期刊
JOURNAL OF SURGICAL RESEARCH
卷 169, 期 1, 页码 E27-E36出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jss.2011.01.043
关键词
IL-1 beta; IL-6; MAPKAP Kinase 2; MK2; TNF-alpha; abdominal adhesion
类别
资金
- NIH (National Institutes of Health
- Bethesda, MD, USA) [K25HL074968]
- Purdue Research Foundation
- NIH [GM077229]
- Moerae Matrix
- NSF
Background. Abdominal adhesions are a common side effect of surgical procedures with complications including infertility, chronic pain, and bowel obstruction, which may lead to the need for surgical lyses of the adhesions. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been implicated in several diseases, involving inflammation and fibrosis. Thus, the development of a cell-penetrating peptide (CPP) that modulates MK2 activity may confer therapeutic benefit after abdominal surgery in general and more specifically after bowel anastomosis. Methods. This study evaluated the function of a CPP inhibitor of MK2 in human mesothelial cells and in a rat bowel anastomosis model. To determine IC50 and basic specificity, kinase inhibition was performed using a radiometric assay. Enzyme-linked immunoassay (ELISA) was used to evaluate interleukin-6 (IL-6) expression in response to IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) stimulation in vitro to validate MK2 kinase inhibition. Following bowel anastomosis (10 rats for each control and treatment at 4 and 10 d), the rats were evaluated for weight loss, normal healing (colonic burst strength and hydroxyproline content at the anastomosis), and number and density of adhesions. Results. The IC50 of the MK2 inhibitor peptide (22 mu M) was similar to that of the nonspecific small molecule rottlerin (IC50 = 5 mu M). The MK2 inhibitor peptide was effective at suppressing IL-1 beta and TNF-alpha stimulated IL-6 expression in mesothelial cells. In vivo, the MK2 inhibitor peptide was effective at suppressing both the density and number of adhesions formed as a result of bowel an anastamosis. Importantly, the peptide had no negative effect on normal healing. Conclusions. In conclusion, the peptide inhibitor of MK2, MMI-0100, has the potential to significantly reduce inflammation through suppression of inflammatory cytokine expression and showed promise as a therapeutic for abdominal adhesions. (C) 2011 Elsevier Inc. All rights reserved.
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