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Laboratory and Animal InvestigationsFourteen-Membered Ring Macrolides Inhibit Vascular Cell Adhesion Molecule 1 Messenger RNA Induction and Leukocyte Migration: Role in Preventing Lung Injury and Fibrosis in Bleomycin-Challenged Mice*
Section snippets
Animals
Male, 7-week-old ICR mice (Nippon CLEA; Tokyo, Japan), weighing 30 g each on average, were randomly classified into groups.
Materials
Bleomycin (Nippon Kayaku; Tokyo, Japan) was dissolved in normal saline solution (NS) and administered IV to ICR mice at a dosage of 100 mg/kg (0.3 mL per mouse). Erythromycin, 50 mg/kg (Dainabott; Osaka, Japan); clarithromycin, 8.9 mg/kg (Dainabott); and roxithromycin, 10 mg/kg (Aventis Pharma; Tokyo, Japan) were suspended in 5% arabic gum (AG) [Wako Pure Chemical
Histopathologic Assessment of Late-Phase Pulmonary Fibrosis
Bleomycin-induced lung fibrosis was significantly inhibited by treatment with erythromycin, clarithromycin, and pretreatment with roxithromycin at day 28 after bleomycin injection in ICR mice. Comparison of Ashcroft scores revealed significant difference between pretreatment and posttreatment with 14-MRMLs (Fig 1). A typical picture of attenuation of fibrosis is shown in Figure 2. Administration of 14-MRMLs alone resulted in no remarkable changes in results of histopathologic assessment of lung
Discussion
Idiopathic pulmonary fibrosis (IPF) is the prototype of many other interstitial lung disorders in which parenchymal inflammation is a typical features; such disorders number > 100. Although the pathogenesis of pulmonary fibrosis remains unclear, many investigators have found that neutrophil-mediated lung injury occurs prior to initiation and progression of the fibrogenic process.20,21 Neutrophil adhesion to vascular endothelial cells is an important process in cell-mediated lung injury, along
Conclusion
We conclude that 14-MRMLs successfully inhibited the induction of VCAM-1 mRNA during the early phase of bleomycin-induced lung injury. This might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs, and subsequent fibrotic effects of 14-MRMLs. Inhibition of adhesion of leukocytes to endothelial cells may be useful for prevention of leukocyte-mediated lung injury and subsequent fibrosis, including IPF in humans. 14-MRMLs are thus promising agents
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