Expression of matrix metalloproteinases and tissue inhibitor metalloproteinases increases in X-irradiated rat ileum despite the disappearance of CD8a T cells.
OBJECTIVE
To investigate their expression and activity in the rat ileum after exposure to ionizing radiation along with that of the cellular effectors and molecular mediators involved in the regulation of MMPs.


METHODS
Rats were exposed to a single 10-Gy dose of X-rays delivered to the abdomen. A combination of methods, such as zymography, immunohistochemistry and real time reverse transcriptase-polymerase chain reaction, were used to localize and quantify MMPs and the molecules involved in MMP activating and inhibitory pathways (plasmin/plasminogen, TIMPs), CD8+, as well as inflammatory (interleukin (IL)-1beta, IL-8, tumor necrosis factor-alpha, TNF-alpha) and fibrogenic mediators (transforming growth factor-beta1-3) within ileal tissue at 1, 3, and 7 d after irradiation.


RESULTS
A marked increase in MMP-2 and -14 mRNA and protein levels associated with an increased activity of MMP-2 was observed in irradiated ileal tissue. MMP-2 and -14 expression was mainly observed in inflammatory, epithelial, and mesenchymal cells, whereas a slight increase in MMP-3 expression was detected in the few infiltrating macrophages at d 1 after irradiation. Conversely, MMP-1, -7, and -9 mRNA levels were not found to be affected by abdominal irradiation. Irradiation was found to induce disappearance of CD8+ cells. Furthermore, we have observed that TNF-alpha and IL-1beta protein levels increased 6 h after irradiation, whereas those of IL-8 only increased after 3 d and was concomitant with neutrophil infiltration. In addition, the expressions of molecules involved in MMP activating and inhibitory pathways (urokinase-type plasminogen activator and tissue-type plasminogen activator; TIMP-1, TIMP-2, and plasminogen activator-inhibitor-1) were found to be increased after abdominal irradiation.


CONCLUSIONS
This study showed that abdominal irradiation induces an acute remodeling of the ileum associated with an increased expression of MMPs and TIMPs that do not involve CD8+ T cells but involve mesenchymal and epithelial cells, although to a lesser extent, and probably even soluble inflammatory and fibrogenic mediators.
Strup-Perrot
Carine
C
Laboratoire d'étude des pathologies Radio-induites, SRBE/DRPH, Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses 92262, France. carine.strup@irsn.fr
Vozenin-Brotons
Marie-Catherine
MC
Vandamme
Marie
M
Linard
Christine
C
Mathé
Denis
D
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D004789:Enzyme Activation; D007082:Ileum / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014965:X-Rays
D016827:CD8 Antigens; C431698:CD8alpha antigen; D007527:Isoenzymes; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2