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Am. J. Respir. Crit. Care Med., Volume 163, Number 5, April 2001, 1153-1157

Improved Activity of an Actin-resistant DNase I Variant on the Cystic Fibrosis Airway Secretions

JEAN-MARIE ZAHM, CÉLINE DEBORDEAUX, CYRIL MAURER, DOMINIQUE HUBERT, DANIEL DUSSER, NOEL BONNET, ROBERT A. LAZARUS, and EDITH PUCHELLE

INSERM U514, IFR53, Reims, Groupe Hospitalier Cochin, Paris, France; and Genentech, South San Francisco, California

In cystic fibrosis (CF), actin and DNA originating from inflammatory cells contribute to the thickness of airway secretions. Actin can bind to DNA-rich fibers and potently inhibit the enzymatic activity of rhDNase. The in vitro effects of the actin-resistant rhDNase variant (A114R) were analyzed and compared with those of the wild-type rhDNase. Frozen and thawed CF airway secretions were incubated for 30 min with different concentrations (0.1, 0.5, 1, 5, or 10 µg/ml) of either actin-resistant rhDNase or wild-type rhDNase. We observed that both the wild-type and the actin-resistant rhDNase significantly decreased (p < 0.05 and p < 0.001, respectively) the airway secretion viscosity. The decrease in airway secretion viscosity was significant even at low concentrations (0.1 µg/ml) of the actin-resistant variant. Incubation with the actin-resistant variant resulted in a significant decrease (p < 0.02) of the airway secretion contact angle and cough transport. A significantly higher (p < 0.01) increase in contact angle and cough transport of airway secretions was observed at 10 µg/ml with the actin-resistant variant as compared with the wild-type rhDNase. The present study had demonstrated that the actin-resistant rhDNase variant (A114R) has an enhanced capacity to improve the physical properties and cough transport of airway secretions from patients with cystic fibrosis.




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