Leukotoxin, 9,10-epoxy-12-octadecenoate causes edematous lung injury via activation of vascular nitric oxide synthase.
We examined the mechanism of leukotoxin, 9,10-epoxy-12-octadecenoate (Lx)-induced lung injury in blood-free, physiological salt solution-perfused rat lungs under constant flow conditions. Mean pulmonary arterial (Ppa) and pulmonary capillary pressure (Pcap, estimated by the double-occlusion method), wet lung weight (WLW), pulmonary capillary filtration coefficient (Kfc), lung perfusate lactate dehydrogenase (LDH) activity, and nitrite levels were assessed. Bolus injection of Lx (200 microM) caused insidious and significant lung weight gain, which was not associated with remarkable elevation of Ppa or Pcap but was associated with an increase of perfusate LDH activity and nitrite levels. Lx (20 microM) elevated Kfc, indicating that Lx had affected pulmonary vascular permeability. Because Lx causes endothelium dependent pulmonary vasodilation, we studied the effect of NG-monomethyl-L-arginine (L-NMMA), NG-monomethyl-D-arginine (D-NMMA), superoxide dismutase (SOD), human oxyhemoglobin (oxyHb), and methylene blue (MB) on Lx-induced lung injury. L-NMMA, SOD, and oxyHb, but not MB or D-NMMA, protected the lungs against Lx (200 microM)-induced injury. Lx increased pulmonary vascular permeability and caused lung injury. Because both nitric oxide synthase inhibitors and SOD inhibited the Lx-induced lung injury, it is possible that peroxynitrite is involved in the mechanism whereby Lx causes lung injury.
Ishizaki
T
T
Department of Internal Medicine, Fukui Medical School, Japan.
Shigemori
K
K
Nakai
T
T
Miyabo
S
S
Ozawa
T
T
Chang
S W
SW
Voelkel
N F
NF
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001808:Blood Vessels / Q000201:enzymology*; D004789:Enzyme Activation; D005098:Exotoxins / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008041:Linoleic Acids / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D010108:Oxyhemoglobins / Q000494:pharmacology; D010477:Perfusion; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D019323:omega-N-Methylarginine
D005098:Exotoxins; D008041:Linoleic Acids; D009573:Nitrites; D010108:Oxyhemoglobins; C018579:leukotoxin; D019323:omega-N-Methylarginine; C051208:9,10-epoxy-12-octadecenoic acid; D001120:Arginine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000594:Amino Acid Oxidoreductases