AIRWAY BIOLOGY Effects of antiplatelet agents on pulmonary haemodynamic response to fMLP in endotoxin primed rats

Background: The interaction between neutrophils and platelets may be important in the modulation of pulmonary haemodynamics under systemic inflammatory conditions. A study was undertaken to examine whether antiplatelet agents inhibit platelet-neutrophil adherence and ameliorate the pulmonary haemodynamic response to fMLP by inhibiting thromboxane release in endotoxin primed lungs. fMLP stimulates neutrophils but not platelets; however, thromboxane synthesis in neutrophils is very low. Methods: Rats were pretreated with either cilostazol (300 mg/kg) or aspirin (50 mg/kg) before endotoxin priming (5 mg/kg). Platelets in the lung were identified by fluorescent immunohistochemistry. Plateletneutrophil adherence was analysed by flow cytometry of the lung vascular flush. The effect of fMLP (10 M) on thromboxane release, lung weight (an indicator of pulmonary vasoconstriction), and lung filtration coefficient was determined in an isolated lung system perfused at a constant pressure difference. Results: Endotoxin induced platelet accumulation and platelet-neutrophil adherence in the lung capillary were completely inhibited by cilostazol and aspirin while neutrophil recruitment was not affected. The fMLP challenge caused a significant increase in thromboxane B2 levels in endotoxin primed lungs. The fMLP induced decrease in lung weight was enhanced by endotoxin priming (from 24.9 to 263.9 mg, 95% CI of mean difference 299.5 to 210.5 mg, p,0.05). The fMLP induced increase in the lung filtration coefficient was also enhanced by endotoxin priming (from 0.63 to 2.40 mg/min/cm H2O/g, 95% CI of mean difference 1.17 to 2.37 mg/min/cm H2O/g, p,0.05). Treatment with cilostazol and aspirin completely inhibited the enhanced pulmonary haemodynamic response to fMLP. Conclusion: The neutrophil–platelet interaction is of critical importance in the modulation of pulmonary haemodynamics via thromboxane.