title: Pulmonary inflammation is regulated by the levels of the vesicular acetylcholine transporter.
abstract: Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti-inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-α and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kB) in lung of VAChT-deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kB pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis.
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors: Nathalia M
authors: NM
authors: Pinheiro
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors: Claudia J C P
authors: CJ
authors: Miranda
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors: Adenir
authors: A
authors: Perini
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors: Niels O S
authors: NO
authors: Câmara
authors: Department of Pharmacology Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
authors: Soraia K P
authors: SK
authors: Costa
authors: Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.
authors: Maria Isabel C
authors: MI
authors: Alonso-Vale
authors: Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.
authors: Luciana C
authors: LC
authors: Caperuto
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors: Iolanda F L C
authors: IF
authors: Tibério
authors: Molecular Medicine Group, Robarts Research Institute, Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, University of Western Ontario, London, Canada.
authors: Marco Antônio M
authors: MA
authors: Prado
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.
authors: Mílton A
authors: MA
authors: Martins
authors: Molecular Medicine Group, Robarts Research Institute, Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, University of Western Ontario, London, Canada.
authors: Vânia F
authors: VF
authors: Prado
authors: Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil; Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.
authors: Carla M
authors: CM
authors: Prado
mesh_terms: D000109:Acetylcholine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004487:Edema / Q000209:etiology / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050494:Vesicular Acetylcholine Transport Proteins / Q000502:physiology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D000109:Acetylcholine