Cyclooxygenase and lipoxygenase inhibition by BW-755C reduces acrolein smoke-induced acute lung injury.
Inhalation of smoke containing acrolein, the most common toxin in urban fires after carbon monoxide, causes vascular injury with non-cardiogenic pulmonary edema containing potentially edematogenic eicosanoids such as thromboxane (Tx) B2, leukotriene (LT) B4, and the sulfidopeptide LTs (LTC4, LTD4, and LTE4). To determine which eicosanoids are important in the acute lung injury, we pretreated sheep with BW-755C (a combined cyclooxygenase and lipoxygenase inhibitor), U-63557A (a specific Tx synthetase inhibitor), or indomethacin (a cyclooxygenase inhibitor) before a 10-min exposure to a synthetic smoke containing carbon particles (4 microns) with acrolein and compared the results with those from control sheep that received only carbon smoke. Acrolein smoke induced a fall in arterial PO2 and rises in peak inspiratory pressure, main pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and the blood-free wet-to-dry weight ratio. BW-755C delayed the rise in peak inspiratory pressure and prevented the fall in arterial PO2, the rise in lymph flow, and the rise in wet-to-dry weight ratio. Neither indomethacin nor U-63557A prevented the increase in lymph flow or wet-to-dry weight ratio, although they did blunt and delay the rise in airway pressure and did prevent the rises in pulmonary arterial pressure and pulmonary vascular resistance. Thus, cyclooxygenase products, probably Tx, are responsible for the pulmonary hypertension after acrolein smoke and to some extent for the increased airway resistance but not the pulmonary edema. Prevention of high-permeability pulmonary edema after smoke with BW-755C suggests that LTB4, may be etiologic, as previous work has eliminated LTC4, LTD4, and LTE4.
Janssens
S P
SP
Department of Medicine, Massachusetts General Hospital, Boston.
Musto
S W
SW
Hutchison
W G
WG
Spence
C
C
Witten
M
M
Jung
W
W
Hales
C A
CA
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000627:therapeutic use*; D000171:Acrolein / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015777:Eicosanoids / Q000096:biosynthesis; D007213:Indomethacin / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008196:Lymph / Q000378:metabolism / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D001572:Benzofurans; D001798:Blood Proteins; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D018836:Inflammation Mediators; D016859:Lipoxygenase Inhibitors; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000171:Acrolein; D013930:Thromboxane-A Synthase; C039936:furegrelate; D007213:Indomethacin