Their study is published in the September 1 issue of the “Proceedings of the National Academy of Sciences” and is available at http://www.pnas.org/content/early/2009/08/27/0907996106.full.pdf+html
The significance of the team’s work includes the discovery of the mechanism responsible for the therapeutic benefit and the development of a human lung-injury model that makes research of potential clinical therapies – like stem cells – possible. Acute lung injury is a leading cause of acute respiratory failure in critically ill patients.
“This is an exciting finding,” said Jae W. Lee, MD, associate professor in the UCSF Department of Anesthesiology and lead author on the paper. “As a clinician and researcher, acute lung injury is a condition that needs innovative therapies. Current treatment for acute lung injury is only supportive with lung protective mechanical ventilation. Our findings show that mesenchymal stem cells should be studied further as a potential therapy.”
Human allogenic mesenchymal stem cells are adult stem cells from a source other than the host tissue. To study their potential therapeutic effect, the team created a lung-injury model that behaved like the lungs of patients with acute respiratory failure.
The model uses human research lungs donated from the Northern California Transplant Donor Network that do not meet criteria for transplantation. In the lab, the team perfused the lung with a protein-salt solution and human blood, making it possible to study the mechanisms of lung injury and repair.
Researchers created injury by administering E. coli endotoxin into distal airspaces of perfused lungs. This resulted in acute pulmonary edema (extravascular water and fluid in the lungs), an increase in lung vascular permeability, and an almost complete loss of alveolar fluid clearance (AFC). AFC is the ability of lung epithelium to remove alveolar edema.
Researchers then administered the mesenchymal stem cells one hour after endotoxin-induced lung injury. They found that the injured lung tissue was fully restored to normal fluid balance: alveolar lung endothelial permeability to protein was normalized and alveolar fluid clearance returned to control levels.
“In a clinical sense, the stem cells reversed what we often see as complications of severe pneumonia—edema, inflammation and injury. Our group has been testing mesenchymal stem cells by administering them into the lung, and we have found impressive therapeutic benefit,” said Michael Matthay, MD, senior author, professor of medicine in the UCSF Division of Pulmonary and Critical Care, and senior associate in the UCSF Cardiovascular Research Institute.
In a previous study published in the “Journal of Immunology” in November 2007, the team reported that intrapulmonary treatment with mesenchymal stem cells four hours after endotoxin delivery to the lung improved survival and reduced pulmonary edema in mice. However, the exact mechanisms of the stem cells’ benefit were not then identified.
In this study, the mechanism was identified. The team found that keratinocyte growth factor was essential for the restorative effects of the mesenchymal stem cells, and in fact, was responsible for 80 percent of the therapeutic benefit.
The team plans further mechanistic study of the therapeutic role of mesenchymal stem cells as well as the best route of delivery, either intravenously or intra-bronchially. Plans for an upcoming clinical trial are in the works to test the safety and dosing of a stem cell therapy for severely lung-injured patients with complications from H1N1 or pneumonia.
Additional authors on the study were Naveen Gupta, MD, adjunct assistant professor in the UCSF Division of Pulmonary and Critical Care; Vladimir Serikov, MD, PhD, staff scientist with Children’s Hospital Oakland Research Institute, and Xiao Fang, MD, PhD, scientific specialist at UCSF.
The study was supported by the National Heart, Lung, and Blood Institute, the Foundation of Anesthesia Education and Research, and the Parker B. Francis grant.
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