Lung Injury and Repair

The University of Michigan has a longstanding history of a productive multidisciplinary approach to understanding basic mechanisms of lung injury and repair. Investigators have employed innovative cellular, molecular, and genetic approaches in both animal models and tissues from diseased patients. Considerable research has focused on the initial insult to the alveolarcapillary membrane, including mechanisms of leukocyte recruitment/activation, cellular damage, and how this initial injury response is regulated. Specific areas of emphasis include chemokine biology, toll receptor signaling in non-infectious lung injury, epithelial cell biology, and cell death by necrosis, apoptosis, or autophagy. The influence of environmental factors (e.g. mechanical stretch, hyperoxia, infection) on lung injury responses is a major focus of investigation.   

Epithelial-mesenchymal interactions, protease-antiprotease balance, eicosanoid mediators, and growth factors are all crucial to the ability of the lung to repair with eventual return to normal architecture. Mechanisms by which lung cells differentiate and how the development and interactions of different cell types are orchestrated to generate tissues are an active focus of research that has been greatly facilitated by the development of the human de-cellularized lung model. Complementary areas of research within the division include epithelial cell-fibroblast interactions, epithelial-mesenchymal cell transition, protease, eicosanoid and growth factor biology, mesenchymal stem cells, lung extracelluar matrix biology, and the role of macrophages in the regulation of lung reparative responses. 

Preclinical research performed in cellular systems and animal models has motivated innovative trials in patients with acute lung injury (ALI). The University of Michigan was awarded both a Specialized Center of Research (SCOR) and Specialized Center of Clinically-Oriented Research (SCCOR) to perform multidisciplinary translational research focused on pathogenesis and treatment of ALI. Research supported by these programs resulted in the identification of a mesenchymal progenitor cell population present in the airspace of ALI patients, and the phenotype of this cell population was predictive of clinical outcomes in this patient population. Preclinical studies performed by SCCOR investigators also led to the design and performance of a randomized multi-center therapeutic trial of growth factor (GM-CSF) administration in patients with ALI. This trial has generated additional hypothesis-generating data that has directed the design of future trials in patients with ALI or at risk for the development of ALI.