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This Article Full Text Free Full Text (PDF) Free All Versions of this Article: 102/6/2324    most recent 00568.2006v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Scuri, M. Articles by Abraham, W. M. Search for Related Content PubMed PubMed Citation Articles by Scuri, M. Articles by Abraham, W. M.

Hyaluronan blocks porcine pancreatic elastase-induced mucociliary dysfunction in allergic sheep

Division of Pulmonary and Critical Care Medicine, Miller School of Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach Florida

Submitted 19 May 2006 ; accepted in final form 25 March 2007

Neutrophil elastase is a mediator common to asthma, chronic obstructive pulmonary disease, and cystic fibrosis and thought to contribute to the pathophysiology of these diseases. Previously, we found that inhaled hyaluronan blocked elastase-induced bronchoconstriction in allergic sheep through its control of tissue kallikrein. Here, we extend those studies by determining if inhaled hyaluronan can protect against the elastase-induced depression in tracheal mucus velocity, a surrogate marker of whole lung mucociliary clearance. We measured tracheal mucus velocity in allergic sheep before, and sequentially for 6 h after, aerosol challenge with porcine pancreatic elastase alone and after pretreatment with 1.5 or 6 mg aerosolized hyaluronan. Elastase (2.55 U) decreased tracheal mucus velocity. Pretreatment with 6 mg, but not 1.5 mg, hyaluronan inhibited the elastase-induced decrease in tracheal mucus velocity. Hyaluronan (6 mg) given 1 h after elastase challenge was ineffective, suggesting the involvement of secondary mediators. The elastase-induced depression in mucus transport appeared to be mediated, in part, by reactive oxygen species and bradykinin because pretreatment with either aerosolized catalase (38 mg/3 ml) or the bradykinin B₂-receptor antagonist HOE140 (400 nM/kg) was also effective in blocking the response. These latter two findings are consistent with oxygen radical-induced degradation of hyaluronan with concomitant loss of its regulatory effect on tissue kallikrein, resulting in kinin generation. This hypothesis is supported by the demonstration that hyaluronan failed to block the oxygen radical-induced fall in tracheal mucus velocity resulting from xanthine-xanthine oxidase challenge and that inhaled bradykinin itself can slow mucociliary transport.

polysaccharides; asthma; chronic obstructive pulmonary disease; serine proteases; cystic fibrosis