys‐<jats:styled-content style="fixed-case">LT1</jats:styled-content> receptor antagonist, in fibroblasts from transgenic significantly (<jats:italic><jats:styled-content style="fixed-case">P</jats:styled-content></jats:italic> < 0.05) decreased the expression of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 <jats:styled-content style="fixed-case">mRNA</jats:styled-content> (by ∼50%) compared with those from <jats:styled-content style="fixed-case">WT</jats:styled-content> mice.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Overexpression of <jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content>, amplifies bleomycin‐induced pulmonary fibrosis in mice. Our findings suggest a role for <jats:styled-content style="fixed-case">LTC<jats:sub>4</jats:sub></jats:styled-content> in lung fibrosis.</jats:p></jats:sec>