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. 2017 Jan;31(1):320-332.
doi: 10.1096/fj.201600431R. Epub 2016 Oct 11.

Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile

Nathalia M Pinheiro  1 , Fernanda P R Santana  1   2 , Rafael Ribeiro Almeida  3 , Marina Guerreiro  2 , Milton A Martins  1 , Luciana C Caperuto  2 , Niels O S Câmara  3 , Lislaine A Wensing  3 , Vânia F Prado  4   5 , Iolanda F L C Tibério  1 , Marco Antônio M Prado  4   5 , Carla M Prado  6   7
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Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile

Nathalia M Pinheiro et al. FASEB J. 2017 Jan.

Abstract

Nicotinic α-7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU-282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1β, TNF-α, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P < 0.05). In addition, lung NF-κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9+ and -2+ cells, whereas the number of tissue inhibitor of metalloproteinase-1+ cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of α7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Câmara, N. O. S., Wensing, L. A., Prado, V. F., Tibério, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.

Keywords: ARDS; acetylcholine experimental model; lung inflammation; nicotine receptor; nicotinic agonist.

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