期刊
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
卷 2, 期 5, 页码 297-306出版社
HINDAWI LTD
DOI: 10.4161/oxim.2.5.9541
关键词
apoptosis; ASK1; intestinal epithelial cells; JNK; mitochondrial membrane potential; mitogen-activated protein kinases; necrotizing enterocolitis; p38; TNF alpha
类别
资金
- National Institutes of Health [R01 DK61470, R01 DK48498, P01 DK35608, T32 DK07639]
- Shriners Hospital for Children [8580]
Background. Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)alpha is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNF alpha/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. Results: We found (a) abundant tissue TNF alpha and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNF alpha/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNF alpha-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNF alpha-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-rho degrees) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNF alpha/ROS-induced intestinal epithelial cell injury; (e) TNF alpha induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNF alpha/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNF alpha and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-rho degrees) intestinal epithelial cells were used to determine the effects of TNF alpha on mitochondrial function. Conclusions: Our findings suggest that TNF alpha induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC.
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