Platelet-activating factor induces the processing of nuclear factor-κB p105 into p50, which mediates acute bowel injury in mice

Liu SXL, Tian R, Baskind H, Hsueh W, De Plaen IG. Platelet-activating factor induces the processing of nuclear factor-kappa B p105 into p50, which mediates acute bowel injury in mice. Am J Physiol Gastrointest Liver Physiol 297: G76-G81, 2009. First published May 21, 2009; doi:10.1152/ajpgi.00053.2009.-Platelet-activating factor (PAF), an endogenous proinflammatory phospholipid, when injected intravascularly to rats and mice, causes shock, acute bowel injury, and a rapid activation of NF-kappa B p50-p50 with upregulation of the chemokine CXCL2 in the intestine. In this study, we investigate the mechanism of NF-kappa B activation and the role of the NF-kappa B p50 subunit in PAF-induced shock and acute bowel injury. NF-kappa B p50-deficient mice and wild-type mice were anesthetized and tracheotomized, and their carotid artery was cannulated for blood pressure monitoring, blood sampling, and PAF administration. For determination of bowel injury, shock, and survival, PAF (2.2 mu g/kg, intraarterially, i.a.) was injected. Two hours later, animals were euthanized, and their small intestines were removed for histological examination. For biochemical studies, PAF (1.5 mu g/kg i.a.) was administered and the small intestine removed after 15-60 min. We found that PAF induced an increase in p105 processing within 30 min, but there were no changes in the levels of the NF-kappa B inhibitory proteins I kappa B alpha and beta. NF-kappa B p50-deficient mice were protected against PAF-induced mortality, shock, intestinal hypoperfusion, and injury compared with wild-type animals. We also found that p50-deficient mice had decreased gene expression of CXCL2 and TNF and a decrease in CXCL2 protein production compared with wild-type mice. Our study suggests that PAF increases the processing of NF-kappa B p105 into p50, with upregulation of proinflammatory cytokines, which leads to PAF-induced systemic inflammatory response and acute bowel injury.