Inducible Nitric Oxide Synthase Expression in the Intestinal Muscularis Mediates Severe Smooth Muscle Dysfunction During Acute Rejection in Allogenic Rodent Small Bowel Transplantation

Background Acute rejection in small bowel transplantation is associated with dysmotility. Therefore, host and organ not only face the threat of destructive immunological processes but also the risk of bacterial translocation, endotoxemia, and systemic inflammatory response syndrome. We hypothesized...

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Published in:The Journal of surgical research 2008-12, Vol.150 (2), p.159-168
Main Authors: Schaefer, Nico, M.D, Tahara, Kazunori, M.D., Ph.D, Pech, Thomas, M.D, Websky, Martin V, Fujishiro, Jun, M.D., Ph.D, Pantelis, Dimitrios, M.D, Abu-Elmagd, Kareem, M.D., Ph.D, Kalff, Jörg C., M.D, Hirner, Andreas, M.D, Türler, Andreas, M.D
Format: Article
Language:English
Subjects:
acute rejection
Animals
Biological and medical sciences
Gastrointestinal Motility
General aspects
Graft Rejection - enzymology
Graft Rejection - pathology
Graft Rejection - physiopathology
Immunohistochemistry
In Vitro Techniques
inflammation
Inflammation - physiopathology
iNOS
intestinal muscularis propria
intestinal transplantation
Intestine, Small - enzymology
Intestine, Small - pathology
Intestine, Small - physiopathology
Intestine, Small - transplantation
leukocyte infiltrate
Leukocytes - pathology
Leukocytes - physiology
macrophages
Male
Medical sciences
Muscle, Smooth - pathology
Muscle, Smooth - physiopathology
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - antagonists & inhibitors
Nitric Oxide Synthase Type II - metabolism
Rats
Rats, Inbred Lew
RNA, Messenger - metabolism
smooth muscle dysfunction
Surgery
Transplantation, Isogeneic
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Summary:Background Acute rejection in small bowel transplantation is associated with dysmotility. Therefore, host and organ not only face the threat of destructive immunological processes but also the risk of bacterial translocation, endotoxemia, and systemic inflammatory response syndrome. We hypothesized that dysmotility during acute rejection is based on an alloreactive leukocyte infiltrate and coexpression of the kinetically active mediator inducible nitric oxide synthase (iNOS) in the muscularis propria. Materials and methods Allogenic and isogenic rat small bowel transplantation (SBTx; Brown Norway [BN] to Lewis and BN to BN) was performed without immunosuppression. Animals were sacrificed 4 and 7 d after SBTx. Leukocyte infiltration and iNOS protein was investigated by immunohistochemistry and immunohistology. Real-time reverse transcription polymer chain reaction was used to detect iNOS expression. Griess reaction was used to evaluate NO production. Spontaneous, bethanechol-stimulated, and l -N6 -(1-iminoethyl)- l -Lysin-blocked jejunal circular muscle contractions were measured in a standard organ bath in vitro. Results On d 7 after SBTx, allogenic transplanted animals showed significant infiltration with ED-1- and ED-2-positive monocytes and macrophages within the muscularis parallel to the manifestation of acute rejection. Additionally, immunohistochemistry localized iNOS protein in leukocytes within the muscularis. Reverse transcription polymer chain reaction showed a significant increase in iNOS mRNA expression (460-fold) in allogenic transplanted muscularis compared to isogenic transplanted muscularis (2.5-fold). Compared to controls, allogenic grafts showed a 73% decrease in smooth muscle contractility, while isogenic grafts showed only an 8% decrease of contractility on d 7. l -N6 -(1-iminoethyl)- l -Lysin application in vitro significantly improved muscle contractility and decreased NO production. Conclusion The data show that inflammation associated iNOS expression in the intestinal graft muscularis is involved in motoric graft dysfunction during acute rejection.
ISSN:0022-4804
1095-8673
DOI:10.1016/j.jss.2008.01.019