Platelet-activating factor acetylhydrolase inhibits alveolar macrophage activation in vivo.
Platelet-activating factor (PAF) is an important proinflammatory mediator of septic shock. PAF is produced by activated macrophages and acts to perpetuate the response to endotoxin. PAF is metabolized by an endogenous PAF-acetylhydrolase (PAF-AH). Low circulating levels of PAF-AH have been associated with the development of postinjury multiple organ failure. We have previously shown that PAF-AH significantly inhibits macrophage activation by lipopolysaccharide (LPS) in vitro. The purpose of these studies was to determine whether this effect would translate to an in vivo model of remote lung injury. Wistar rats were administered a single intravenous dose of PAF-AH (5 mg/kg) or its carrier solution simultaneous with the induction of zymosan peritonitis. After 24 h, alveolar macrophages were obtained by bronchoalveolar lavage and stimulated in vitro with LPS (1 microg/mL). Supernatants were collected at 18 h for cytokine production and cellular and nuclear protein extractions were performed at 30 and 60 min to assess the activation of p38 and extracellular signal-regulated kinase (ERK) 1/2 kinases and the nuclear translocation of nuclear factor (NF)-kappaB. Administration of PAF-AH significantly inhibited LPS-induced tumor necrosis factor alpha and interleukin-1beta production by alveolar macrophages from zymosan-treated animals. This functional inhibition was associated with inhibition of ERK 1/2 kinase and NF-kappaB activation but not p38 kinase activation. Interleukin 6 production was depressed in the macrophages from zymosan-treated animals but no additional inhibition resulted from PAF-AH treatment. In conclusion, zymosan peritonitis leads to priming of alveolar macrophages such that their subsequent tumor necrosis factor alpha response to LPS is enhanced. In vivo administration of PAF-AH abrogates this response, suggesting that this priming may be PAF dependent. This effect of PAF-AH may be mediated by the inhibition of intracellular signaling via inhibition of ERK kinase and NF-kappaB activation.
Bulger
Eileen M
EM
Department of Surgery, University of Washington, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98104, USA.
Gourlay
David
D
Cuschieri
Joseph
J
Jelacic
Sandra
S
Staudenmeyer
Kristen
K
Garcia
Iris
I
Maier
Ronald V
RV
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D055370:Lung Injury; D008262:Macrophage Activation / Q000187:drug effects* / Q000502:physiology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D010741:Phospholipases A / Q000494:pharmacology*; D011014:Pneumonia / Q000209:etiology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015054:Zymosan / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D016328:NF-kappa B; D015054:Zymosan; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase