Endothelial thrombospondin-1 in matrix proteolysis during Pseudomonal lung injury

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Project Summary/Abstract: Acute Respiratory Distress Syndrome (ARDS) is a syndrome characterized by rapidly progressive respiratory failure and refractory hypoxemia and is a major cause of morbidity and mortality in critically ill patients worldwide. The most common risk factor for ARDS is severe bacterial pneumonia and patients with ARDS are also frequently plagued by nosocomial infections including lower respiratory tract infections (LRTIs). Pseudomonas aeruginosa (PA) is a common ICU pathogen and PA pneumonia is associated with increased mortality in ventilator associated pneumonia compared to other gram-negative pathogens. PA has been shown to cause extensive proteolytic injury leading to tissue damage and degradation of the alveolar-capillary barrier in animal models, in part through secreted exoproteases such as LasB. The metalloprotease LasB has also been shown to degrade junctional proteins important in barrier integrity. While pathogen derived virulence factors have been extensively characterized, there is limited knowledge regarding the host mechanisms that protect against proteolytic injury and vascular permeability in the lungs. Thrombospondin-1 (TSP-1) is a matrix glycoprotein with a variety of functions including regulation of inflammation. TSP-1 has been previously shown to inhibit host- derived serine proteases and the pathogen-derived exoprotease, LasB. TSP-1 is expressed by lung endothelial cells but its role in pathogen-induced injury is unknown. The main objective of this proposal is to determine the role of endothelial TSP-1 in protection against matrix proteolysis and barrier dysfunction following PA induced lung injury. Aim 1 will determine if TSP-1 is protective against the disruption of intercellular junctional complexes and barrier function in vitro. Aim 2 will determine if endothelial TSP-1 promotes vascular integrity in vivo. By improving our understanding of host protective mechanisms during pathogen triggered lung injury, this project may provide rationale for potential therapeutic targets in patients with ARDS. The proposed training plan will promote development of advanced laboratory skills including cell and tissue imaging, mouse genetics and in vivo models of infection-induced lung injury. Moreover, this project with provide the applicant with the opportunity to develop expertise as a physician-scientist under the close mentoring and involvement of dedicated sponsors in a robust research environment at the University of Pittsburgh.