A novel formulation of inhaled doxycycline reduces allergen-induced inflammation, hyperresponsiveness and remodeling by matrix metalloproteinases and cytokines modulation in a mouse model of asthma.
BACKGROUND
In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced inflammation, hyperresponsiveness and remodeling. MMPs play key roles in the complex cascade of events leading to asthmatic phenotype.


METHODS
Doxycycline was administered by aerosols by the mean of a novel formulation as a complex with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) used as an excipient. BALB/c mice (n=16-24 in each group) were sensitized and exposed to aerosolized ovalbumin (OVA) from day 21 to 27 (short-term exposure protocol) or 5 days/odd weeks from day 22 to 96 (long-term exposure protocol).


RESULTS
In the short-term exposure model, inhaled doxycycline decreased allergen-induced eosinophilic inflammation in bronchoalveolar lavage (BAL) and in peribronchial areas, as well as airway hyperresponsiveness. In lung tissue, exposure to doxycycline via inhaled route induced a fourfold increase in IL-10 levels, a twofold decrease in IL-5, IL-13 levels and diminished MMP-related proteolysis and the proportion of activated MMP-9 as compared to placebo. In the long-term exposure model, inhaled doxycycline significantly decreased the extent of glandular hyperplasia, airway wall thickening, smooth muscle hyperplasia and subepithelial collagen deposition which are well recognized features of airway remodeling.


CONCLUSIONS
Doxycycline administered by aerosols decreases the allergen-induced airway inflammation and hyperresponsiveness and inhibits the development of bronchial remodeling in a mouse model of asthma by modulation of cytokines production and MMP activity.
Gueders
Maud M
MM
Department of Pneumology, GIGA research, Liège and Centre Hospitalier Universitaire de Liège, Belgium.
Bertholet
Pascal
P
Perin
Fabienne
F
Rocks
Natacha
N
Maree
Raphaël
R
Botta
Vincent
V
Louis
Renaud
R
Foidart
Jean-Michel
JM
Noel
Agnès
A
Evrard
Brigitte
B
Cataldo
Didier D
DD
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D002626:Chemistry, Pharmaceutical; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage*; D007249:Inflammation / Q000517:prevention & control*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology
D000485:Allergens; D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D020782:Matrix Metalloproteinases; D004318:Doxycycline