PARP inhibition treatment in a nonconventional experimental mouse model of chronic asthma.
Allergic asthma is an immunological disease that occurs as a consequence of aeroallergen exposure. Inhibition of poly(ADP-ribose) polymerases (PARPs) in conventional models of asthma-like reaction has emerged as an effective anti-inflammatory and airway remodeling intervention. In a house dust mite (HDM) exposure mouse model, we investigated the impact of PARP inhibition on allergic airway inflammation, sensitization, and remodeling. Mice were intranasally exposed to a HDM extract for 5 days per week for up to 5 weeks. Mice were administered, or not, by PARP inhibitors 3-aminobenzamide (3-ABA) or 5-aminoisoquinolinone (5-AIQ) during the last 2 weeks of HDM treatment. Mice treated with PARP inhibitors after HDM stimulation showed a significant decrease in the number of total cells and eosinophils detectable in the bronchoalveolar lavage fluid as compared with the HDM-stimulated ones. In vitro HDM-stimulated splenocyte culture produced considerable amounts of the Th2 cytokines that were not affected by treatment with PARP inhibitors. Immunoglobulin levels in the serum were also unchanged. In the lung tissue, collagen deposition was decreased, whereas α-smooth muscle actin thickening was not significantly affected. Moreover, in HDM-stimulated PARP inhibitor-treated groups, we found a downregulation in the activation of signal transducer and activator of trascription-6 (STAT-6) and a significant decrease in the mRNA levels of C-C motif chemokine 11 (CCL11). In this mouse model of chronic asthma PARP inhibition treatment, although it does not affect sensitization, it effectively reduces the allergic airway inflammation and affects the remodeling through a mechanism involving STAT6 and CCL11.
Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Strada Le Grazie, 8, 37134, Verona, Italy.
Raffaela
R
Zaffini
Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166, Messina, Italy.
Rosanna
R
Di Paola
Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres 31, 98166, Messina, Italy.
Salvatore
S
Cuzzocrea
Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Strada Le Grazie, 8, 37134, Verona, Italy. marta.menegazzi@univr.it.
Marta
M
Menegazzi
D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007136:Immunoglobulins / Q000097:blood; D007546:Isoquinolines / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008807:Mice, Inbred BALB C; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D039981:Pyroglyphidae / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
C549098:5-aminoisoquinoline; D018927:Anti-Asthmatic Agents; D001549:Benzamides; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D016207:Cytokines; D007136:Immunoglobulins; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C025160:3-aminobenzamide; D003094:Collagen; D011065:Poly(ADP-ribose) Polymerases
Airway inflammation; House dust mite; Model of chronic asthma; PARP inhibition; Remodeling; Sensitization