Regulation of Endothelial-Neutrophil Interaction & Lung Vascular Permeability in ALI and Sepsis
Endothelial-neutrophil (PMN) interaction and loss of endothelial barrier integrity are the earliest events that occur in ALI and lead to PMN recruitment and edema formation in the lung. PMN recruitment and endothelial barrier disruption create a vicious cycle that serves to perpetuate and amplify inflammation-permeability axis in ALI, particularly in the setting of sepsis. Therefore, inhibiting/reversing the initial endothelial-PMN interaction and endothelial barrier dysfunction is an attractive strategy to prevent/treat ALI and sepsis. In pursuit of this concept, our lab has identified Spleen Tyrosine Kinase (Syk) as a critical determinant of these events, and found that targeting Syk protects against lung injury and improves survival in septic mice. This project seeks to clarify the mechanism by which Syk regulates endothelial dysfunction (inflammation and permeability) in ALI and evaluate the therapeutic efficacy of Syk inhibition (using R788 [fostamatinib], which has shown positive clinical benefits in arthritis) against evolving ALI in mice with sepsis.