Neutrophils and Pulmonary Infection
The Remold-O’Donnell Laboratory studies the role of SerpinB1 in protecting the host defenses of the lung against microbial infection. SerpinB1 (also called MNEI) is an ancestral and highly conserved serine protease inhibitor and a highly efficient inhibitor of neutrophil proteases. Our studies include work with patient specimens (cystic fibrosis, chronic lung disease of infancy) as well as microbial infection of animal models. We have shown that SerpinB1-/- mice are susceptible to bacterial lung infection with Pseudomonas aeruginosa. On infection with sublethal dose, SerpinB1-/- mice fail to clear infection. This defect is accompanied by an increased inflammatory response and by destruction of innate immune defense molecules in the lung including surfactant protein-D (SP-D). The recruited neutrophils also have a survival defect, accumulating as late apoptotic/necrotic cells and releasing proteases. Current studies are addressing the role of SerpinB1 and neutrophil proteases in lung infection with influenza virus, a highly important pathogen. The contribution of protective molecules such as SP-D that are targeted by neutrophil proteases are being examined through the use of transgenic mice. The role of SerpinB1 in neutrophil generation and neutrophil survival in steady state and in models of lung inflammation is being examined.
Platelet and T cell Defects in Wiskott-Aldrich syndrome
Our lab performs platelet studies based on the hypothesis that platelets from patients with Wiskott-Aldrich syndrome (WAS) are specifically defective in activation processes that depend on integrin “outside in” signaling. On treatment with agonists, the major platelet integrin αIIbβ3 is conformationally activated allowing binding to extracellular matrix. Bound ligand transduces signals across the membrane (integrin “outside-in” signaling) that activate the WAS protein (WASP), localized in platelets in the membrane skeleton. Active WASP generates new actin filaments responsible for altering platelet morphology as occurs when platelets spread on matrices or bind and aggregate at the blood vessel wall. The role of WASP in integrin outside-in alteration of cell morphology is thought to be important in stabilizing platelet aggregates and regulating platelet conversion to the procoagulant phenotype.
SPD (Surfactant protein D) Transgenic