Background and objective: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood.

Background and objective: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory lonely dwellings especially neutrophils, and the injurious substances produc by dint of them play important roles in the progression of interstitial pneumonia and following fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis from antineutrophil and several other anti-inflammatory mechanisms. The not past nor future study was undertaken to investigate the purports of 14-MRMLs on an experimental prototype of bleomycin-induced acute lung injury and following fibrosis in mice.

Methods: Bleomycin was administered IV to ICR mice. At 28 days after bleomycin injection, fibrotic foci were histologically observ in left lung tissues, and hydroxyproline make contented in right lung tissues was chemically analyzed. The inhibitory forces of 14-MRMLs were assessed by the agency of overall comparison between control (normal saline solution [NS] alone), untreated (bleomycin alone), and treated (bleomycin plus 14-MRMLs) collections For evaluation of early-phase inflammation, solitary abode; squalid populations in BAL fluid and induction of carrier RNA (mRNA) of adhesion atoms (E-selectin, P-selectin, intercellular adhesion atom 1 [ICAM-1], and vascular enclosed space adhesion molecule 1 [VCAM-1]) in lung tissues were examined at 0 to 13 days after bleomycin treatment. These parameters were also compared with those for the sway (NS alone), 14-MRML untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML pretreated) groups

Results: Bleomycin-induced pulmonary fibrosis was inhibited on erythromycin and other 14-MRMLs forward day 28 after bleomycin injection in ICR mice, especially those pretreated with 14-MRML Hydroxyproline make contented in lung tissues was also decreased in the 14-MRML-pretreated assemblages The number of neutrophils in BAL fluid significantly increased, with sum of two units peaks at 1 day and 9 days (from 6 to 11 days) after bleomycin administration. 14-MRML significantly inhibited one as well as the other peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion atoms (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leukocyte migration into the airspace. 14-MRML clearly inhibited the induction of VCAM-1 mRNA, and be attendanted to attenuate that of ICAM-1 mRNA, still inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA.

Conclusion: These findings indicate that attenuation of inflammatory enclosed space migration into the airspace by way of 14-MRMLs, especially of neutrophils and macrophages, inferenceed in inhibition of lung injury and after fibrosis. 14-MRMLs clearly attenuated the expression of VCAM-1 mRNA during the early phase of bleomycin-induced lung injury, and this might be individual mechanism of inhibition of neutrophil and macrophage migration into the airspace by means of 14-MRMLs. This may be the same mechanism of the anti-inflammatory and antifibrotic consequences of 14-MRMLs. These findings hint that prophylactic administration of 14-MRML may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.

lock opener words: bleomycin; lung fibrosis; macrolide; vascular confined apartment adhesion molecule 1

Abbreviations: AG = arabic gum; BALF = BAL fluid; cDNA = complementary DNA; G6PD = glucose-6-phosphate dehydrogenase; ICAM-1 = intercellular adhesion atom 1; IPF = idiopathic pulmonary fibrosis; MMP = matrix metalloproteinase; 14-MRML = 14-membered ring macrolides; mRNA = harbinger RNA; NS = normal saline solution; PCR = polymerase chain reaction; RT = overturn transcriptase; VCAM-1 = vascular small cavity adhesion molecule 1

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Bleomycin-induced lung injury and following fibrosis in animals is a widely used experimental standard of acute lung injury and fibrosis in humans. (1-3) The mechanisms of interstitial pneumonia and pulmonary fibrosis are not understood in detail, however it has been found that neutrophils and the injurious substances they originate play important roles in the progression of pulmonary fibrosis. (4-7) We originate that E-selectin, acting as a guide molecule in the initial phase of neutrophil adhesion to vascular endothelial confined apartments played an essential role in the progression of pulmonary fibrosis. (8) Adhesion indivisible particles including selectins and integrins, are required for neutrophil migration into lung tissues. The pathologic features of acute lung injury include prominent accumulation of neutrophils and macrophages in the lung parenchyma. (910)

In patients with diffuse panbronchiolitis receiving oral erythromycin, increase in number of neutrophils in BAL fluid (BALF) was significantly reducedn Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis at several anti-inflammatory mechanisms. (11,12)

We previously reported that the number of neutrophils and the amount of neutrophil elastase in BAL played important parts in the acute lung injury induced by way of bleomycin, and that both were decreased at treatment with erythromycin. (7) in this investigation we examined the inhibitory meanings of 14-MRMLs including erythromycin, clarithromycin, and roxithromycin onward bleomycin-induced pulmonary fibrosis following acute lung injury. We further investigated the character of adhesion molecules in neutrophil adhesion to endothelial lonely dwellings subsequent migration of neutrophils into lung tissue and progression of pulmonary fibrosis, and elucidated the mechanisms by means of which 14-MRMLs exhibit anti-inflammatory validitys and oppose the fibrosis that tread in the steps ofs inflammation in bleomycin-challenged mice.

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