title: Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.
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.
authors.affiliation: Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Nathalia M
authors.initials: NM
authors.lastname: Pinheiro
authors.affiliation: Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil.|Department of Biological Science, Universidade Federal de São Paulo, Diadema, Brazil.
authors.forename: Fernanda P R
authors.initials: FP
authors.lastname: Santana
authors.affiliation: Department of Immunology, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Rafael Ribeiro
authors.initials: RR
authors.lastname: Almeida
authors.affiliation: Department of Biological Science, Universidade Federal de São Paulo, Diadema, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Guerreiro
authors.affiliation: Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Milton A
authors.initials: MA
authors.lastname: Martins
authors.affiliation: Department of Biological Science, Universidade Federal de São Paulo, Diadema, Brazil.
authors.forename: Luciana C
authors.initials: LC
authors.lastname: Caperuto
authors.affiliation: Department of Immunology, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Câmara
authors.affiliation: Department of Immunology, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Lislaine A
authors.initials: LA
authors.lastname: Wensing
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada; and.
authors.forename: Vânia F
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Iolanda F L C
authors.initials: IF
authors.lastname: Tibério
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada; and.
authors.forename: Marco Antônio M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo, Brazil; carla.prado@unifesp.br.|Department of Bioscience, Federal University of São Paulo, Campus Baixada Santista, Santos, Brazil.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Prado
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control*; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D012313:RNA / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D016207:Cytokines; D008070:Lipopolysaccharides; C498513:PNU-282987; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012313:RNA
keywords: ARDS; acetylcholine experimental model; lung inflammation; nicotine receptor; nicotinic agonist