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


CONCLUSIONS
Rho kinase activity constitutes an important signalling mechanism in radiation-induced inflammation and intestinal barrier dysfunction.
Mihaescu
A
A
Department of Surgery, Malmö University Hospital, Lund University, 205 02 Malmö, Sweden.
Santén
S
S
Jeppsson
B
B
Thorlacius
H
H
D000577:Amides / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D018925:Chemokines / Q000378:metabolism; D003092:Colitis / Q000201:enzymology*; D003106:Colon / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000577:Amides; D015415:Biomarkers; D018925:Chemokines; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D009195:Peroxidase; D054460:rho-Associated Kinases