title: Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice.
abstract: OBJECTIVE
  Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury.
  
  
  METHODS
  Prospective randomized controlled experimental study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  One hundred forty-three females and 24 male C57BL/6 mice.
  
  
  METHODS
  Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 10 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration.
  
  
  RESULTS
  At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype.
  
  
  CONCLUSIONS
  Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions.
authors.affiliation: 1Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 2Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 3The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. 4Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada. 5Laboratory of Cellular and Molecular Cardiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 6Laboratory of Inflammation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 7The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Maron-Gutierrez
authors.forename: Johnatas D
authors.initials: JD
authors.lastname: Silva
authors.forename: Karina D
authors.initials: KD
authors.lastname: Asensi
authors.forename: Ilka
authors.initials: I
authors.lastname: Bakker-Abreu
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Shan
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Diaz
authors.forename: Regina C S
authors.initials: RC
authors.lastname: Goldenberg
authors.forename: Shirley H J
authors.initials: SH
authors.lastname: Mei
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Morales
authors.forename: Patricia R M
authors.initials: PR
authors.lastname: Rocco
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Dos Santos
mesh_terms: D055371:Acute Lung Injury / Q000503:physiopathology / Q000628:therapy*; D056151:Airway Remodeling / Q000502:physiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D015656:Respiratory Mechanics
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D003094:Collagen; D020782:Matrix Metalloproteinases