Hyaluronan blocks human neutrophil elastase (HNE)-induced airway responses in sheep.
ABSTRACT Hyaluronan (HA) blocks inhaled porcine pancreatic elastase-induced bronchoconstriction in sheep with airway hypersensitivity to Ascaris suum antigen. Since elastases from other species may display different catalytic properties compared to the human enzyme, we tested the efficacy of HA on human neutrophil elastase (HNE)-induced airway responses. We measured pulmonary resistance in allergic sheep before and after inhalation of HNE alone and after pretreatment with a 150 kD-HA (LKDHA; 3 and 15 mg), or a 300 kD-HA (HKDHA; 6, 7.5, and 15 mg). HKDHA (3 mg) was given either 0.5, 4, or 8 h before HNE challenge; LKDHA (15 mg) and HKDHA (6, 7.5, and 15 mg) were given 8 h before challenge. HNE caused an acute bronchoconstriction which was blocked by 3 mg LKDHA given 0.5 or 4 h before challenge. LKDHA (3 mg) given 8 h before challenge was ineffective, but protection was achieved by increasing the dose to 15 mg. When HKDHA at 6, 7.5, and 15 mg was given 8 h before challenge a dose-dependent inhibition of the HNE-induced airway response was observed. We conclude that HA inhibits HNE-induced airway responses and that within the range of 150-300 kD, dose rather than molecular weight may be the most important determinant of pretreatment time resulting in a protective effect.
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ABSTRACT: Abstract Trial Design and Methods: Between December 2009 and July 2011, four cystic fibrosis (CF) centers in Italy participated in a randomized, double-blind, controlled clinical trial to test whether 7% hypertonic saline (HS) administered together with 0.1% hyaluronic acid (HA) was better tolerated by patients who previously did not tolerate HS well on its own. Participants were CF patients at least 8 years old, in clinically stable conditions, with forced expiratory volume in 1 sec (FEV1) at least 50% predicted. Forty patients were recruited and randomized to receive either HS or HS plus HA (5 mL to be inhaled over 15 min, twice daily for 28 days). Primary endpoints were cough, throat irritation, salty taste, and overall acceptability, as assessed by each patient on a semiquantitative scale on a diary card. Secondary endpoint was FEV1 change at the end of treatment. Patients were randomized into randomly permuted blocks. The first and last doses were administered in hospital. In between, patients were treated at home. Patients, all caregivers, and the statistician who conducted the analysis (different from the one who generated the random list) were blinded to group assignment. Results: Severity of cough, throat irritation, and saltiness were more severe in patients treated with HS alone, both after the first inhalation and over the entire treatment period. Overall pleasantness was rated higher by patients treated with the combination product. All differences were highly significant. There were no changes in FEV1 between the first and last administrations. Five patients did not complete the study. Four patients (two from each group) withdrew because of cough or throat irritation. One more patient from the HS group withdrew because of a respiratory exacerbation at week 3. Conclusions: HS is currently a cornerstone in the treatment of CF patients. The addition of HA to HS reduces the prevalence and severity of cough, throat irritation, and saltiness and may improve compliance in patients who previously did not tolerate HS well on its own. Longer-term studies could further assess the benefit of chronic treatment.Journal of Aerosol Medicine and Pulmonary Drug Delivery 06/2013; DOI:10.1089/jamp.2012.1034 · 2.40 Impact Factor
Article: α-inhibitor through bikunin release
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ABSTRACT: Background Chronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease. Objective To assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF. Methods In a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15 years (range 5–26 yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N = 14) or hyaluronate alone (N = 13) for 14 days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms. Results The formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects. Conclusions The present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. Trial registration number: EudraCT 2007-003628-39.Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 07/2014; 13(4). DOI:10.1016/j.jcf.2014.02.006 · 3.82 Impact Factor