Poly(ADP-ribose) polymerase inhibition with HYDAMTIQ reduces allergen-induced asthma-like reaction, bronchial hyper-reactivity and airway remodelling.
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.
Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Laura
L
Lucarini
Alessandro
A
Pini
Elisabetta
E
Gerace
Roberto
R
Pellicciari
Emanuela
E
Masini
Flavio
F
Moroni
D056151:Airway Remodeling / Q000187:drug effects*; D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006636:Histamine Release; D007249:Inflammation / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
C000595230:2-((dimethylamino)methyl)-9-hydroxythieno(2,3-c)isoquinolin-5(4H)-one; D000485:Allergens; D016207:Cytokines; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; D011064:Poly Adenosine Diphosphate Ribose; D010047:Ovalbumin; D011065:Poly(ADP-ribose) Polymerases
airway inflammation and remodelling; asthma-like reaction; histamine release; hydroxyl-dimethylaminomethyl-thieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ); poly (ADP-ribose) polymerase (PARP)