JNK (c-Jun NH2 terminal kinase) and p38 during ischemia reperfusion injury in the small intestine.
BACKGROUND
In small intestinal ischemia reperfusion injury, we investigated the pathophysiological role of c-Jun NH2 terminal kinase (JNK) and p38 in order to determine whether the dual inhibition of JNK and p38 was beneficial.


METHODS
Ischemia reperfusion injury was induced by clamping the superior mesenteric artery for 30 min in Wistar male rats. The inhibition of JNK and p38 was achieved with LL-Z1640-2 as a novel JNK and p38 dual inhibitor in vivo. Between the non-treatment group (Control group) and the LL-Z1640-2 treatment group (LL-Z group), the following findings were compared; histological damage by hematoxylin and eosin (H. E.) staining, JNK and p38 activation by a kinase assay, the localization of apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, the localization of activated JNK and activated p38 based on immunohistochemistry.


RESULTS
The activation of JNK and p38 increased remarkably after reperfusion according to a kinase assay. In immunohistochemistry for activated JNK and activated p38, a remarkable degree of positive staining was revealed in the nucleus of the detached epithelial cells from the tip of villi after reperfusion. In addition, many TUNEL positive cells were observed in the detached epithelial cells where JNK and p38 were activated. Pretreatment of LL-Z1640-2 inhibited the activation of JNK and p38, and also significantly improved the histological damage.


CONCLUSIONS
These results suggest that JNK and p38 both play a key role during small intestinal ischemia reperfusion injury through a proapoptotic action on the tip of villi.
Murayama
Takaya
T
Department of Surgery, Keio University School of Medicine, and Department of Pathology, Saiseikai Central Hospital, Tokyo, Japan.
Tanabe
Minoru
M
Matsuda
Satoshi
S
Shimazu
Motohide
M
Kamei
Shusaku
S
Wakabayashi
Go
G
Kawachi
Shigeyuki
S
Matsumoto
Kenji
K
Yamazaki
Kazuto
K
Matsumoto
Koshi
K
Koyasu
Shigeo
S
Kitajima
Masaki
M
D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008871:Microvilli / Q000201:enzymology / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D023421:Models, Animal; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases