Human stem cells administered intravenously can restore alveolar epithelial tissue to a normal function in a novel ex vivo perfused human lung after E. coli endotoxin-induced acute lung injury (ALI), according to research from the University of California San Francisco.
The findings will be reported at the ATS 2010 International Conference in New Orleans.
ALI is a common cause of respiratory failure in the intensive care units, often leading to death. It can be caused by both direct injury such as aspiration and pneumonia, and indirect injury such as sepsis and from trauma. ALI is characterized by diffuse bilateral infiltrates on chest x-ray, hypoxemia and both lung endothelial and epithelial injury. Because ALI causes injury to the alveolar epithelium, it impairs its ability to reabsorb pulmonary edema fluid from the airspaces of the lung. Yearly, ALI affects approximately 200,000 patients in the US and has a 40 percent mortality rate despite extensive investigations into its causes and pathophysiology. Innovative therapies are desperately needed.
To determine whether stem cell therapy given intravenously would be able to repair the damaged alveolar epithelium, researchers used right human lungs that had been declined for transplantation by the Northern California Transplant Donor Network. The lungs were perfused with whole blood and ventilated with continuous positive airway pressure. The researchers then infused the right middle lung with endotoxin, which induces acute lung injury. One hour following injury, clinical grade human mesenchymal stem cells (hMSC)—those that are derived from bone marrow of healthy adults— were given intravenously.
"We found that intravenous infusion of clinical grade cryo-preserved allogeneic hMSC were effective in restoring the capacity of the alveolar epithelium to resolve pulmonary edema when given after the establishment of E. coli endotoxin-induced acute lung injury in an ex vivo perfused human lung preparation," explained Jae-Woo Lee, M.D., who led the study in the laboratory of Michael A. Matthay, M.D. "In addition, we found that intravenous infusion of hMSC preferentially homed to the injured areas of the lung, which means that the cells find their way from the bloodstream to the sites in the lung of injury."
Prior research from the group focused on delivering stem cells intrabronchially. Importantly, in this study, the group found that intravenous delivery of hMSC worked as well as intrabronchial administration. Intravenous administration would be preferred in critically ill mechanically ventilated patients with ALI because bronchoscopy may lead to transient problems with oxygenation and ventilation.
In addition to having restored function of alveolar epithelial cells, lungs treated with hMSC showed a reduction in inflammatory cytokine, IL-1 and IL-8, levels suggesting a favorable shift away from a proinflammatory environment in the injured alveolus.
"These results suggest that the intravenous route would be ideal for potential clinical trials of hMSC for severe acute lung injury, a syndrome of acute respiratory failure in critically ill patients that is associated with 40 percent mortality," said Dr. Lee.
"These results extend our recent publication, which demonstrated that hMSC may have therapeutic potential clinically in patients with severe acute lung injury. We need to do more experiments with testing the effect of hMSC against live bacterial induced lung injury in the perfused human lung and now advance to doing Phase I and II safety and efficacy studies in patients."
University of California San Francisco