Grant: Operating Grant

Sepsis is a leading cause of acute respiratory distress syndrome (ARDS). The mortality in these patients is 38-60%, and the morbidity in survivors represents a significant burden of illness and cost to our health care. No specific treatment exists and the best we can do is provide patients with antibiotics, source control and a reduction in ventilation parameters to avoid the development of ventilator induced lung injury. Accordingly, novel treatments are urgently needed. My research focuses on identifying novel molecular targets of therapy. Recently, mesenchymal stem/stromal cell (MSC) have been shown to reduce mortality and lung injury in animal models of sepsis. How these cells exert their beneficial effect is unknown. In this grant, we explore the hypothesis that MSCs modulate the innate-immune response of the lung by regulating microRNA expression. MiRNAs are small noncoding RNAs that control gene expression. To this end we have profiled miRNAs in the lung of septic mice treated with MSCs or placebo and identified two miRNAs that are regulated by MSCs. Both are novel, share extensive similarities with their human counterpart and may be involved in inflammation and lung edema formation (when fluid leaks from the vessels into the tissues). To translate our mouse findings to humans, we aim to determine the role of the miR-193-5p and 27a-3p in human pulmonary cell dysfunction (inflammation and barrier function). Preliminary experiments with miR-193b-5p show its involvement in preserving cell-cell contact thus preventing the development of leaky vessels and lung edema formation. Similarly, miR-27a-3p regulates genes involved in inflammation, mechanical stretch, and edema handling. We will also block these miRNAs in mouse models of lung injury to determine if this strategy is feasible for the treatment of sepsis-induced lung injury in vivo. The clinical relevance of our project lies in the translational potential for identifying novel targets for therapy in ARDS.