Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice.
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.
Souza
Danielle G
DG
Immunopharmacology, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Ferreira
Flávio Lopes
FL
Fagundes
Caio T
CT
Amaral
Flávio A
FA
Vieira
Angélica T
AT
Lisboa
Rodolfo Assis
RA
Andrade
Marcus Vinícius Melo
MV
Trifilieff
Alexandre
A
Teixeira
Mauro M
MM
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply* / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D018925:Chemokines; D016207:Cytokines; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C455823:N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide; C460060:N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-phenylsuccinamide; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse