Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia

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 less than 0.01); bronchoalveolar lavage (BAL) fluid leukotriene (LT) B4 levels increased to 594 +/- 46 relative to 200 +/- 38 pg/ml in shams (P less than 0.01); increased permeability was documented by BAL fluid protein content of 599 +/- 91 compared with 214 +/- 35 micrograms/ml in sham animals (P less than 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 less than 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 micrograms/ml) and lung wet-to-dry weight ratio (4.21 +/- 0.17) were reduced (both P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)