Impact of arachidonic versus eicosapentaenoic acid on exotonin-induced lung vascular leakage: relation to 4-series versus 5-series leukotriene generation.
Escherichia coli hemolysin (HlyA) is a proteinaceous pore-forming exotoxin that is implicated as a significant pathogenicity factor in extraintestinal E. coli infections including sepsis. In perfused rabbit lungs, subcytolytic concentrations of the toxin evoke thromboxane-mediated vasoconstriction and prostanoid-independent protracted vascular permeability increase (11). In the present study, the influence of submicromolar concentrations of free arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the HlyA-induced leakage response was investigated. HlyA at concentration from 0.02 to 0.06 hemolytic units/ml provoked a dose-dependent, severalfold increase in the capillary filtration coefficient (Kfc), accompanied by the release of leukotriene(LT)B4, LTC4, and LTE4 into the recirculating buffer fluid. Simultaneous application of 100 nmol/L AA markedly augmented the HlyA-elicited leakage response, concomitant with an amplification of LTB4 release and a change in the kinetics of cysteinyl-LT generation. In contrast, 50 to 200 nmol/L EPA suppressed in a dose-dependent manner the HlyA-induced increase in Kfc values. This was accompanied by a blockage of 4-series LT generation and a dose-dependent appearance of LTB5, LTC5, and LTE5. In addition, EPA fully antagonized the AA-induced amplification of the HlyA-provoked Kfc increase, again accompanied by a shift from 4-series to 5-series LT generation. We conclude that the vascular leakage provoked by HlyA in rabbit lungs is differentially influenced by free AA versus free EPA, related to the generation of 4- versus 5-series leukotrienes. The composition of lipid emulsions used for parenteral nutrition may thus influence inflammatory capillary leakage.
Grimminger
F
F
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
Wahn
H
H
Mayer
K
K
Kiss
L
L
Walmrath
D
D
Seeger
W
W
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000633:toxicity*; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006460:Hemolysin Proteins / Q000633:toxicity*; D015289:Leukotrienes / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011817:Rabbits
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D015289:Leukotrienes; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid