Journal of Nippon Medical School: Vol.69 No.3 page.252

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ArticleTitle Attenuated mRNA Induction of Molecules Associated with Neutrophil Migration by 14-Membered Ring Macrolides Inhibits Bleomycin Induced Acute Lung Injury in Mice

AuthorList YingJi Li, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Akinori Aoyama, Shoji Kudoh

Affiliation Fourth Department of Internal Medicine, Nippon Medical School

Language JA

Volume 69

Issue 3

Year 2002

Page 252-261

Received November 12, 2001

Accepted December 11, 2001

Keywords macrolides, bleomycin, acute lung injury, adhesion molecule, TNF-α

Abstract
Background: Although the pathogeneses of interstitial pneumonia are not well understood, it has been reported that inflammatory cells, especially neutrophils, and their injurious substances play important roles in the progression of interstitial pneumonia. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to inhibit chronic airway inflammation by mechanisms of anti-neutrophil and several other anti-inflammatory activities. The present study was undertaken to investigate the effects and mechanisms of 14-MRMLs (erythromycin: EM; clarithromycin: CAM; roxithromycin: RXM) on an experimental model of bleomycin (BLM) -induced acute lung injury in mice.

Methods: BLM was administered intravenously to ICR mice. For the evaluation of early-phase inflammation, cell populations in broncho-alveolar lavage fluid (BALF) and induction of mRNA of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) and TNF-α tested by RT-PCR in lung tissues were examined at 0 to 13 days after BLM. These parameters were also compared with those of the control (NS alone), 14-MRMLs-untreated (BLM alone) and-pre-treated (BLM+pre 14-MRMLs) groups.

Results: The number of neutrophils, macrophages, and lymphocytes significantly increased in BAL. Neutrophils especially increased with two peaks after BLM administration. 14-MRMLs significantly inhibited both peaks of neutrophil. The increase in number of macrophages in BALF was significantly attenuated by EM and RXM, and slightly attenuated by CAM. Number of lymphocytes in BALF was significantly attenuated by EM and CAM, and slightly attenuated by RXM. Changes in mRNA expression of E-selectin, P-selectin, ICAM-1, VCAM-1, and TNF-α were associated with the number of neutrophils migrating into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, but did not inhibit the induction of E-selectin and P-selectin mRNA.

Discussion: These findings show that 14-MRMLs clearly attenuated the expression of VCAM-1mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, and subsequently inhibited leucocyte, especially neutrophil migration into the airspace during the early phase of BLM-induced lung injury and finally inhibited lung fibrosis. This might be one potent mechanism of the anti-inflammatory effects of 14-MRMLs in BLM-induced acute lung injury. The findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.

Correspondence to YingJi Li, Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
lyj@nms.ac.jp

ArticleTitle	Attenuated mRNA Induction of Molecules Associated with Neutrophil Migration by 14-Membered Ring Macrolides Inhibits Bleomycin Induced Acute Lung Injury in Mice
AuthorList	YingJi Li, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Akinori Aoyama, Shoji Kudoh
Affiliation	Fourth Department of Internal Medicine, Nippon Medical School
Language	JA
Volume	69
Issue	3
Year	2002
Page	252-261
Received	November 12, 2001
Accepted	December 11, 2001
Keywords	macrolides, bleomycin, acute lung injury, adhesion molecule, TNF-α
Abstract	Background: Although the pathogeneses of interstitial pneumonia are not well understood, it has been reported that inflammatory cells, especially neutrophils, and their injurious substances play important roles in the progression of interstitial pneumonia. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to inhibit chronic airway inflammation by mechanisms of anti-neutrophil and several other anti-inflammatory activities. The present study was undertaken to investigate the effects and mechanisms of 14-MRMLs (erythromycin: EM; clarithromycin: CAM; roxithromycin: RXM) on an experimental model of bleomycin (BLM) -induced acute lung injury in mice. Methods: BLM was administered intravenously to ICR mice. For the evaluation of early-phase inflammation, cell populations in broncho-alveolar lavage fluid (BALF) and induction of mRNA of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) and TNF-α tested by RT-PCR in lung tissues were examined at 0 to 13 days after BLM. These parameters were also compared with those of the control (NS alone), 14-MRMLs-untreated (BLM alone) and-pre-treated (BLM+pre 14-MRMLs) groups. Results: The number of neutrophils, macrophages, and lymphocytes significantly increased in BAL. Neutrophils especially increased with two peaks after BLM administration. 14-MRMLs significantly inhibited both peaks of neutrophil. The increase in number of macrophages in BALF was significantly attenuated by EM and RXM, and slightly attenuated by CAM. Number of lymphocytes in BALF was significantly attenuated by EM and CAM, and slightly attenuated by RXM. Changes in mRNA expression of E-selectin, P-selectin, ICAM-1, VCAM-1, and TNF-α were associated with the number of neutrophils migrating into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, but did not inhibit the induction of E-selectin and P-selectin mRNA. Discussion: These findings show that 14-MRMLs clearly attenuated the expression of VCAM-1mRNA, and tended to attenuate the induction of ICAM-1 and TNF-α mRNA, and subsequently inhibited leucocyte, especially neutrophil migration into the airspace during the early phase of BLM-induced lung injury and finally inhibited lung fibrosis. This might be one potent mechanism of the anti-inflammatory effects of 14-MRMLs in BLM-induced acute lung injury. The findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.
Correspondence to	YingJi Li, Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan lyj@nms.ac.jp