Suppressive effects of tranilast on pulmonary fibrosis and activation of alveolar macrophages in mice treated with bleomycin: role of alveolar macrophages in the fibrosis.
We have reported that tranilast, an anti-allergic drug that inhibits chemical mediator release from mast cells, suppresses bleomycin (BLM)-induced pulmonary fibrosis in mice through mechanisms other than inhibiting chemical mediator release from mast cells. The purpose of this paper is to examine the effect of tranilast on alveolar macrophage (AM) activation and on the development of fibrosis in ICR mice instilled with BLM intratracheally. Twenty eight days after the BLM instillation (0.01 mg/mouse), AM often migrated into alveolar spaces surrounding the fibrotic areas. Flow cytometry analysis for the size and density of AM (MAC-1 positive cells) suggested that AM were activated not only in the earlier acute inflammatory phase, but also in the later chronic phase. The p.o. administration of tranilast suppressed an increase of AM activity to produce reactive oxygen species in BLM-instilled mice, and it inhibited the subsequent development of pulmonary fibrosis. In vitro treatment with tranilast suppressed the reactive oxygen species production from murine peritoneal macrophages. However, several different anti-oxidants failed to inhibit the development of fibrosis. These results suggest that the activation of AM plays an important role in the development of fibrosis, and it is likely that tranilast suppresses fibrosis by inhibiting AM activation but not by scavenging reactive oxygen species.
Mori
H
H
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Tanaka
H
H
Kawada
K
K
Nagai
H
H
Koda
A
A
D000284:Administration, Oral; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000009:adverse effects; D014132:Trachea / Q000187:drug effects / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D016166:Free Radical Scavengers; D006634:Histamine H1 Antagonists; D017382:Reactive Oxygen Species; D062367:ortho-Aminobenzoates; D001761:Bleomycin; D006861:Hydrogen Peroxide; C012293:tranilast; D006909:Hydroxyproline