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. Platelet-neutrophil adherence was analysed by flow cytometry of the lung vascular flush. The effect of fMLP (10(-6) 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 -4.9 to -63.9 mg, 95% CI of mean difference -99.5 to -10.5 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.


CONCLUSIONS
The neutrophil-platelet interaction is of critical importance in the modulation of pulmonary haemodynamics via thromboxane.
Song
C
C
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan 980-8575.
Suzuki
S
S
Kubo
H
H
Chida
M
M
Hoshikawa
Y
Y
Tabata
T
T
Kondo
T
T
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D000077407:Cilostazol; D004731:Endotoxins / Q000494:pharmacology; D005434:Flow Cytometry; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000502:physiology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism
D004731:Endotoxins; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D013928:Thromboxane A2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000077407:Cilostazol; D001241:Aspirin