Endothelin-1 and thromboxane A2 increase pulmonary vascular resistance in granulocyte-mediated lung injury.
OBJECTIVE
To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature.


METHODS
Prospective experimental study in rabbits.


METHODS
Experimental laboratory in a university teaching hospital.


METHODS
Thirty adult rabbits.


METHODS
The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution.


RESULTS
The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase.


CONCLUSIONS
Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.
Schmeck
J
J
Department of Anesthesiology and Operative Intensive Care, University of Heidelberg, Mannheim, Germany.
Janzen
R
R
Münter
K
K
Neuhof
H
H
Koch
T
T
Janzen
R
R
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010477:Perfusion / Q000379:methods; D010666:Phenylpropionates / Q000494:pharmacology; D011446:Prospective Studies; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D013928:Thromboxane A2 / Q000032:analysis / Q000502:physiology*; D013929:Thromboxane B2 / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D004008:Diclofenac; C107831:darusentan; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine