This grant seeks to investigate the mechanisms by which PMN interactions with epithelial cells during transmigration activate 2-catenin-dependent signaling pathways in lung epithelial cells and the importance of these pathways in epithelial repair. We will determine the signaling pathways that trigger epithelial 2-catenin activation including E-cadherin cleavage by PMN elastase. We will determine the mechanisms by which 2- catenin activation promotes repair of epithelial injury induced by PMN transmigration in vitro and in murine models of ALI using gene-targeted mice.

Public Health Relevance

Acute Lung Injury (ALI) is a frequent complication in critically ill patients that is responsible for significant morbidity, mortality, and the expenditure of >$50 billion annually in health care costs. To date, aside from lung protective mechanical ventilation strategies and supportive care, there are no specific therapies for ALI and mortality rates remain unacceptably high (20-50%). Recovery from ALI is dependent on repair of the cells that line the air sacs of the lung (epithelial cells). We have discovered that 2-catenin, an intracellular protein, promotes repair of these lining cells. We propose to study how this beneficial effect is exerted with the goal of identifying specific targets for therapies to speed recovery from this devastating disorder.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-U (M1))
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Colombini-Hatch, Sandra
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National Jewish Health
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Jansing, Nicole L; McClendon, Jazalle; Henson, Peter M et al. (2017) Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice. Am J Respir Cell Mol Biol 57:519-526
Schmidt, Eric P; Kuebler, Wolfgang M; Lee, Warren L et al. (2016) Adhesion Molecules: Master Controllers of the Circulatory System. Compr Physiol 6:945-73
Zemans, Rachel L; Henson, Peter M; Henson, Jan E et al. (2015) Conceptual approaches to lung injury and repair. Ann Am Thorac Soc 12 Suppl 1:S9-15
Aschner, Yael; Zemans, Rachel L; Yamashita, Cory M et al. (2014) Matrix metalloproteinases and protein tyrosine kinases: potential novel targets in acute lung injury and ARDS. Chest 146:1081-1091
Leissinger, Mary; Kulkarni, Ritwij; Zemans, Rachel L et al. (2014) Investigating the role of nucleotide-binding oligomerization domain-like receptors in bacterial lung infection. Am J Respir Crit Care Med 189:1461-8
Long, Huaicong; O'Connor, Brian P; Zemans, Rachel L et al. (2014) The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 9:e93550
Aschner, Yael; Khalifah, Anthony P; Briones, Natalie et al. (2014) Protein tyrosine phosphatase ? mediates profibrotic signaling in lung fibroblasts through TGF-? responsiveness. Am J Pathol 184:1489-502
Zemans, Rachel L; McClendon, Jazalle; Aschner, Yael et al. (2013) Role of ?-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 304:L415-27
Bhatia, Madhav; Zemans, Rachel L; Jeyaseelan, Samithamby (2012) Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol 46:566-72
Schmidt, Eric P; Yang, Yimu; Janssen, William J et al. (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18:1217-23

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