title: Platelet-activating factor antagonist (TCV-309) attenuates the priming effects of bronchoalveolar macrophages in cerulein-induced pancreatitis rats.
abstract: We investigated the role of platelet-activating factor (PAF) as a priming signal for cytokine-induced neutrophil chemoattractant (CINC) expression by bronchoalveolar macrophages in acute pancreatitis. Pancreatitis was induced by four intramuscular injections of cerulein (50 micrograms/kg at 1-h intervals) in Wistar rats. The animals were injected intraperitoneally with 10 micrograms/kg of lipopolysaccharide (LPS) as a septic challenge. Pancreatitis rats were treated with a bolus intravenous injection of TCV-309 (3 or 30 micrograms/kg) 30 min before the septic challenge. Intense mononuclear cell infiltration and lung hemorrhage occurred in pancreatitis rats complicated with sepsis but were not seen in pancreatitis rats receiving a bolus TCV-309. Pancreatitis rats treated with TCV-309 had lower serum concentrations of CINC after septic challenge and lower levels of CINC messenger RNA (mRNA) in the lung, as well as fewer pulmonary infiltrates immunoreactive for CINC or Mac-1 (CD11b/CD18). In vitro CINC production in response to LPS by bronchoalveolar macrophages obtained from pancreatitis rats 6 h after the first cerulein injection, immediately before septic challenge, was enhanced but was significantly reduced in a TCV-309-sensitive manner. LPS-stimulated in vitro CINC production by naive bronchoalveolar macrophages was significantly enhanced by pretreatment with PAF. TMB-8 (an inhibitor of calcium release from endoplasmic reticulum) or W7 (calmodulin antagonist) completely abrogated the chemoattractant production by bronchoalveolar macrophages pretreated with PAF after LPS stimulation. Altered intracellular calcium, due to Ca2+ efflux from intracellular stores, may be involved in the "priming" of bronchoalveolar macrophages to release CINC after triggering with LPS during acute cerulein-induced pancreatitis. The PAF antagonist TCV-309 effectively prevented hyperactivity of bronchoalveolar macrophages and pancreatitis-associated lung injury after the septic challenge.
authors.affiliation: Department of Surgery II, Kumamoto University Medical School, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: F
authors.initials: F
authors.lastname: Matsumura
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.forename: K
authors.initials: K
authors.lastname: Okabe
authors.forename: T
authors.initials: T
authors.lastname: Matsuda
authors.forename: H
authors.initials: H
authors.lastname: Ohshiro
authors.forename: K
authors.initials: K
authors.lastname: Ishihara
authors.forename: E
authors.initials: E
authors.lastname: Akizuki
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D002108:Ceruletide; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000097:blood / Q000235:genetics; D006131:Growth Inhibitors / Q000097:blood; D006133:Growth Substances / Q000097:blood / Q000235:genetics; D006470:Hemorrhage / Q000150:complications; D036341:Intercellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000737:chemistry; D008171:Lung Diseases / Q000150:complications; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000150:complications; D044005:Tetrahydroisoquinolines
chemical_list: D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D002108:Ceruletide; C067430:TCV 309