| Autor: |
Piero Del Soldato, Antonio Morelli, Giuseppe Cirino, G. Coata, Stefano Fiorucci, Elisabetta Antonelli, E. Distrutti, G. D. Renzo, B. Federici, Olivia Morelli, Luca Santucci |
| Rok vydání: |
1999 |
| Předmět: |
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| Zdroj: |
Alimentary Pharmacology & Therapeutics. 13:421-435 |
| ISSN: |
0269-2813 |
| DOI: |
10.1046/j.1365-2036.1999.00442.x |
| Popis: |
Background : Nitric oxide (NO)-releasing NSAIDs are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. Although it has been demonstrated that NO-NSAIDs spare gastric mucosal blood flow, molecular determinants involved in this effect are unknown. Aim : To investigate the effect of aspirin, naproxen and flurbiprofen, and their NO-derivatives, on gastric apoptosis and endothelial cell damage induced by tumour necrosis factor-α (TNFα). In other systems, TNFα-induced apoptosis is mediated by caspases, a growing family of cysteine proteases similar to the IL-1β converting enzyme (ICE), and so we have investigated whether NO-NSAIDs modulate ICE-like endopeptidases. Methods : Rats were treated orally with aspirin, naproxen and flurbiprofen, or their NO-releasing derivatives in equimolar doses, and were killed 3 h later to assess mucosal damage and caspase activity. Endothelial cells (HUVECs) were obtained from human umbilical cord by enzymatic digestion. Caspase 1 and 3 activities were measured by a fluorimetric assay using selective peptides as substrates and inhibitors. Apoptosis was quantified by ELISA specific for histone-associated DNA fragments and by the terminal transferase nick-end translation method (TUNEL). Results : In vivo NSAID administration caused a time-dependent increase in gastric mucosal damage and caspase activity. NCX-4016, NO-naproxen and NO-flurbiprofen did not cause any mucosal damage and prevented cysteine protease activation. NSAIDs and NO-NSAIDs stimulated TNFα release. Exposure to TNFα resulted in a time- and concentration-dependent HUVEC apoptosis, an effect that was prevented by pretreating the cells with NCX-4016, NO-naproxen, NO-flurbiprofen, SNP or Z-VAD.FMK, a pan-caspase inhibitor. The activation of ICE-like cysteine proteases was required to mediate TNFα-induced apoptosis of HUVECs. Exogenous NO donors inhibited TNFα-induced cysteine protease activation. Inhibition of caspase activity was due to S-nitrosylation of ICE/CPP32-like proteases. NO-NSAIDs prevented IL-1β release from endotoxin-stimulated macrophages. Conclusions : NO-releasing NSAIDs are a new class of non-peptide caspase inhibitors. Inhibition of ICE-like cysteine proteases prevents endothelial cell damage induced by pro-inflammatory agents and might contribute to the gastro-protective effects of NO-NSAIDs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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