Abstract |
Tumor necrosis factor ( TNF)-alpha plays an important role in the mediation of reperfusion-induced tissue injury and lethality. Here, we assessed the effects of PKF242-484 and PKF241-466, two dual inhibitors of TNF-alpha converting enzyme (TACE) and matrix metalloproteinases ( MMPs), in a model of ischemia and reperfusion injury in mice. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose-dependent reduction of TNF-alpha concentrations in serum. Both drugs delayed and partially inhibited the reperfusion-associated lethality. Maximal inhibition occurred at 10 mg/kg. At this dose, both inhibitors reduced reperfusion-associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and hemorrhage. In addition, the compounds markedly reduced production of TNF-alpha, CXCL1 (keratinocyte-derived chemokine, KC) and CCL2 ( monocyte chemoattractant protein-1, MCP-1) in intestine and lungs of animals which underwent reperfusion. FN-439, an inhibitor of MMPs which possesses no effect on TACE, decreased MMP-2 and MMP-3 activity, but failed to affect tissue injury, TNF-alpha production or lethality. Thus, combined TACE and MMP inhibitors might be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. The effects of these drugs on TNF-alpha production appear to be more relevant than their effects on MMP inhibition.
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Authors | Danielle G Souza, Flávio Lopes Ferreira, Caio T Fagundes, Flávio A Amaral, Angélica T Vieira, Rodolfo Assis Lisboa, Marcus Vinícius Melo Andrade, Alexandre Trifilieff, Mauro M Teixeira |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 571
Issue 1
Pg. 72-80
(Sep 24 2007)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 17619015
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
- Chemokines
- Cytokines
- Hydroxamic Acids
- Matrix Metalloproteinase Inhibitors
- N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
- N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-phenylsuccinamide
- Oligopeptides
- Tumor Necrosis Factor-alpha
- Interleukin-10
- ADAM Proteins
- Matrix Metalloproteinases
- ADAM17 Protein
- Adam17 protein, mouse
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Topics |
- ADAM Proteins
(antagonists & inhibitors, metabolism)
- ADAM17 Protein
- Animals
- Capillary Permeability
(drug effects)
- Chemokines
(blood, metabolism)
- Cytokines
(blood, metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Hydroxamic Acids
(administration & dosage, pharmacology)
- Interleukin-10
(blood, metabolism)
- Intestinal Mucosa
(metabolism)
- Intestines
(blood supply, drug effects)
- Lung
(drug effects, metabolism, pathology)
- Male
- Matrix Metalloproteinase Inhibitors
- Matrix Metalloproteinases
(metabolism)
- Mice
- Mice, Inbred C57BL
- Oligopeptides
(administration & dosage, pharmacology)
- Reperfusion Injury
(metabolism, mortality, prevention & control)
- Survival Rate
- Tumor Necrosis Factor-alpha
(blood, metabolism)
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