HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1779    most recent 00902.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Penn, A. H. Articles by Schmid-Schönbein, G. W. Search for Related Content PubMed PubMed Citation Articles by Penn, A. H. Articles by Schmid-Schönbein, G. W.

The intestine as source of cytotoxic mediators in shock: free fatty acids and degradation of lipid-binding proteins

Department of Bioengineering, The Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla, California

Submitted 2 August 2007 ; accepted in final form 4 February 2008

Shock and multiple organ failure remain primary causes of late-stage morbidity and mortality in victims of trauma. During shock, the intestine is subject to extensive cell death and is the source of inflammatory factors that cause multiorgan failure. We (34) showed previously that ischemic, but not nonischemic, small intestines and pancreatic protease digested homogenates of normal small intestine can generate cytotoxic factors capable of killing naive cells within minutes. Using chloroform/methanol separation of rat small intestine homogenates into lipid fractions and aqueous and sedimented protein fractions and measuring cell death caused by those fractions, we found that the cytotoxic factors are lipid in nature. Recombining the lipid fraction with protein fractions prevented cell death, except when homogenates were protease digested. Using a fluorescent substrate, we found high levels of lipase activity in intestinal homogenates and cytotoxic levels of free fatty acids. Addition of albumin, a lipid binding protein, prevented cell death, unless the albumin was previously digested with protease. Homogenization of intestinal wall in the presence of the lipase inhibitor orlistat prevented cell death after protease digestion. In vivo, orlistat plus the protease inhibitor aprotinin, administered to the intestinal lumen, significantly improved survival time compared with saline in a splanchnic arterial occlusion model of shock. These results indicate that major cytotoxic mediators derived from an intestine under in vitro conditions are free fatty acids. Breakdown of free fatty acid binding proteins by proteases causes release of free fatty acids to act as powerful cytotoxic mediators.

multiorgan failure; pancreatic digestive enzymes; albumin; apoptosis; necrosis; inflammation

This article has been cited by other articles:

				M. W. Dunser and W. R. Hasibeder Sympathetic Overstimulation During Critical Illness: Adverse Effects of Adrenergic Stress J Intensive Care Med, September 1, 2009; 24(5): 293 - 316. [Abstract] [PDF]