Sulphonamides as Anti-Inflammatory Agents: Old Drugs for New Therapeutic Strategies in Neutrophilic Inflammation?

Abstract

1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (alpha 1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of alpha 1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent alpha 1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the alpha 1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation.

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…Structure-activity relationships have also been identified for sulfasalazine, which suggests the importance of the azo link between S-aminosalicylic acid and sulfapyridine in the neutrophil-inhibiting effect, rather than release of S-aminosalicylic acid (274). Scavenging of HOCl by sulfapyridine but not sulfamethoxazole has also been reported (289).…”

Chemoattractant-induced release of elastase by lipopolysaccharide (LPS)-primed neutrophils; inhibitory effect of the anti-inflammatory drug nimesulide

“…Owing to the ability, shown here, to reduce neutrophil secretion, nimesulide can limit the local burden of azurophil granule-derived proteases such as elastase at tissue sites of inflammation. Thus, taking into account the drug's ability to rescue a 1 -AT from inactivation by neutrophils [7,8] and the drug's anti-inflammatory properties [26], nimesulide can be considered a relevant candidate to counteract elastase-anti-elastase imbalances and, in turn, elastase-dependent histotoxicity at sites of inflammation.…”

“…Neutrophils were isolated by dextran sedimentation and subsequent centrifugation on a Ficoll-Hypaque density gradient, as previously described [8]. Contaminating erythrocytes were removed by hypotonic lysis [8].…”

“…We have recently found that, among various drugs, the methane-sulphonamide anti-inflammatory drug nimesulide is capable of rescuing a 1 -AT from neutrophil-promoted inactivation [7,8]. Therefore, this drug can counteract the elastase-anti-elastase imbalance by rescuing a 1 -AT, in turn favouring the control of released elastase by its natural inhibitor [7,8].…”

“…Therefore, this drug can counteract the elastase-anti-elastase imbalance by rescuing a 1 -AT, in turn favouring the control of released elastase by its natural inhibitor [7,8]. The possibility of influencing the elastase-anti-elastase imbalance by limiting the release of the enzyme is also an attractive option.…”