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α1 Proteinase inhibitor (α1PI), a natural inhibitor of the serine proteinase leukocyte elastase, is also an intravenous therapeutic agent used to treat hereditary emphysema and may be useful in other respiratory disorders. However, to achieve sustained suppression of leukocyte elastase, α1PI must be given frequently and in large amounts, thus limiting its clinical use. We hypothesized that conjugating α1PI with polyethylene glycol (PEG) at Cys232 could extend the in vivo half-life of α1PI in blood and lung. We present evidence that site-specific conjugation with either 20 or 40 kD PEG at Cys232 of nonglycosylated recombinant human α1PI (rhα1PI) results in an active inhibitor with prolonged in vivo stability. In addition, 72 h after airway instillation PEG-rhα1PI was found to be significantly better than glycosylated α1PI in protecting the lung against leukocyte elastase-mediated lung hemorrhage. We conclude that thiol-specific PEGylation markedly improves the in vivo pharmacokinetic profile of rhα1PI and represents a simple, novel strategy to address the therapeutic goal of human leukocyte elastase inhibition.