Dual effect of nitrogen dioxide on rat alveolar macrophage arachidonate metabolism.
Significant deficits in alveolar macrophage (AM) function have been associated with acute exposure to nitrogen dioxide (NO2). The present investigation examined changes in enzymatic production of arachidonate metabolites from rat AM exposed to NO2. While in vitro exposure of AM to NO2 concentrations between 0.1 and 5 ppm alone had small effects on basal synthesis of cyclooxygenase or lipoxygenase products, exposure to either 1 ppm (2 or 4 h) or 5 ppm (1 h) markedly enhanced the response of AM to stimulation by the calcium ionophore, A23187. This pre-exposure led to significant increases in cyclooxygenase products (thromboxane B2 (thromboxane), the stable metabolite of thromboxane A2, and 12-hydroxyheptadecatrienoic acid (12-HHT)) and lipoxygenase products (leukotriene B (LTB4) and monohydroxyeicosatetraenoate isomers) in response to A23187. In contrast, a 1-h exposure to 20 ppm NO2 alone significantly increased AM synthesis of thromboxane and 12-HHT, but suppressed the effect of subsequently added A23187. Increased synthesis of cyclooxygenase products with 20 ppm NO2 alone were blocked with the phospholipase inhibitor mepacrine and the cyclooxygenase inhibitor indomethacin. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) significantly reduced release of arachidonate; however, levels of thromboxane and 12-HHT were significantly increased. The results suggest a dual effect of NO2 on AM arachidonate metabolism in which low concentrations of NO2 had small effects on basal metabolism but markedly amplified the response to stimuli, while a high concentration of NO2 did the reverse. Such a complex dose-response effect may have significant impact in explaining the pathologic effects of NO2.
Robison
T W
TW
Department of Pediatrics, University of Southern California, Los Angeles.
Forman
H J
HJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009585:Nitrogen Dioxide / Q000494:pharmacology*; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013931:Thromboxanes / Q000096:biosynthesis
D005231:Fatty Acids, Unsaturated; D013931:Thromboxanes; D016718:Arachidonic Acid; D000001:Calcimycin; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D009637:Masoprocol; D011796:Quinacrine; D009585:Nitrogen Dioxide; D007213:Indomethacin