SULFONAMIDES AS ANTIINFLAMMATORY AGENTS - OLD DRUGS FOR NEW THERAPEUTIC STRATEGIES IN NEUTROPHILIC INFLAMMATION

1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is p resently thought to involve proteinases and oxidants, primarily hypoch lorous acid (HOCl). This oxidant is also capable of inactivating the s pecific inhibitor of neutrophil elastase (alpha(1)-antitrypsin), there by favouring digestion of the connective matrix. 2. In the present wor k, we found that sulphanilamide and some sulphanilamide-related anti-i nflammatory drugs such as dapsone, nimesulide and sulphapyridine reduc e the availability of HOCl in the extracellular microenvironment of ac tivated neutrophils and prevent the inactivation of alpha(1)-antitryps in by these cells in a dose-dependent manner. The ability of each drug to prevent alpha(1)-antitrypsin from inactivation by neutrophils corr elates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs wer e completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to red uce the bioavailability of neutrophil-derived HOCl and, in turn, to fa vour the alpha(1)-antitrypsin-dependent control of neutrophil elastoly tic activity. These drugs appear as a well-defined group of agents whi ch are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starling point for the development of new compounds in order to plan rational therapeutic st rategies for controlling tissue injury during neutrophilic inflammatio n.