|Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Background and objective : Although the pathogeneses of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis (DPB) by anti-neutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effete of 14-MRMLs on an experimental model of bleomycin (BLM)-induced acute lung injury and subsequent fibrosis in mice.
Methods : BLM was administered intravenously to ICR mice. At 28 days after BLM injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline (HOP) content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were as
sessed by overall comparison between control (NS alone), untreated (BLM alone), and treated (BLM + 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in bronchoalveolar lavage fluid (BALF) and induction of mRNA of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) in lung tissues were examined at 0 to 13 days after BLM. These parameters were also compared wife those for the control (NS alone), 14-MRML-unteated (BLM alone) and -pre-treated (BLM + pre14-MRMLs) groups.
Results : BLM-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after BLM injection in ICR mice, especially those pre-treated with 14-MRMLs, HOP content in lung tissues was also decreased in the l4-MRML-pre-1reated groups. The number of neutrophils in BALF significantly increased, with two peaks at 1 and 9 (from 6 to 11) days after BLM administration. 14-MRMLs significantly inhibited both peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leucocyte migration into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA and tended to attenuate that of ICAM-1 mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA.
Conclusion : These findings indicate that attenuation of inflammatory cell migration into the airspace by 14-MRMLs, especially of neutrophils and macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14-MRMLs clearly attenuated the expression of VCAM- 1 mRNA during the early phase of BLM-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This might be one potent mechanism of the anti-inflammatory and subsequent fibrotic effects of 14-MRMLs. These findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury. Less