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Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction.

AbstractBACKGROUND:
Radiotherapy is important in the management of pelvic malignancies, but radiation-induced intestinal damage is a dose-limiting factor. Microvascular injury and epithelial barrier dysfunction are considered to be rate-limiting aspects in radiation-induced enteropathy. This study investigated the role of Rho kinase signalling in radiation-induced inflammation and intestinal barrier dysfunction.
METHODS:
The specific Rho kinase inhibitor Y-27632 (1 and 10 mg/kg) was given to C57BL/6J mice before challenge with 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractant), and intestinal leakage were quantified after 16 h.
RESULTS:
Radiation increased leucocyte and platelet recruitment, MPO activity, CXC chemokine production and intestinal leakage. Y-27632 significantly reduced radiation-induced leucocyte rolling and abolished adhesion; it also decreased platelet rolling and adhesion by 55 and 74 per cent respectively (P < 0·050). Inhibition of Rho kinase signalling significantly decreased radiation-provoked formation of CXC chemokines, MPO activity by 52 per cent, and intestinal leakage by 67 per cent (P < 0·050).
CONCLUSION:
Rho kinase activity constitutes an important signalling mechanism in radiation-induced inflammation and intestinal barrier dysfunction.
AuthorsA Mihaescu, S Santén, B Jeppsson, H Thorlacius
JournalThe British journal of surgery (Br J Surg) Vol. 98 Issue 1 Pg. 124-31 (Jan 2011) ISSN: 1365-2168 [Electronic] England
PMID20882561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
Chemical References
  • Amides
  • Biomarkers
  • Chemokines
  • Enzyme Inhibitors
  • Pyridines
  • Y 27632
  • Peroxidase
  • rho-Associated Kinases
Topics
  • Amides (pharmacology)
  • Animals
  • Biomarkers
  • Chemokines (metabolism)
  • Colitis (enzymology)
  • Colon (radiation effects)
  • Enzyme Inhibitors (pharmacology)
  • Enzyme-Linked Immunosorbent Assay
  • Leukocytes (enzymology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Permeability
  • Peroxidase (metabolism)
  • Platelet Activation (physiology)
  • Pyridines (pharmacology)
  • Radiation Injuries, Experimental (enzymology)
  • Signal Transduction (physiology)
  • rho-Associated Kinases (antagonists & inhibitors, physiology)

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