Intestinal lipid alterations occur prior to antibody-induced prostaglandin E2 production in a mouse model of ischemia/reperfusion

Abstract

Original article can be found at: http://www.sciencedirect.com/science/ Copyright Elsevier [Full text of this article is not available in the UHRA]Ischemia/reperfusion (IR) induced injury results in significant tissue damage in wild-type, but not antibody-deficient, Rag-1???/??? mice. However, Rag-1???/??? mice sustain intestinal damage after administration of wild-type antibodies or naturally occurring, specific anti-phospholipid related monoclonal antibodies, suggesting involvement of a lipid antigen. We hypothesized that IR initiates metabolism of cellular lipids, resulting in production of an antigen recognized by anti-phospholipid antibodies. At multiple time points after Sham or IR treatment, lipids extracted from mouse jejunal sections were analyzed by electrospray ionization triple quadrupole mass spectrometry. Within 15 min of reperfusion, IR induced significantly more lysophosphatidylcholine (lysoPC), lysophosphatidylglycerol (lysoPG) and free arachidonic acid (AA) production than Sham treatment. While lysoPC, lysoPG, and free AA levels were similar in C57Bl/6 (wild-type) and Rag-1???/??? mice, IR led to Cox-2 activation and prostaglandin E2 (PGE2) production in wild-type, but not in the antibody-deficient, Rag-1???/??? mice. Administration of wild-type antibodies to Rag-1???/??? mice restored PGE2 production and intestinal damage. These data indicate that IR-induced intestinal damage requires antibodies for Cox-2 stimulated PGE2 production but not for production of lysoPC and free AA

TLR2 Modulates Antibodies Required for Intestinal Ischemia/Reperfusion-Induced Damage and Inflammation

“…Previous studies indicated that the appropriate Ab repertoire is required for recognition of IR-induced neoantigens, complement activation, and eicosanoid production (14, 37). Importantly, TLR4 was not required for production of the appropriate Ab repertoire to induce damage in Ab-deficient, IR-resistant, Rag-1−/− mice (8, 14, 37) .…”

“…Importantly, TLR4 was not required for production of the appropriate Ab repertoire to induce damage in Ab-deficient, IR-resistant, Rag-1−/− mice (8, 14, 37) . To determine if TLR2 −/− mice have the proper Ab repertoire, we injected Rag-1 −/− mice with sera or Ig purified from C57Bl/6 or TLR2 −/− mice and subjected the mice to IR.…”

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury

“…Several in vivo studies have documented increased PGE 2 production in response to intestinal IR [13, 25–29]. While increased transcription of the Cox enzymes begins during the ischemic period, reperfusion is necessary for PGE 2 production [27]. Endothelial cells produce prostaglandins (reviewed in [22]); however, not all endothelial cells generate the same prostaglandin profile.…”

“…Rag-1 −/− mice do not produce antibodies and do not sustain IR damage; however, administration of pooled wildtype antibodies as well as the IgM fraction alone results in intestinal damage similar to that seen in wildtype animals [27, 55]. It was later shown that human IgM can also elicit injury and complement deposition in Rag-1 −/− and Rag -2 −/− mice [56, 57].…”

Physiological Significance of Lysophospholipids that Act on the Lumen Side of Mammalian Lower Digestive Tracts

“…58) On the other hand, the production of LPC was suggested not to be involved in intestinal injury after ischemia and reperfusion stress in mice, but rather production of prostaglandin E 2 participated in the intestinal damage. 59) At high concentrations LPC impaired the mucosal barrier function and increased gastrointestinal permeability in isolated rat ileum, 60) rat stomach, 61) rat intestine, 62) guinea-pig proximal jejunum 63) and human intestinal cells. 64) Intraduodenally injected lipopolysaccharide induced the release of sPLA 2 , increasing the luminal level of LPC in rats, 52) although LPC was found to be protective when injected intravenously in rats.…”