herbimycin and Reperfusion-Injury

The role of C-Jun N-terminal Kinase (c-Jun Kinase) in apoptosis is unclear. It is likely that c-Jun Kinase activation is cell type and stimulus dependent. c-Jun Kinase promotes tumor necrosis factor (TNF)-alpha mediated apoptosis in nuclear factor (NF)-KB deficient cells. Minimal NF-KB expression may be enough to abrogate c-Jun Kinase-mediated apoptosis during reperfusion injury.. Forty Sprague-Dawley rats underwent hemorrhagic ischemia and reperfusion. Twenty experimental animals were treated with the NF-KB inhibitor herbimycin A, and 20 control animals underwent only hemorrhage and reperfusion. Serum TNF-alpha and c-Jun Kinase levels were measured. Adrenal, kidney, liver, ileum, colon, and skeletal muscle tissues were evaluated for apoptosis by hematoxylin and eosin staining.. TNF-alpha levels were 400 pg/mL (control) and 385 pg/mL (experimental) during ischemia (p=0.46), increased in controls to 450 pg/mL, and decreased in the experimental arm to 175 pg/mL (p=0.028). c-Jun Kinase levels were 1,525 pg/mL (control) and 1,475 pg/mL (experimental) during ischemia (p=0.35) and increased to 5,250 pg/mL (control) and 5,000 pg/mL (experimental) after reperfusion (p=0.26). In control animals, necrosis was seen in kidney, adrenal, and liver specimens. Compared with controls, experimental animals had average tissue hemorrhage scores of less than 1 (p < 0.001), with no necrosis seen in any experimental arm (p<0.001).. During inhibition of NF-KB, c-Jun Kinase levels remained unchanged. But no increase in cell death or necrosis was seen in tissue samples. Antiapoptotic effects were unchanged with the down-regulation of NF-KB. Minimal expression of NF-KB may be enough to protect against apoptosis in reperfusion injury.

Topics: Animals; Apoptosis; Benzoquinones; Enzyme Inhibitors; Female; JNK Mitogen-Activated Protein Kinases; Lactams, Macrocyclic; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rifabutin; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Benzoquinones; Cell Survival; Cells, Cultured; Enzyme Inhibitors; Glutathione; Hepatocytes; Ischemia; Lactams, Macrocyclic; Liver; Male; Malondialdehyde; Quinones; Rats; Rats, Wistar; Reperfusion Injury; Rifabutin; Superoxides

To determine whether pharmacological induction of heat shock proteins (HSPs) by herbimycin-A (a tyrosine-kinase inhibitor) would protect against neutrophil-mediated lung injury in an animal model of lower torso ischaemia-reperfusion.. Sprague-Dawley rats were randomised into three groups: the control group underwent midline laparotomy only; the ischaemia-reperfusion (IR) group underwent laparotomy and clamping of the infrarenal abdominal aorta for 30 min followed by 2 h of reperfusion; the third group (HerbIR) was pretreated with herbimycin-A 18 h prior to IR insult. Wet to dry lung weight ratio (W:D), bronchoalveolar lavage protein concentration (BALprot), tissue myeloperoxidase activity (MPO) and bronchoalveolar lavage neutrophil count (BALPMN) were measured. Heat shock protein 72 (HSP72) expression in lung, intestine, mesentery and liver was measured using Western immunoblotting.. IR resulted in acute lung injury with tissue oedema (W:D) and neutrophil infiltration (PMO, BALPMN). Herbimycin-A, in vivo, induced HSP expression and attenuated neutrophil infiltration (MPO, BALPMN).. These data indicate that herbimycin-A protects against ischaemia-reperfusion induced pulmonary neutrophil infiltration, possibly by increasing the expression of heat shock proteins.

Topics: Animals; Benzoquinones; Blotting, Western; Bronchoalveolar Lavage; Heat-Shock Proteins; Heat-Shock Response; HSP72 Heat-Shock Proteins; Lactams, Macrocyclic; Lung; Male; Neutrophils; Protein-Tyrosine Kinases; Quinones; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rifabutin