title: Cardiopulmonary and histological characterization of an acute rat lung injury model demonstrating safety of mesenchymal stromal cell infusion.
abstract: OBJECTIVE
  In the field of cellular therapy, potential cell entrapment in the lungs following intravenous administration in a compromised or injured pulmonary system is an important concern that requires further investigation. We developed a rat model of inflammatory and fibrotic lung disease to mimic the human clinical condition of obliterative bronchiolitis (OB) and evaluate the safety of intravenous infusion of mesenchymal stromal cells (MSCs). This model was used to obtain appropriate safety information and functional characterization to support the translation of an ex vivo-generated cellular product into human clinical trials. To overcome spontaneous recovery and size limitations associated with current animal models, we used a novel multiple dose bleomycin strategy to induce lasting lung injury in rats.
  
  
  METHODS
  Intratracheal instillation of bleomycin was administered to rats on multiple days. MSCs were intravenously infused 7 days apart. Detailed pulmonary function tests including forced expiratory volume, total lung capacity, and invasive hemodynamic measurements were conducted to define the representative disease model and monitor cardiopulmonary hemodynamic consequences of the cell infusion. Post-euthanasia assessments included a thorough evaluation of lung morphology and histopathology.
  
  
  RESULTS
  The double dose bleomycin instillation regimen resulted in severe and irreversible lung injury and fibrosis. Cardiopulmonary physiological monitoring reveled that no adverse events could be attributed to the cell infusion process.
  
  
  CONCLUSIONS
  Although our study did not show the infusion of MSCs to result in an improvement in lung function or rescue of damaged tissue this study does confirm the safety of MSC infusion into damaged lungs.
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI, United States.
authors.forename: Rudolf K
authors.initials: RK
authors.lastname: Braun
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Koch
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI, United States.
authors.forename: David
authors.initials: D
authors.lastname: Pegelow
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: Jaehyup
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: Amish N
authors.initials: AN
authors.lastname: Raval
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Schmuck
authors.affiliation: Research Animal Resource Center, University of Wisconsin, Madison, WI, United States.
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Schwahn
authors.affiliation: Waisman Biomanufacturing, University of Wisconsin, Madison, WI, United States.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hei
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Centanni
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI, United States.
authors.forename: Marlowe
authors.initials: M
authors.lastname: Eldridge
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, United States; University of Wisconsin Carbone Cancer Center, Madison, WI, United States. Electronic address: pxh@medicine.wisc.edu.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D006339:Heart Rate; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000473:pathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests
chemical_list: D001761:Bleomycin
keywords: MSC; cardiac function; cardiopulmonary characterization; cellular therapy; lung injury; mesenchymal stromal cells; pulmonary function; safety; stem cells