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Lung Edema and Mortality Induced by Intestinal Ischemia and Reperfusion Is Regulated by VAChT Levels in Female Mice

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Abstract

Acute lung injury induced by intestinal ischemia/reperfusion (I/R) is a relevant clinical condition. Acetylcholine (ACh) and the α7 nicotinic ACh receptor (nAChRα-7) are involved in the control of inflammation. Mice with reduced levels of the vesicular ACh transporter (VAChT), a protein responsible for controlling ACh release, were used to test the involvement of cholinergic signaling in lung inflammation due to intestinal I/R. Female mice with reduced levels of VAChT (VAChT-KDHOM) or wild-type littermate controls (WT) were submitted to intestinal I/R followed by 2 h of reperfusion. Mortality, vascular permeability, and recruitment of inflammatory cells into the lung were investigated. Parts of mice were submitted to ovariectomy (OVx) to study the effect of sex hormones or treated with PNU-282,987 (nAChRα-7 agonist). A total of 43.4% of VAChT-KDHOM-I/R mice died in the reperfusion period compared to 5.2% of WT I/R mice. The I/R increased lung inflammation in both genotypes. In VAChT-KDHOM mice, I/R increased vascular permeability and decreased the release of cytokines in the lung compared to WT I/R mice. Ovariectomy reduced lung inflammation and permeability compared to non-OVx, but it did not avoid mortality in VAChT-KDHOM-I/R mice. PNU treatment reduced lung permeability, increased the release of proinflammatory cytokines and the myeloperoxidase activity in the lungs, and prevented the increased mortality observed in VAChT-KDHOM mice. Cholinergic signaling is an important component of the lung protector response against intestinal I/R injury. Decreased cholinergic signaling seems to increase pulmonary edema and dysfunctional cytokine release that increased mortality, which can be prevented by increasing activation of nAChRα-7.

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Funding

This work was supported by the São Paulo Research Foundation (FAPESP) [grant numbers 2018/06088-0 and 2014/25689-4], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001, and by the National Council for Technologic and Scientific Development (CNPq) [grant number 306278/2015-4].

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Authors and Affiliations

  1. Department of Biological Science, Federal University of São Paulo, Diadema, Brazil

    Fernanda P. R. Santana & Carla Máximo Prado

  2. Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

    Fernanda Y. Ricardo-da-Silva, Luiz Felipe Pinho Moreira & Ana Cristina Breithaupt-Faloppa

  3. Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil

    Evelyn T. Fantozzi & Wothan Tavares-de-Lima

  4. Department of Bioscience, Federal University of São Paulo, Campus Baixada Santista, Rua Silva Jardim, 136 – Vila Mathias, Santos, SP, Brazil

    Nathália M. Pinheiro & Carla Máximo Prado

  5. Department of Internal Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil

    Nathália M. Pinheiro, Iolanda F. L. C. Tibério & Carla Máximo Prado

  6. Robarts Research Institute, Department of Physiology & Pharmacology, The University of Western Ontario, London, Canada

    Marco Antônio M. Prado & Vânia F. Prado

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

    Marco Antônio M. Prado & Vânia F. Prado

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  1. Fernanda P. R. Santana
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  2. Fernanda Y. Ricardo-da-Silva
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  10. Carla Máximo Prado
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  11. Ana Cristina Breithaupt-Faloppa
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Fernanda P.R. Santana, Fernanda Y. Ricardo-da-Silva, Evelyn T. Fantozzi, Nathália P. Montouro, Carla M. Prado, and Ana Cristina Breithaupt-Faloppa. The first draft of the manuscript was written by Fernanda P.R. Santana, Carla M. Prado, and Ana Cristina Breithaupt-Faloppa, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Carla Máximo Prado.

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The entire experiments were reviewed and proved by the Animal Ethics Committee of the School of Medicine of the University of São Paulo (FM-USP (Document number 1189/2019).

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Highlights

• Cholinergic signaling is an important component of lung responses.

• Decreased cholinergic signaling induces increased mortality after intestinal I/R.

• Decreased cholinergic signaling induces a dysfunctional cytokine release.

• Activation of nAChRα-7 can be considered a therapeutic target in lung inflammation.

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Santana, F.P.R., Ricardo-da-Silva, F.Y., Fantozzi, E.T. et al. Lung Edema and Mortality Induced by Intestinal Ischemia and Reperfusion Is Regulated by VAChT Levels in Female Mice. Inflammation 44, 1553–1564 (2021). https://doi.org/10.1007/s10753-021-01440-z

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