Tuesday November 30, from 12.00 to 13.00
Seminar with Arnaud Goolaerts, Université Paris 7, INSERM U773, Paris
"PAI-1 is an essential component of pulmonary host responses during pseudomonas aeruginosa pneumonia in mice"
Critically ill patients with elevated BAL (Bronchoalveolar lavage) and plasma levels of PAI-1 have a higher incidence of P. aeruginosa pneumonia and poor outcomes compared to other patients. However, whether PAI-1 plays a pathogenic or protective role in the P. aeruginosa-induced acute lung injury is unknown. Using gene deletion and pharmacologic inhibition, we tested the role of PAI-1 as a determinant of survival, pulmonary host defense and lung fluid/protein balance during P. aeruginosa pneumonia in mice. Compared to control mice, PAI-1 (-/-) mice and mice treated with the PAI-1 inhibitor TiplaxtininÒ had a higher mortality at 25 hours. In addition, PAI-1 -/- mice and Tiplaxtinin-treated mice had a higher lung bacterial load associated with lower levels of KC and fewer neutrophils in the BAL fluid. On the other hand, PAI-1 (-/-) mice as well as mice treated with the PAI-1 inhibitor TiplaxtininÒ had significantly less lung protein permeability and a lower lung water than wild type. Using in vitro experiments, we have shown that PAI-1 production by endothelial cells was increased by PAK in a TLR-4/p38/RhoA/NfkB manner. These experiments also showed that PAI-1 disrupts the endothelial barrier by modulating the activity of the small GTPases RhoA and Rac-1.All together, our results indicate that PAI-1 is an essential component of the lung host response during P. aeruginosa pneumonia.