title: Intratracheal Administration of Mesenchymal Stem Cells Modulates Tachykinin System, Suppresses Airway Remodeling and Reduces Airway Hyperresponsiveness in an Animal Model.
abstract: BACKGROUND
  The need for new options for chronic lung diseases promotes the research on stem cells for lung repair. Bone marrow-derived mesenchymal stem cells (MSCs) can modulate lung inflammation, but the data on cellular processes involved in early airway remodeling and the potential involvement of neuropeptides are scarce.
  
  
  OBJECTIVE
  To elucidate the mechanisms by which local administration of MSCs interferes with pathophysiological features of airway hyperresponsiveness in an animal model.
  
  
  METHODS
  GFP-tagged mouse MSCs were intratracheally delivered in the ovalbumin mouse model with subsequent functional tests, the analysis of cytokine levels, neuropeptide expression and histological evaluation of MSCs fate and airway pathology. Additionally, MSCs were exposed to pro-inflammatory factors in vitro.
  
  
  RESULTS
  Functional improvement was observed after MSC administration. Although MSCs did not adopt lung cell phenotypes, cell therapy positively affected airway remodeling reducing the hyperplastic phase of the gain in bronchial smooth muscle mass, decreasing the proliferation of epithelium in which mucus metaplasia was also lowered. Decrease of interleukin-4, interleukin-5, interleukin-13 and increase of interleukin-10 in bronchoalveolar lavage was also observed. Exposed to pro-inflammatory cytokines, MSCs upregulated indoleamine 2,3-dioxygenase. Moreover, asthma-related in vivo upregulation of pro-inflammatory neurokinin 1 and neurokinin 2 receptors was counteracted by MSCs that also determined a partial restoration of VIP, a neuropeptide with anti-inflammatory properties.
  
  
  CONCLUSIONS
  Intratracheally administered MSCs positively modulate airway remodeling, reduce inflammation and improve function, demonstrating their ability to promote tissue homeostasis in the course of experimental allergic asthma. Because of a limited tissue retention, the functional impact of MSCs may be attributed to their immunomodulatory response combined with the interference of neuropeptide system activation and tissue remodeling.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Spaziano
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Piegari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Matteis
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Russo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Gioia
authors.initials: G
authors.lastname: Tartaglione
authors.affiliation: Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000276:immunology*; D018041:Receptors, Neurokinin-2 / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: C556062:IL10 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018793:Interleukin-13; D015848:Interleukin-5; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D015847:Interleukin-4; D010047:Ovalbumin