Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Abstract

Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-alpha-tocopherol were all studied over the range of 10(-2) to 10(-7) M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10(-3) M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5 X 10(-5) M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.

Pharmacologic Inhibitors of Tumor Necrosis Factor Production Exert Differential Effects in Lethal Endotoxemia and in Infection with Live Microorganisms in Mice

“…As antag onism of IL-1 increases survival after lethal endotoxemia in mice [7], interference wilh the production of this cytokine may contribute to the effects observed. Chlorpromazine has a wide range of pharmacologic activities, from antipsychotic and antihistaminic actions [32] to inhibition of phospholipase A2 [33]. To what extent these activities contribute to the effects in lethal endotoxemia is not clear.…”

Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

“…Among PLA 2 s, a 85-kDa cytoplasmic PLA 2 (cPLA 2 ) is known to play a critical role in the pathogenesis and progression of inflammation, including endotoxic shock. The protective effects of PLA 2 inhibitors in endotoxic shock (10,11), or reduced septic symptoms in PLA 2 -deficient mice (12,13), indicate that PLA 2 is an essential component in the pathogenesis of endotoxic shock. We have previously shown that Gln protects animals from endotoxic shock through its inhibition of cPLA 2 activity (14), and this activity of Gln was also associated with suppression of asthma in mice (15).…”

Inhibitory Effect of LPS-Induced Tumor Necrosis Factor in Calves Treated with Chlorpromazine or Pentoxifylline.

“…CPZ has a wide range of pharmacological activities, such as the anti-psychotic and anti-histaminic actions and the phospholipase A2-inhibitory properties [1,11]. This protective effect has been associated with more specific inhibition of TNF, unlike DEX [7].…”