The role of microRNA-223 in acute lung injury (ALI

• Applicant: Dr. Viola Dengler
• Subject Area: Anatomy and Physiology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 204424974

Acute lung injury (ALI) is characterized by acute hypoxemic respiratory failure in the setting of non-cardiogenic pulmonary edema. Mortality of ALI ranges between 35-60%. Among the hallmarks of ALI are activation and massive pulmonary accumulation of inflammatory cells into lungs and a disruption of the alveolar-capillary barrier function. In consequence this leads to an activation of hypoxia- and inflammation-elicited transcriptional pathways and changes in gene expression. Targeting molecular pathways that control lung inflammation during ALI may be of therapeutical potential. MicroRNAs (miRNA) are short non-coding RNAs that function as post-transcriptional gene regulators. While previous reports have implicated miRNAs in the post-transcriptional regulation of inflammatory and hypoxia-dependent gene expression, the role of miRNAs in modulating lung inflammation during ALI are essentially unknown. In pilot studies we induced ALI in mice and analyzed expression patterns of pulmonary miRNAs. These studies revealed profound increases in 10 miRNAs, with strongest induction of miR-223. Subsequent studies with pulmonary epithelial cells exposed to an in vitro model of mechanical ventilation demonstrated robust induction of miR-223, implicating a mucosal contribution of miR-223 induction. In conjunction with previous studies implicating miR-223 in dampening inflammatory responses, we hypothesize that mucosal induction of miR-223 should represent an endogenous anti-inflammatory pathway to attenuate lung inflammation during ALI. To study this hypothesis, we will examine the mechanisms of miR-223 induction during cyclic mechanical stretch in vitro, or during ALI in vivo. We will define the functional role of miR-223 during different phases of ALI and we attempt to target miR-223 for the treatment of ALI. These studies are designed to identify regulatory pathways during ALI and intend to introduce miRNA-based therapy as novel therapeutic approach into the treatment of ALI.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Holger Klaus Eltzschig, Ph.D.