An inhaled matrix metalloprotease inhibitor prevents cigarette smoke-induced emphysema in the mouse.
Inadequately regulated proteolytic activity is responsible for the chronic lung tissue degeneration and irreversible loss of pulmonary function that define emphysema. In this study, we show that an inhaled broad-spectrum matrix metalloprotease inhibitor, ilomastat, can provide protection against the development of emphysema in cigarette smoke-treated mice. Control animals were exposed to daily cigarette smoke for 6 months. As has been reported previously, cigarette smoke was seen to increase significantly the recruitment of macrophages into the lungs of these animals, leading to concomitant alveolar airspace enlargement and emphysema. In animals treated daily with nebulized ilomastat for 6 months, lung macrophage levels were greatly reduced, and neutrophil accumulation was also inhibited. Corresponding reductions in airspace enlargement of up to 96% were observed. These striking observations suggest that delivery of ilomastat directly into the lungs of smoke-treated mice can not only inhibit lung tissue damage mediated by metalloproteases, but may also reduce that component of tissue degeneration mediated by excess neutrophil-derived products. Our data also suggest that the matrix metalloprotease inhibitors may represent a class of drugs that, when delivered by inhalation, could be used practically to treat cigarette smoking-related chronic obstructive pulmonary disease by modifying the course of the disease.
Pemberton
Philip A
PA
Arriva Pharmaceuticals, Alameda, California 94501, USA. ppemberton@arrivapharm.com
Cantwell
John S
JS
Kim
Karen M
KM
Sundin
David J
DJ
Kobayashi
Dale
D
Fink
James B
JB
Shapiro
Steven D
SD
Barr
Philip J
PJ
D000280:Administration, Inhalation; D000818:Animals; D005260:Female; D006877:Hydroxamic Acids; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009330:Nebulizers and Vaporizers; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000517:prevention & control*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D006877:Hydroxamic Acids; D007211:Indoles; D012906:Smoke; C119203:ilomastat