Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute respiratory failure, affecting nearly 200,000 patients annually with an estimated mortality of 25-40%. Pneumonia is the most common cause, and viral pneumonia, most commonly influenza, is a major contributor. Influenza kills tens of thousands of patients each year, and the next pandemic has the potential to kill hundreds of thousands. Although antiviral therapies produce modest clinical improvements, there is little benefit when initiated 48hours after febrile illness begins, and drug resistance is increasing. The mechanisms of viral-induced lung injury are not well understood, specifically the pathways of injury to the barriers ofthe lung that normally separate the blood from the airspaces. In mice, influenza results in a clinical syndrome similar to human disease. Intense innate immune responses develop in humans and mice following infection with various strains of influenza virus, and preclinical data suggest anti-inflammatory therapies may attenuate viral-induced lung injury. Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells that secrete an array of anti-inflammatory cytokines, lipid mediators, and growth factors. MSCs have been shown to improve outcomes in preclinical models of several diseases characterized by uncontrolled pro- inflammatory cascades. Therefore MSCs are a potential but as yet untested therapy in viral-induced lung injury. The objectives of the proposed research are (1) to investigate the mechanisms of influenza-induced disruption of the lung's air-blood barrier, and (2) to test the potential therapeutic mechanisms of MSCs in viral-induced lung injury. We propose to infect mice intranasally with influenza, and analyze temporal changes in the barrier function of the lung, inflammatory cell infiltrates, and viral load during sickness. We will then administer MSCs or their conditioned growth media by different routes to test for therapeutic effects and mechanisms.

Public Health Relevance

Influenza kills tens of thousands of patients annually; and has the potential to kill hundreds of thousands during the next pandemic; largely by causing acute lung injury [2]. Thus influenza constitutes a major threat to public health. Little is known about the mechanisms by which this virus disrupts the barriers between blood and the airspaces. The proposed research will add to our understanding of how influenza causes respiratory failure; and will test a promising novel cell-based therapy (mesenchymal stem cells).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Colombini-Hatch, Sandra
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Gotts, Jeffrey E; Abbott, Jason; Matthay, Michael A (2014) Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy. Am J Physiol Lung Cell Mol Physiol 307:L395-406
Gotts, Jeffrey E; Matthay, Michael A (2014) Endogenous and exogenous cell-based pathways for recovery from acute respiratory distress syndrome. Clin Chest Med 35:797-809