Role of eicosanoids in staphylococcal alpha-toxin-induced lung injury in the rat.
We investigated the role of arachidonic acid-derived eicosanoids in staphylococcal alpha-toxin (alpha-T)-induced lung injury. Bolus injection of 200 and 500 micrograms alpha-T into isolated perfused rat lungs resulted in increased pulmonary perfusion pressure followed by lung weight gain. Inhibition of pressure change with papaverine (10(-4) M) failed to abolish lung edema. Furthermore, alpha-T increased the permeability-surface area product in papaverine-treated lungs and caused marked endothelial cell injury and interstitial edema as documented by electron microscopy. alpha-T dose dependently increased lung tissue thromboxane B2 (TxB2) levels and leukotriene C4 levels. In lungs given 0, 200, and 500 micrograms of alpha-T, TxB2 (in micrograms/g wet lung) values were 16.3 +/- 2.8, 25.0 +/- 3.0, and 54.2 +/- 6.2; and leukotriene C4 values were 4.6 +/- 1.1, 6.7 +/- 1.2, and 22.1 +/- 3.8, respectively. Inhibition of cyclooxygenase enzyme with indomethacin (10(-5) M) or lipoxygenase enzyme with 2(12-hydroxydodeca-5,10-dinyl)-3,5,6-trimethyl-1,4-benzoq uin one (AA861, 10(-5) M) attenuated the vasoconstriction and prevented lung edema due to low dose (200 micrograms) but not high dose (500 micrograms) alpha-T. The protective effect of these inhibitors on lung edema is in part due to decreases in alpha-T-stimulated venoconstriction because alpha-T-induced increase in lung microvascular pressure was attenuated by indomethacin and AA861 pretreatment. We conclude that both eicosanoid-dependent and eicosanoid-independent mechanisms contribute to alpha-T-induced lung edema in the rat.
Chang
S W
SW
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Czartolomna
J
J
Voelkel
N F
NF
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015777:Eicosanoids / Q000032:analysis / Q000502:physiology*; D006460:Hemolysin Proteins; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains; D013210:Staphylococcus
D001427:Bacterial Toxins; D015777:Eicosanoids; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin