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PARP inhibition treatment in a nonconventional experimental mouse model of chronic asthma

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Abstract

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.

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References

  • Barnes PJ (2004) New drugs for asthma. Nat Rev Drug Discov 3:831–844

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ (2006) Transcription factors in airway diseases. Lab Investig 86:867–872

    Article  CAS  PubMed  Google Scholar 

  • Boulares AH, Zoltoski AJ, Sherif ZA, Jolly P, Massaro D, Smulson ME (2003) Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma. Am J Respir Cell Mol Biol 28:322–329

    Article  CAS  PubMed  Google Scholar 

  • Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O’Byrne P (2007) GINA guidelines on asthma and beyond. Allergy 62:102–112

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Bürkle A (2005) Poly(ADP-ribose). The most elaborate metabolite of NAD+. FEBS J 272:4576–4589

    Article  CAS  PubMed  Google Scholar 

  • Cates EC, Fattouh R, Wattie J, Inman MD, Goncharova S, Coyle AJ, Gutierrez-Ramos JC, Jordana M (2004) Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J Immunol 173:6384–6392

    Article  CAS  PubMed  Google Scholar 

  • Cates EC, Fattouh R, Johnson JR, Llop-Guevara A, Jordana M (2007) Modeling responses to respiratry house dust mite exposure. Models of exacerbation of asthma and COPD. Contrib Microbiol 14:42–67

    Article  PubMed  Google Scholar 

  • Chomczynsky P, Sacchi N (1987) Single step method of RNA isolation by acid guanidinium thiocynate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Google Scholar 

  • Cuzzocrea S (2005) Shock, inflammation and PARP. Pharmacol Res 52:72–82

    Article  CAS  PubMed  Google Scholar 

  • Cuzzocrea S, Mc Donald MC, Mazzon E, Dugo L, Serraino I, Threadgill M, Caputi AP, Thiemermann C (2002) Effect of 5-amminoisoquinolinone, a water-soluble, potent inhibitor of the activity of poly(ADP-ribose) polymerase, in a rodent model of lung injury. Biochem Pharmacol 63:293–304

    Article  CAS  PubMed  Google Scholar 

  • D’Amours D, Desnoyers S, D’Silva I, Poirer GG (1999) Poly(ADP-rybosil)ation reactions in the regulation of nuclear functions. Biochem J 342:249–268

    Article  PubMed  PubMed Central  Google Scholar 

  • Fahy JV (2001) Remodelling of the airway epithelium in asthma. Am. J. Respir. Crit Care Med 164:S46–S51

    Article  CAS  Google Scholar 

  • Fattouh R, Al-Garawi A, Fattouh M, Arias K, Walker TD, Goncharova S, Coyle AJ, Humbles AA, Jordana M (2011) Eosinophils are dispensable for allergic remodeling and immunity in a model of house dust mite-induced airway disease. Am J Respir Crit Care Med 183:179–188

    Article  PubMed  Google Scholar 

  • Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Rothenberg ME (2004) Pulmonary chemokine expression is coordinately regulated by STAT-1, STAT-6 and IFN-gamma. J Immunol 173:7565–7574

    Article  CAS  PubMed  Google Scholar 

  • Hammad H, Lambrecht BN (2006) Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J Allergy Clin Immunol 118:331–336

    Article  CAS  PubMed  Google Scholar 

  • Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A (2006) Signalling mechanisms, interaction partners, and target genes of STAT-6. Cytokine Growth Factors Rev 17:173–188

    Article  CAS  Google Scholar 

  • Hoeck J, Woisetschlager M (2001) STAT-6 mediates eotaxin-1 expression in IL-4 or TNF-alpha-induced fibroblasts. J Immunol 166:4507–4515

    Article  CAS  PubMed  Google Scholar 

  • Holgate ST (2002) Airway inflammation and remodelling in asthma: current concepts. Mol Biotechnol 22:179–189

    Article  CAS  PubMed  Google Scholar 

  • Jagtap P, Szàbo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421–440

    Article  CAS  PubMed  Google Scholar 

  • Johnson RJ, Wiley ER, Fattouh R, Swirski KF, Gajewska UB, Coyle JA, Gutierrez-Ramos JC, Ellis R, Inman DM, Jordana M (2004) Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med 169:378–385

    Article  PubMed  Google Scholar 

  • Kay AB (2005) The role of eosinophils in the pathogenesis of asthma. Trends Mol Med 11:148–152

    Article  CAS  PubMed  Google Scholar 

  • Kuperman D, Schofield B, Wills-Karp M, Grusby MJ (1998) Signal transducer and activator of transcription 6 (STAT6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med 187:939–948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurucz I, Szeleny I (2006) Current animal models of bronchial asthma. Curr Pharm Des 12:3175–3194

    Article  CAS  PubMed  Google Scholar 

  • Lucarini L, Pini A, Gerace E, Pellicciari R, Masini E, Moroni F (2014) Poly(ADP-ribose) polymerase inhibition with HYDAMTIQ reduces allergen-induced asthma-like reaction, bronchial hyper-reactivity and airway remodeling. J Cell Mol Med 18:468–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lukacs NW, Oliveira SHP, Hogaboam CM (1999) Chemokines and asthma: redundancy of function or a coordinated effort? J Clin Invest 104:995–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacNee W (2001) Oxidative stress and lung inflammation airways disease. Eur J Pharmacol 429:195–207

    Article  CAS  PubMed  Google Scholar 

  • Masoli M, Fabian D, Holt S, Beasley R (2004) Global initiative for asthma (GINA) program: the global burden of asthma: executive summary of the GINA dissemination committee report. Allergy 59:469–478

    Article  PubMed  Google Scholar 

  • Mehrotra P, Hollenbeck A, Riley JP, Li F, Patel RJ, Akhtar N, Goenka S (2013) Poly (ADP-ribose)polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. J Allergy Clin Immunol 131:521–531

    Article  CAS  PubMed  Google Scholar 

  • Menegazzi M, Di Paola R, Mazzon E, Genovese T, Crisafulli C, Dal Bosco M, Zou Z, Suzuki H, Cuzzocrea S (2008) Glycyrrhizin attenuates the development of carrageenan-induced lung injury in mice. Pharmacol Res 58:22–31

    Article  CAS  PubMed  Google Scholar 

  • Naura AS, Hans CP, Zerfaoui M, You D, Cormier SA, Oumouna M, Boulares AH (2008) Post-allergen challenge inhibition of poly(ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation. Clin Exp Allergy 38:839–846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ngoc LP, Gold DR, Tzianabos AO, Weiss ST, Celedon JC (2005) Cytokines, allergy and asthma. Curr Opin Allergy Clin Immunol 5:161–166

    Article  CAS  PubMed  Google Scholar 

  • Oumouna M, Datta R, Oumouna-Benachour K, Suzuki Y, Hans C, Matthews K, Fallon K, Boulares H (2006) Poly(ADP-ribose) polymerase-1inhibition prevents eosinophils recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation: a potential specific effect on IL-5. J Immunol 177:6489–6496

    Article  PubMed  Google Scholar 

  • Pease JE, Williams TJ (2001) Eotaxin and asthma. Curr Opin Pharmacol 1:248–253

    Article  CAS  PubMed  Google Scholar 

  • Robinson CB, Leonard J, Panettieri RA Jr (2012) Drug development for severe asthma: what are the metrics? Pharmacol There 135:176–118

    Article  CAS  Google Scholar 

  • Sampath D, Castro M, Look DC, Holtzman MJ (1999) Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J Clin Invest 103:1353–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh AM, Busse WW (2006) Asthma exacerbation 2: aetiology. Thorax 61:809–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stampfli MR, Wiley RE, Neigh GS, Gajewska BU, Lei XF, Snider DP, Xing Z, Jordana M (1998) GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Inves 102:1704–1714

    Article  CAS  Google Scholar 

  • Steffen JD, Brody JR, Armen RS, Pascal JM (2013) Structural implications for selective targeting of PARPs. Front Oncol doi. doi:10.3389/fonc.2013.00301

    Google Scholar 

  • Suzuki Y, Masini E, Mazzocca C, Cuzzocrea S, Ciampa A, Suzuki H, Bani D (2004) Inhibition of poly(ADP-ribose) polymerase prevents allergen-induced asthma-like reaction in sensitized Guinea pigs. J Pharmacol Exp Therapy 311:1241–1248

    Article  CAS  Google Scholar 

  • Virag L, Bay P, Bak I, Pacher P, Mabley JD, Liaudet L, Bakondi E, Gergely P, Kollai M, Szabo C (2004) Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma. Med Sci Monit 10:BR77–BR83

    CAS  PubMed  Google Scholar 

  • Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2002) Mediation of poly(ADP-ribose) polymerase −1-dependent cell death by apoptosis-inducing factor. Science 297:259–263

    Article  CAS  PubMed  Google Scholar 

  • Zock JP, Heinrich J, Jarvis D, Verlato G, Norback D, Plana E, Sunyer J, Chinn S, Olivieri M, Soon A, Villani S, Ponzio M, Dahlmann-Hoglund A, Svanes C, Luczynska C (2006) Distribution and determinants of house dust mite allergens in Europe: the European Community respiratory health survey II. J Allergy Clin Immunol 118:682–690

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to Ramzi Fattouh for technical assistance and to Manel Jordana that allows Raffaela Zaffini to join his laboratory: Dep. of Pathology and Molecular Medicine and Division of Respiratory Diseases and Allergy, Center of Gene Therapeutics, MDCL, McMaster University, Hamilton, Ontario, Canada. Part of the results reported in the manuscript has been presented by RZ at the XIX National Congress of Poly-ADP Ribosylation Reaction.

This work was supported by Fondo Unico per la Ricerca (FUR)/Menegazzi, Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Rome, Italy.

This paper is dedicated to the memory of Hisanori Suzuki, who passed away on 19 March 2012 due to a rapidly overwhelming disease. We all remember our friend as a master in life and science, and we hope that he will continue to help us from the place where he is now.

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Authors and Affiliations

  1. Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Strada Le Grazie, 8, 37134, Verona, Italy

    Raffaela Zaffini & Marta Menegazzi

  2. Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166, Messina, Italy

    Rosanna Di Paola & Salvatore Cuzzocrea

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  1. Raffaela Zaffini
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  2. Rosanna Di Paola
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  4. Marta Menegazzi
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Correspondence to Marta Menegazzi.

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Zaffini, R., Di Paola, R., Cuzzocrea, S. et al. PARP inhibition treatment in a nonconventional experimental mouse model of chronic asthma. Naunyn-Schmiedeberg's Arch Pharmacol 389, 1301–1313 (2016). https://doi.org/10.1007/s00210-016-1294-7

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  • DOI: https://doi.org/10.1007/s00210-016-1294-7

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