Our results demonstrate for the first time that treatment of mice with 15d-PGJ(2) reduces influenza morbidity and mortality through activation of the PPARγ pathway. PPARγ agonists could thus represent a potential therapeutic avenue for influenza infections.
alpha1 Proteinase inhibitor (alpha1PI), 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, alpha1PI must be given frequently and in large amounts, thus limiting its clinical use. We hypothesized that conjugating alpha1PI with polyethylene glycol (PEG) at Cys(232) could extend the in vivo half-life of alpha1PI in blood and lung. We present evidence that site-specific conjugation with either 20 or 40 kD PEG at Cys(232) of nonglycosylated recombinant human alpha1PI (rhalpha1PI) results in an active inhibitor with prolonged in vivo stability. In addition, 72 h after airway instillation PEG-rhalpha1PI was found to be significantly better than glycosylated alpha1PI in protecting the lung against leukocyte elastase-mediated lung hemorrhage. We conclude that thiol-specific PEGylation markedly improves the in vivo pharmacokinetic profile of rhalpha1PI and represents a simple, novel strategy to address the therapeutic goal of human leukocyte elastase inhibition.
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