Inhaled recombinant alpha 1-antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse.
In alpha 1-antitrypsin deficiency in humans, inadequately regulated activity of serine protease activity is responsible for the chronic lung tissue degeneration and irreversible loss of pulmonary function seen in those individuals with emphysema. Typically, disease symptoms in this patient population are exacerbated by cigarette smoke. Here we show that inhaled recombinant alpha 1-antitrypsin (rAAT) can provide significant protection against the development of emphysema in cigarette smoke-treated mice. As has been reported previously, cigarette smoke was seen to increase significantly the recruitment of neutrophils and macrophages into the lungs of these animals, leading to concomitant alveolar airspace enlargement and emphysema. In smoking animals treated for 6 months with inhaled rAAT, effects on lavage levels of neutrophils and macrophages were only moderate when compared with untreated animals. Furthermore, neutralizing antibodies to rAAT were generated in all rAAT-treated animals. Despite this, however, reductions in airspace enlargement of up to 73% were observed. These findings demonstrate that delivery of rAAT directly to the lungs of smoke-treated mice can inhibit lung tissue damage mediated by proteases, suggesting that rAAT inhalation therapy might represent a practical approach towards treating emphysema in humans, by modifying the course of the disease.
Pemberton
Philip A
PA
Arriva Pharmaceuticals, Inc., Alameda, California 94501, USA. ppemberton@arrivapharm.com
Kobayashi
Dale
D
Wilk
Barry J
BJ
Henstrand
John M
JM
Shapiro
Steven D
SD
Barr
Philip J
PJ
D000818:Animals; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D009330:Nebulizers and Vaporizers; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000209:etiology*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012906:Smoke; D014026:Nicotiana; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology*
D007074:Immunoglobulin G; D015842:Serine Proteinase Inhibitors; D012906:Smoke; D000515:alpha 1-Antitrypsin