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[摘要]：Hypohalous acids are generated by activated leucocytes, via the formation of H2O2 and the release of peroxidase enzymes (myelo-peroxidase and eosinophil peroxidase). These species are important bactericidal agents, but HOCl (hypochlorous acid) and HOBr (hypobromous acid) have also been implicated in tissue damage in a number of inflammatory diseases. HOSCN (hypothiocyanous acid; cyanosulfenic acid) is a milder, more thiol-specific, oxidant than HOCl or HOBr and as such may be a more potent inducer of cellular dysfuntion due to selective targeting of critical thiol residues on proteins. In the present study, HOCl and HOBr are shown to react rapidly with macrophage (J774A.1) cells, resulting in a greater extent of cell lysis compared with HOSCN. However, HOSCN induces apoptosis and necrosis with greater efficacy, and at lower concentrations, than HOCl or HOBr. Apoptosis occurs in conjunction with an increased release of cytosol, but no associated increase in caspase activity. Similarly, apoptosis is observed on treating the cells in the presence of a caspase inhibitor, suggesting that it is mediated by a caspase-independent pathway. HOSCN oxidized protien thiols more efficiently than either HOCl or HOBr. The greater efficacy of HOSCN in inducing apoptosis is attributed to selective damage to critical mitochondrial membrane protien thiol groups, resulting in increased permeability and subsequent leakage of cytochrome c into the cytosol. This induction of damage by HOSCN may be of critical importance in people with elevated levels of SCN-(thiocyanate ions) arising from cigarette smoking, and plays a role in the pathologies associated with this biological insult. |
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