Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice

Abstract

Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

“…However, the results of this study suggest that mepenzolate belongs to the short-acting muscarinic antagonists, which are used as supplemental drugs for the temporary improvement of airflow limitation 24 . On the other hand, we recently reported that steroids do not provide protective or therapeutic benefits against PPE-induced pulmonary emphysema, alterations in lung mechanics or respiratory dysfunction 23 , whereas here we have shown that mepenzolate is effective against these disorders under the same experimental conditions. Based on these observations, we consider that a combination treatment regime involving the administration of long-acting muscarinic antagonists or b 2 -agonists along with inhaled mepenzolate may prove to be therapeutically beneficial for COPD patients.…”

“…We recently established a technique to monitor PPE-induced respiratory dysfunction in mice, and found that the FEV 0.05 /FVC ratio clearly decreased in PPE-treated mice compared with control mice 23 . Using this technique, we examined here the effects of mepenzolate and other muscarinic antagonists on the PPE-induced decrease in FEV 0.05 /FVC.…”

“…The level of superoxide anions was determined by ESR spin trapping with DPhPMPO 32,33 . Cells collected from BALF were incubated with 0.9% NaCl containing 500 mM diethylenetriamine-N, N, N 0 , N 00 , N 00 -pentaacetic acid and 10 mM DPhPMPO for 10 min at 37°C.…”

“…Measurement of lung mechanics and airway resistance was performed with a computer-controlled smallanimal ventilator (FlexiVent, SCIREQ, Montreal, Canada) 32,33 . Mice were anesthetized with chloral hydrate (500 mg kg À 1 ), a tracheotomy was performed, and an 8-mm section of metallic tube was inserted into the trachea.…”

“…Determination of the FEV0.05/FVC ratio was performed with the same computer-controlled small-animal ventilator connected to a negative pressure reservoir (SCIREQ, Montreal, Canada) 32,33 . Mice were tracheotomized and ventilated as described above.…”