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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. © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


Fernanda P R Santana, Fernanda Y Ricardo-da-Silva, Evelyn T Fantozzi, Nathália M Pinheiro, Iolanda F L C Tibério, Luiz Felipe Pinho Moreira, Marco Antônio M Prado, Vânia F Prado, Wothan Tavares-de-Lima, Carla Máximo Prado, Ana Cristina Breithaupt-Faloppa. Lung Edema and Mortality Induced by Intestinal Ischemia and Reperfusion Is Regulated by VAChT Levels in Female Mice. Inflammation. 2021 Aug;44(4):1553-1564

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PMID: 33715111

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