Pentamidine blocks the pathophysiologic effects of endotoxemia through inhibition of cytokine release

Pentamidine isethionate, an antiprotozoal agent with therapeutic value against Pneumocystis carinii pneumonia, has been used for over 30 years without a precise understanding of its mechanism of pharmacologic action. We have previously reported that pentamidine has the capacity to inhibit the release of cytokines from macrophages through a post-translational processing event. The present studies were undertaken to assess the ability of pentamidine to modulate the detrimental effects of murine endotoxemia, a disease with a pathophysiology clearly linked to host-produced cytokines. Under conditions where normal B6C3F1 mice succumbed to the lethal effects of endotoxin, mice pretreated with pentamidine were significantly protected from both mortality and loss of thermoregulatory control. The EC50 for protection from mortality by pentamidine was approximately 11.4 mg/kg. These observations correlated with decreased serum levels of tumor necrosis factor (TNF) and interleukin 6. Inhibition of cytokines was not manifested as part of a generalized inhibition of protein synthesis as demonstrated by the lack of significant modulation of serum albumin in pentamidine-treated animals. In addition to decreased serum concentrations of cytokines, lungs isolated from mice treated with both pentamidine and endotoxin exhibited a decreased release of TNF compared to lungs isolated from mice treated with vehicle and endotoxin. The lower levels of TNF released from lung tissue in pentamidine-treated mice correlated with a lesser degree of alveolar deterioration than was observed in vehicle-treated mice. These data indicate that following endotoxin administration, pentamidine has a protective and antiinflammatory role both systemically and in the lung and suggest that inhibition of inflammatory cytokines may be one mechanism operable in the therapeutic activity of the drug against P carinii pneumonia.