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Shock survival improved by combined protease and lipase inhibition in the intestinal lumen
Author(s) -
Penn Alexander Hayes,
SchmidSchönbein Geert W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1227.12
Subject(s) - aprotinin , proteases , protease , lumen (anatomy) , lipase , small intestine , albumin , lisinopril , shock (circulatory) , biology , chemistry , biochemistry , medicine , pharmacology , enzyme , endocrinology , angiotensin converting enzyme , blood pressure
Shock and multiple‐organ failure remain one of the leading causes of death. Our evidence shows it is triggered by a failure of the mucosal barrier in the intestine that is followed by cell death in the intestine and elsewhere. We have recently shown that homogenates of ischemic, but not non‐ischemic, intestines or intestinal wall homogenates digested with proteases from the intestinal lumen contain cytotoxic mediators. We have identified these mediators as free fatty acids (FFAs), already present or created by the action of a lipolytic enzyme present in the intestinal wall. The FFAs are bound to FFA‐binding proteins, such as albumin, unless those proteins are digested, as may occur in shock when the mucosal barrier fails and proteases enter the walls. To test this hypothesis in vivo, we injected saline, aprotinin (protease inhibitor), orlistat (lipase inhibitor), or a combination of the two into the lumen of the small intestine of Wistar rats and subjected them to 120 min of splanchnic arterial occlusion followed by up to 180 min of observed reperfusion. Saline treated animals all died after 86±43 min of reperfusion. Only the combination aprotinin and orlistat treatment significantly improved survival time to 164±11, suggesting that in severe models of shock both luminal protease and luminal lipase inhibition should be explored.