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Alpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase

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Abstract

Pulmonary emphysema is a primary component of chronic obstructive pulmonary disease (COPD), a life-threatening disorder characterized by lung inflammation and restricted airflow, primarily resulting from the destruction of small airways and alveolar walls. Cumulative evidence suggests that nicotinic receptors, especially the α7 subtype (α7nAChR), is required for anti-inflammatory cholinergic responses. We postulated that the stimulation of α7nAChR could offer therapeutic benefits in the context of pulmonary emphysema. To investigate this, we assessed the potential protective effects of PNU-282987, a selective α7nAChR agonist, using an experimental emphysema model. Male mice (C57BL/6) were submitted to a nasal instillation of porcine pancreatic elastase (PPE) (50 µl, 0.667 IU) to induce emphysema. Treatment with PNU-282987 (2.0 mg/kg, ip) was performed pre and post-emphysema induction by measuring anti-inflammatory effects (inflammatory cells, cytokines) as well as anti-remodeling and anti-oxidant effects. Elastase-induced emphysema led to an increase in the number of α7nAChR-positive cells in the lungs. Notably, both groups treated with PNU-282987 (prior to and following emphysema induction) exhibited a significant decrease in the number of α7nAChR-positive cells. Furthermore, both groups treated with PNU-282987 demonstrated decreased levels of macrophages, IL-6, IL-1β, collagen, and elastic fiber deposition. Additionally, both groups exhibited reduced STAT3 phosphorylation and lower levels of SOCS3. Of particular note, in the post-treated group, PNU-282987 successfully attenuated alveolar enlargement, decreased IL-17 and TNF-α levels, and reduced the recruitment of polymorphonuclear cells to the lung parenchyma. Significantly, it is worth noting that MLA, an antagonist of α7nAChR, counteracted the protective effects of PNU-282987 in relation to certain crucial inflammatory parameters. In summary, these findings unequivocally demonstrate the protective abilities of α7nAChR against elastase-induced emphysema, strongly supporting α7nAChR as a pivotal therapeutic target for ameliorating pulmonary emphysema.

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Funding

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grants 08/55359-5, 14/25689-4 and 20/13480-4) and by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Grant number #306278/2015-4) received by C.M.P and by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grants 18/15738-9) received by N.M.P-M.

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Authors and Affiliations

  1. Department of Internal Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil

    Rosana Banzato, Clarice R. Olivo, Silvia Fukuzaki, Fernanda D. T. Q. S. Lopes, Iolanda F. L. C. Tibério & Carla M. Prado

  2. Department of Biosciences, Instituto de Saúde e Sociedade, Universidade Federal de São Paulo, Rua Silva Jardim 136 sala 312, Santos, SP, 11015-020, Brazil

    Nathalia M. Pinheiro-Menegasso, Laura Taguchi, Stheffany de Oliveira Santos & Carla M. Prado

  3. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil

    Fernanda Paula Roncon Santana Novelli

  4. Rheumatology Division of the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil

    Walcy Paganelli Rosolia Teodoro

  5. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Alessandra Choqueta de Toledo-Arruda

  6. Department of Physiology & Pharmacology, University of Western Ontario, London, Canada

    Marco Antônio M. Prado & Vânia F. Prado

  7. Department of Anatomy & Cell Biology, University of Western Ontario, London, Canada

    Marco Antônio M. Prado & Vânia F. Prado

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  1. Rosana Banzato
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  2. Nathalia M. Pinheiro-Menegasso
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  3. Fernanda Paula Roncon Santana Novelli
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  4. Clarice R. Olivo
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  6. Stheffany de Oliveira Santos
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  7. Silvia Fukuzaki
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  8. Walcy Paganelli Rosolia Teodoro
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  12. Marco Antônio M. Prado
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  13. Vânia F. Prado
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  14. Carla M. Prado
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Contributions

R.B., N.M.P., F.D.T.Q.L., I.F.L.C.T., A.C.T-A, M.A.M.P., V.F.P, C.M.P concept the study and design the experiments. R.B, N.M.P., F.P.R.S–N., C.R.O., L.T., S.O.S, S.F, W.P.R.T are involved in the material preparation, data collection and analysis. R.B and C.M.P first draft of the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Carla M. Prado.

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Banzato, R., Pinheiro-Menegasso, N.M., Novelli, F.P.R.S. et al. Alpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase. Inflammation (2024). https://doi.org/10.1007/s10753-023-01953-9

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