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Ex Vivo Sputum Analysis Reveals Impairment of Protease-dependent Mucus Degradation by Plasma Proteins in Acute Asthma

¹ Cardiovascular Research Institute and ² Department of Medicine, University of California, San Francisco, San Francisco, California; ³ Veterinary Sciences Centre, University College Dublin, Dublin, Ireland; ⁴ Wellcome Trust Center for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; ⁵ Veterans Research Health Institute and ⁶ Veterans Affairs Medical Center, San Francisco, California; and ⁷ Department of Chemical Engineering, University of California, Berkeley, Berkeley, California

Correspondence and requests for reprints should be addressed to John V. Fahy, M.D., M.Sc., Box 0130, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail: john.fahy{at}ucsf.edu

Rationale: Airway mucus plugs, composed of mucin glycoproteins mixed with plasma proteins, are an important cause of airway obstruction in acute severe asthma, and they are poorly treated with current therapies.

Objectives: To investigate mechanisms of airway mucus clearance in health and in acute severe asthma.

Methods: We collected airway mucus from patients with asthma and nonasthmatic control subjects, using sputum induction or tracheal aspiration. We used rheological methods complemented by centrifugation-based mucin size profiling and immunoblotting to characterize the physical properties of the mucus gel, the size profiles of mucins, and the degradation products of albumin in airway mucus.

Measurements and Main Results: Repeated ex vivo measures of size and entanglement of mucin polymers in airway mucus from nonasthmatic control subjects showed that the mucus gel is normally degraded by proteases and that albumin inhibits this degradation. In airway mucus collected from patients with asthma at various time points during acute asthma exacerbation, protease-driven mucus degradation was inhibited at the height of exacerbation but was restored during recovery. In immunoblots of human serum albumin digested by neutrophil elastase and in immunoblots of airway mucus, we found that albumin was a substrate of neutrophil elastase and that products of albumin degradation were abundant in airway mucus during acute asthma exacerbation.

Conclusions: Rheological methods complemented by centrifugation-based mucin size profiling of airway mucins in health and acute asthma reveal that mucin degradation is inhibited in acute asthma, and that an excess of plasma proteins present in acute asthma inhibits the degradation of mucins in a protease-dependent manner. These findings identify a novel mechanism whereby plasma exudation may impair airway mucus clearance.

Key Words: airway mucus • rheology • neutrophil elastase • plasma • asthma exacerbation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway mucus plugs are an important cause of airway obstruction in acute asthma exacerbations, and are poorly treated with current therapies. What This Study Adds to the Field We show that inhibition of protease-dependent mucin digestion occurs in acute asthma and that plasma proteins may mediate this inhibition by competing with mucin substrates for proteolysis. These data provide mechanistic insights into the pathophysiology of mucus impaction of the airways in acute asthma and highlight potential areas for the development of mucolytic therapies.