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Effects of chlorpromazine on PMN-mediated activities in vivo and in vitro
R Bertini1, J M Wang, M Mengozzi
1Istituto di Ricerche Farmacologiche Mario Negri Via Eritrea, Milan, Italy.
Abstract:
Polymorphonuclear neutrophils (PMN) play a central role in the acute inflammatory response and functions associated with phagocytosis and bacterial killing, including lysosomal enzyme release and superoxide anion (O2-) generation, are also implicated in tissue injury. We have studied the modulation by chlorpromazine (CPZ) on the effects of lipopolisaccharide (LPS) in vivo in mice. Pretreatment with CPZ (4 mg/kg) and, to lesser extent, promethazine, inhibited LPS-induced hypoferraemia and lethality in mice. We have also observed that CPZ (1-15 microns) inhibited lactoferrin release by PMN in vitro, suggesting that this effect could be responsible for the inhibition of hypoferraemia. We have also evaluated the effect of CPZ on other PMN functions implicated in tissue damage and inflammation, chemotaxis and O2- production. CPZ inhibited both activities, although it had chemokinetic activity per se. These data indicate that CPZ is a modular of PMN functions in vivo and in vitro and this effect could be directly implicated in the protective action of CPZ against endotoxic shock.
Insights
Chlorpromazine (CPZ) effectively reduces lethal effects of lipopolysaccharide (LPS) in mice by modulating polymorphonuclear neutrophil (PMN) functions. CPZ inhibits PMN-mediated inflammation and tissue damage, offering protection against endotoxic shock.
Area of Science:
- Immunology
- Pharmacology
Background:
- Polymorphonuclear neutrophils (PMNs) are key mediators of acute inflammation and tissue injury.
- Their functions, including phagocytosis, bacterial killing, and release of inflammatory mediators, contribute to both defense and damage.
- Lipopolysaccharide (LPS) is a potent inducer of inflammatory responses and endotoxic shock.
Purpose of the Study:
- To investigate the modulatory effects of chlorpromazine (CPZ) on lipopolysaccharide (LPS)-induced inflammatory responses in vivo and in vitro.
- To determine if CPZ's protective effects against LPS are linked to its impact on polymorphonuclear neutrophil (PMN) functions.
Main Methods:
- In vivo studies in mice involving CPZ pretreatment followed by LPS challenge to assess hypoferremia and lethality.
- In vitro experiments evaluating CPZ's effects on lactoferrin release, chemotaxis, and superoxide anion (O2-) production by PMNs.
Main Results:
- CPZ pretreatment significantly inhibited LPS-induced hypoferremia and lethality in mice.
- CPZ demonstrated inhibitory effects on lactoferrin release, chemotaxis, and O2- production by PMNs in vitro.
- CPZ exhibited chemokinetic activity on its own.
Conclusions:
- Chlorpromazine acts as a modulator of key polymorphonuclear neutrophil functions, both in vivo and in vitro.
- These modulatory effects on PMN functions likely contribute to the observed protective action of CPZ against LPS-induced endotoxic shock.