The effect of marimastat, a metalloprotease inhibitor, on allergen-induced asthmatic hyper-reactivity.
This pilot study was designed to assess whether a synthetic matrix metalloproteinase (MMP) inhibitor has anti-inflammatory properties in mild asthma. Tumor necrosis factor alpha (TNFalpha) has been shown to be an important cytokine in the pathogenesis of allergic airway inflammatory responses, and its release can be inhibited by MMP inhibitors. Twelve atopic asthmatic subjects received the MMP inhibitor marimastat (5 mg) or placebo, twice daily for 3 weeks, separated by a 6-week washout period in a randomized, double-blind, cross-over manner. All subjects underwent an allergen inhalation provocation test to Dermatophagoides pteronyssinus before and after each study phase. Spirometry, exhaled NO (eNO) levels, differential sputum cell counts, an asthma symptom questionnaire, peak flow, and beta(2)-agonist usage were measured. Nine subjects completed the study, and, when compared with placebo, marimastat reduced bronchial hyper-responsiveness to inhaled allergen in these subjects from an allergen PC(20) of 22.2 AU/ml (95%CI 11.7-32.6) to 17.0 AU/ml (95%CI 7.6-26.4, P = 0.02). The marimastat phase showed a nonsignificant fall in sputum inflammatory cells. Marimastat did not modify eNO, FEV(1), asthma symptoms, or albuterol usage. In conclusion, airway responsiveness to allergen may be modified by a MMP inhibitor, perhaps via TNFalpha playing a role in airway inflammation and remodeling.
Bruce
Colleen
C
Department of Respiratory Medicine, Faculty of Medicine, University of New South Wales, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
Thomas
Paul S
PS
D000328:Adult; D039741:Antigens, Dermatophagoides / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D016210:Methacholine Chloride; D008875:Middle Aged; D010865:Pilot Projects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D039741:Antigens, Dermatophagoides; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; C100342:marimastat; D045726:Metalloproteases