Activation of
poly(ADP-ribose) polymerases (PARPs) is considered a key event in the molecular and cellular processes leading from acute
asthma attacks to bronchial hyper-reactivity, leucocyte recruitment, chronic
inflammation,
airway remodelling and lung damage. The present investigation has been carried out to investigate the action of
hydroxyl-dimethylaminomethyl-thieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ), a new potent
PARP inhibitor, in the process leading from
asthma-like events to airway damage.
Ovalbumin-sensitized guinea pigs exposed two times to
allergen inhalation were treated for 8 days with vehicle or HYDAMTIQ.
Asthma-like signs, bronchial hyper-reactivity to
methacholine,
cytokine production, histamine release from mast cells,
airway remodelling,
collagen deposition and lung damage were evaluated. Repeated HYDAMTIQ administration (1-10 mg/kg/day i.p.) reduced lung PARP activity, delayed the appearance and reduced the severity of
allergen-induced
cough and dyspnoea and dampened the increased bronchial responses to
methacholine. HYDAMTIQ-treated animals presented reduced bronchial or alveolar abnormalities, lower number of eosinophils and other leucocytes in the lung and decreased smooth muscle or goblet cell
hyperplasia. The treatment also reduced lung oxidative stress markers, such as
malondialdehyde or
8-hydroxy-2'-deoxyguanosine and the lung content of pro-inflammatory
cytokines (TNF-α,
interleukin (IL)-1β, IL-5, IL-6 and IL-18). Finally, mast cells isolated from the peritoneal or pleural cavities of sensitized, HYDAMTIQ-treated animals had a reduced ability to release
histamine when exposed to
ovalbumin in vitro. Our findings support the proposal that
PARP inhibitors could have a therapeutic potential to reduce chronic
lung inflammation, airway damage and remodelling in severe unresponsive asthmatic patients.