title: Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy.
abstract: Viral pneumonia is a major cause of acute respiratory distress syndrome (ARDS). Anti-inflammatory therapies for viral-induced lung injury show promise in preclinical models. Mesenchymal stem/stromal cells (MSCs) are multipotent, self-renewing cells that secrete anti-inflammatory cytokines and epithelial and endothelial growth factors. We inoculated mice intranasally with influenza A (murine-adapted Puerto Rico/8/34) or PBS, and the mice were killed at multiple time points after infection for measures of lung injury and viral load. We report that influenza induces marked, long-lasting dysfunction of the alveolar-capillary barrier peaking at 1 wk but lasting longer than 3 wk postinfection. Weight loss, commonly employed as a criterion for euthanasia (and hence "survival"), was found to be poorly predictive of the severity of lung injury at its peak; rather, persistent weight loss 11 days postinfection identified mice with impaired injury resolution. Murine and human bone marrow-derived MSCs (obtained from the National Institutes of Health repository) were then administered intravenously during the rapid phase of injury progression. Murine MSCs (mMSCs) given two times 24 h apart failed to improve weight loss, lung water, bronchoalveolar lavage inflammation, or histology. However, mMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load at day 7. Human MSCs administered intravenously showed a similar lack of efficacy. The results demonstrate that the influenza murine model bears important similarities to the slow resolution of ARDS in patients. Despite their potent therapeutic effects in many models of acute inflammation and lung injury, MSCs do not improve influenza-mediated lung injury in mice.
authors.affiliation: Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California Jeffrey.Gotts@ucsf.edu.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gotts
authors.affiliation: Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Abbott
authors.affiliation: Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000473:pathology; D000818:Animals; D015824:Blood-Air Barrier / Q000503:physiopathology*; D018893:Bronchoalveolar Lavage; D002196:Capillaries / Q000503:physiopathology*; D002199:Capillary Permeability; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007251:Influenza, Human / Q000150:complications* / Q000473:pathology / Q000628:therapy / Q000821:virology; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000473:pathology / Q000628:therapy / Q000821:virology; D011650:Pulmonary Alveoli / Q000503:physiopathology*
keywords: acute lung injury; acute respiratory distress syndrome; mesenchymal stem cells; pneumonia; pulmonary edema