Pathophysiology of LPS-induced gastrointestinal injury in the rat: role of secretory phospholipase A2.
A hydrophobic layer of phosphatidylcholine (PC) overlies and protects the surface of the gastrointestinal (GI) tract, contributing to barrier integrity. During critical illness such as sepsis, gut barrier integrity is compromised, which could be related to degradation of PC. The purpose of this study was to investigate a role for luminal (secretory) phospholipase A2 (sPLA(2)) in LPS-induced GI injury. Rats were treated with LPS (5 mg/kg) or saline for 0.5, 1, 3, and 5 h. The gastric and ileal luminal contents were collected for determination of sPLA(2) activity, and the luminal lipids were analyzed using thin layer chromatography for lyso-PC content. The GI permeability was assessed in vivo with fluorescein-isothiocyanate dextran 4000 and rats were tested with or without a specific sPLA(2) inhibitor. LPS induced significant increases in sPLA(2) activity and lyso-PC content in the gastric and ileal lumens at 5 h. In addition, LPS treated rats showed a significant increase in GI permeability to fluorescein-isothiocyanate dextran in both the stomach and ileum at 5 h, which was prevented by pretreatment with the sPLA(2) inhibitor. In response to LPS, sPLA(2) activity increases in the GI tract lumen where it may degrade the extracellular protective phospholipid layer and membranes, producing injurious lyso-PC and increased GI permeability. Pretreatment with an orally active sPLA(2) inhibitor blocks the LPS-induced increase in GI permeability, and may suggest a new approach to fortify the GI mucosal barrier and prevent complications from endotoxin in trauma and other patients.
Zayat
Mayssa
M
Department of Pediatric Gastroenterology, Baylor College of Medicine, Houston, TX, USA.
Lichtenberger
Lenard M
LM
Dial
Elizabeth J
EJ
D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D010539:Permeability; D010713:Phosphatidylcholines / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology
D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D054497:Phospholipases A2, Secretory