Roles of neutrophil elastase and superoxide anion in leukotriene B4-induced lung injury in rabbit.
The effects of a competitive neutrophil elastase (NE) inhibitor, ONO-5046, and a recombinant human superoxide dismutase on leukotriene B4 (LTB4)-induced polymorphonuclear leukocyte (PMN)-mediated increase in microvascular permeability in isolated non-blood-perfused rabbit lungs were studied. Pulmonary microvascular permeability and lung edema were evaluated by use of the fluid filtration coefficient (Kf) and the wet-to-dry lung weight ratio (W/D), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. NE activity in the perfusate was determined using a spectrophotometric method. The PMNs (2-3 x 10(8) cells) were added into the perfusate in all groups of lungs. Injection of LTB4 (5 micrograms) increased Kf and W/D without affecting pulmonary arterial or capillary pressure. The LTB4-induced lung injury was closely associated with the increase in NE activity in the perfusate. Infusion of ONO-5046 (1 or 10 mg.kg-1 x h-1) inhibited the LTB4-induced increases in Kf, W/D, and perfusate NE activity in a dose-dependent fashion. Infusion of recombinant human superoxide dismutase (80,000 U.kg-1 x h-1) attenuated the LTB4-induced increases in Kf and W/D, although it did not influence the elevation of perfusate NE activity induced by LTB4. These results suggest that both NE and superoxide anion play important roles in the LTB4-induced PMN-mediated increase in pulmonary microvascular permeability.
Yoshimura
K
K
Institute of Cardiovascular Diseases, Shinshu University School of Medicine, Matsumoto, Japan.
Nakagawa
S
S
Koyama
S
S
Kobayashi
T
T
Homma
T
T
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007975:Leukotriene B4; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D009929:Organ Size / Q000502:physiology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000502:physiology*; D011652:Pulmonary Circulation / Q000502:physiology; D011654:Pulmonary Edema / Q000503:physiopathology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*
D013449:Sulfonamides; D013481:Superoxides; D007975:Leukotriene B4; C069195:sivelestat; D013482:Superoxide Dismutase; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D005998:Glycine