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.
Article: α-inhibitor through bikunin release
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ABSTRACT: Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV1 88.6 (11.3) %predicted, PC20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma.Pulmonary Pharmacology & Therapeutics 02/2006; 19(4):286-91. DOI:10.1016/j.pupt.2005.04.011 · 2.57 Impact Factor
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ABSTRACT: Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.European Journal of Pharmacology 04/2006; 533(1-3):215-21. DOI:10.1016/j.ejphar.2005.12.071 · 2.68 Impact Factor