Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia
Welbourn, C.R.; Goldman, G.; Paterson, I.S.; Valeri, C.R.; Shepro, D.; Hechtman, H.B.
American Journal of Physiology 260(6 Pt 2): H1852-H1856
1991
ISSN/ISBN: 0002-9513 PMID: 2058722 Document Number: 375003
Hindlimb ischemia and reperfusion lead to lung injury dependent on activated polymorphonuclear neutrophils (PMN) adherence. This study tests whether elastase and oxygen radicals participate in PMN-induced injury once they have become sequestered in lungs. Anesthetized rats treated with saline (n = 9) or the specific elastase inhibitor methoxysuccinyl-L-Ala-L-Ala-L-Pro-L-Val-chloromethylketone (MAAPV, n = 6) underwent 4 h of bilateral hindlimb tourniquet ischemia followed by 4 h of reperfusion. At this time, in saline-treated rats, PMN were sequestered in lungs as assayed by myeloperoxidase activity [(MPO) 51 .+-. 5 U/g tissue], higher than MPO in saline-treated sham rats (n = 9; 18 .+-. 3 U/g MPO; P < 0.01); bronchoalveolar lavage (BAL) fluid leukotriene (LT) B4 levels increased to 594 .+-. 46 relative to 200 .+-. 38 pg/ml in shams (P < 0.01); increased permeability was documented by BAL fluid protein content of 599 .+-. 91 compared with 214 .+-. 35 .mu.g/ml in sham animals (P < 0.01); and edema was shown by increase in lung wet-to-dry weight ratio of 4.77 .+-. 0.14 relative to 4.00 .+-. 0.09 in sham rats (P < 0.01). In MAAPV-treated animals, lung neutrophil sequestration (62 .+-. 9 U/g MPO) and rise of LTB4 in BAL fluid (780 .+-. 244 pg/ml) were not affected, but both BAL fluid protein (335 .+-. 32 .mu.g/ml) and lung wet-to-dry weight ratio (4.21 .+-. 0.17) were reduced (both P < 0.05). Another group of rats (n = 7) was treated with the oxygen radical scavengers superoxide dismutase and catalase 2 h after removal of tourniquets. This did not affect lung neutrophil sequestration (58 .+-. 8 U MPO/g) but prevented the rise of LTB4 in BAL fluid (167 .+-. 44 pg/ml) as well as BAL fluid protein (245 .+-. 95 .mu.g/ml) and lung wet-to-dry weight ratio (4.02 .+-. 0.11) (all P < 0.05). Infusion of MAAPV or oxygen radical scavengers into sham animals was without effect on neutrophil-endothelial interactions (23 .+-. 4 and 16 .+-. 1 U/g MPO, respectively). These data indicate that neutrophils sequestered in lungs after remote ischemia probably mediate permeability edema via release of both elastase and oxygen radicals.