title: Peptide inhibitors of MK2 show promise for inhibition of abdominal adhesions.
abstract: 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-1β and tumor necrosis factor-α (TNF-α) 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 μM) was similar to that of the nonspecific small molecule rottlerin (IC50 = 5 μM). The MK2 inhibitor peptide was effective at suppressing IL-1β and TNF-α 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.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907-2032, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ward
authors.forename: Sandra
authors.initials: S
authors.lastname: Kavalukas
authors.forename: Jamie
authors.initials: J
authors.lastname: Brugnano
authors.forename: Adrian
authors.initials: A
authors.lastname: Barbul
authors.forename: Alyssa
authors.initials: A
authors.lastname: Panitch
mesh_terms: D000005:Abdomen / Q000601:surgery*; D000818:Animals; D057846:Cell-Penetrating Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D023421:Models, Animal; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D013997:Time Factors; D000267:Tissue Adhesions / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D057846:Cell-Penetrating Peptides; D006909:Hydroxyproline; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2