The present data show, for the first time, that the melanocortin ACTH-(1-24) suppresses the NF-kappaB-dependent systemic inflammatory response triggered by hemorrhage, and reverses shock condition, by brain activation (in real-time) of the "cholinergic anti-inflammatory pathway", this pathway seeming to be melanocortin-dependent.

OPG (osteoprotegerin) has been suggested to have an important role in atherogenesis and vascular calcification. In the present study, we have investigated serum OPG and RANKL (receptor activator of nuclear factor kappaB ligand) concentrations in patients with ST elevation AMI (acute myocardial infarction) and established CAD (coronary artery disease). OPG and RANKL were measured in 58 male patients hospitalized in the coronary care unit with ST elevation AMI, in 52 asymptomatic male patients with an established diagnosis of CAD and in 52 healthy male controls. These last two groups were matched with the AMI patients for age and body mass index. OPG was significantly (P<0.05) higher in patients with AMI at 1 h after AMI (8.04+/-4.86 pmol/l) than in both patients with established CAD (4.92+/-1.65 pmol/l) and healthy subjects (3.15+/-1.01 pmol/l). Subjects with established CAD had significantly (P<0.05) increased OPG levels compared with controls. RANKL levels in patients with established CAD (0.02+/-0.05 pmol/l) and with AMI (0.11+/-0.4 pmol/l) were significantly (P<0.05) lower compared with controls (0.32+/-0.35 pmol/l). In the AMI group, OPG decreased significantly (P<0.05) at 1 and 4 weeks after infarction (8.04+/-4.86 compared with 6.38+/-3.87 and 6.55+/-2.6 pmol/l respectively), but OPG levels, either at 1 h or 1-4 weeks after AMI, remained significantly (P<0.05) higher compared with established CAD (4.92+/-1.65 pmol/l) and controls (3.15+/-1.01 pmol/l). Our data show for the first time that OPG levels are increased in ST elevation AMI within 1 h of infarction. Whether the increase in OPG is a consequence or a causal factor of plaque destabilization deserves further investigation.

SUMMARY:Nuclear factor (NF)-B plays a central role in acute pancreatitis. We studied cerulein (CER)-induced pancreatitis in NF-B knockout (KO) mice. NF-B KO mice and normal control littermate wild-type (WT) mice were given four hyperstimulating doses of cerulein every hour to elicit secreatagogue-induced pancreatitis. Malonildialdehyde activity, glutathione levels, myeloperoxidase activity, TNF-␣, and NF-B binding activity and its inhibitory protein IB␣ were studied in the pancreas. Furthermore, we measured plasma lipase and amylase and the histological damage. KO mice had reduced malonildialdehyde levels (WT ϩ CER ϭ 4.083 Ϯ 0.95 mol/g; KO ϩ CER ϭ 1.513 Ϯ 0.63 mol/g), decreased myeloperoxidase activity (WT ϩ CER ϭ 19.3 Ϯ 2.39 mU/g; KO ϩ CER ϭ 10.21 Ϯ 2.05 mU/g), increased glutathione levels (WT ϩ CER 6.22 Ϯ 2.46 mol/g; KO ϩ CER ϭ 15. 516 Ϯ 2.92 mol/g), and reduced serum levels of amylase (WT ϩ CER ϭ 2519 Ϯ 656.9 U/L; KO ϩ CER ϭ 916 Ϯ 280.4 U/L) and lipase (WT ϩ CER ϭ 1420 Ϯ 170 U/L; KO ϩ CER ϭ 861 Ϯ 172. 3 U/L). KO mice showed reduced pancreatic NF-B activation, decreased TNF-␣ tissue content, and reduced histologic alterations. Our data suggest that KO mice have an attenuated cerulein-induced pancreatitis and help to define the possible interaction between NF-B activation and oxidative stress in this deleterious event. (Lab Invest 2003, 83:1723-1732.

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