p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis.
BACKGROUND
: Microvascular injury and epithelial barrier dysfunction are rate-limiting aspects in radiation enteropathy. This study examined the role of p38 mitogen-activated protein kinase (p38 MAPK) signalling in radiation-induced colitis in an experimental model.


METHODS
: The p38 MAPK inhibitor SB239063 was administered to mice immediately before exposure to 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 (MIP) 2 and cytokine-induced neutrophil chemoattractant (KC)), and albumin leakage were quantified 16 h after irradiation.


RESULTS
: Irradiation induced an increase in leucocyte and platelet recruitment, MPO activity, CXC chemokine levels and intestinal leakage. Inhibition of p38 MAPK by SB239063 decreased radiation-induced leucocyte and platelet recruitment (leucocyte rolling and adhesion by 70 and 90 per cent, both P < 0.001; that of platelets by 70 and 74 per cent, both P < 0.001). It also reduced radiation-provoked increases in colonic MPO activity by 88 per cent (P < 0.001), formation of MIP-2 and KC by 72 and 74 per cent respectively (P = 0.003 and P < 0.001), and intestinal leakage by 81 per cent (P < 0.001).


CONCLUSIONS
: p38 MAPK is an important signalling pathway in radiation-induced colitis.
Mihaescu
A
A
Department of Surgery, Malmö University Hospital, Lund University, 205 02 Malmö, Sweden.
Santen
S
S
Jeppsson
B
B
Thorlacius
H
H
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D018925:Chemokines / Q000096:biosynthesis / Q000378:metabolism; D003092:Colitis / Q000201:enzymology*; D003106:Colon / Q000098:blood supply / Q000378:metabolism / Q000528:radiation effects; D004848:Epithelium; D007958:Leukocyte Count; D007962:Leukocytes / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011832:Radiation Injuries / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology; D014657:Vasculitis / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D018925:Chemokines; D048051:p38 Mitogen-Activated Protein Kinases