Acute Respiratory Distress Syndrome (ARDS) is a common form of acute lung injury seen in hospitalized patients with an incidence of 200,000 new cases in the United States each year. While the clinical manifestation and progression of this syndrome is stereotyped, very little is understood about the underlying cause and mechanism of its development. As such, mortality still approaches 25-40%, and currently the only known measures that reduce ARDS mortality are mechanical ventilation and supportive care. Loss of epithelial cell barrier integrity is thought to be a key inciting event in the development of ARDS. Recently, our laboratory discovered a novel role for the Abl family of tyrosine kinases, Abl1 and Abl2, in lung epithelial cell integrity and permeability. We found that treatment of epithelial cells (T7 cells) with an Abl inhibitor ameliorated the effects of potent inducers of permeability, including TGF-, IL-1, and TNF- alpha. Preliminary experiments have shown that treatment of mice given the Abl specific allosteric inhibitor, GNF5, reduces leukocyte and protein extravasation into the air space by 50- 70% with a corresponding reduction of cell damage accumulation. We hypothesize that Abl kinases play an important role in maintaining epithelial barrier function in the lung, and Abl inhibitors might be used to effectively treat sick mice in a model of acute lung injury. We propose to test our hypothesis in the following aims: (1) Evaluate whether pharmacologic and genetic inhibition of Abl kinases effectively treats mice in a model of acute lung injury. (2) Identify the molecular mechanisms by which inhibition of Abl kinases affect epithelial permeability using our in vitro models in Type II pneumocytes (T7).
Acute Respiratory Distress Syndrome (ARDS) is a common form of acute lung injury seen in hospitalized patients with an incidence of 200,000 new cases in the United States each year. Mortality still approaches 25-40%, and currently the only known measures that reduce ARDS mortality are mechanical ventilation and supportive care. This proposal seeks to identify novel pharmacological treatment approaches for this disease based on preliminary findings in mouse studies.
| Khatri, Aaditya; Wang, Jun; Pendergast, Ann Marie (2016) Multifunctional Abl kinases in health and disease. J Cell Sci 129:9-16 |
