Secondary infections due to compromised immune function are a significant cause of mortality in hospitalized trauma patients that have survived hemorrhagic shock. The Gram-negative bacterial pathogen Pseudomonas aeruginosa is one of the most common causes of secondary pneumonia in these patients. Neutrophil recruitment into the airspaces of the lung is critical for host defense against P. aeruginosa pneumonia, and studies suggest that this element of innate immunity is compromised following hemorrhagic shock. Animal models of critical illness and associated immune dysfunction have been developed to probe pathogenesis of secondary infection and evaluate potential therapies. However, a mouse model of pseudomonal pneumonia secondary to hemorrhagic shock has not been characterized. Here, we propose to develop and characterize a mouse model of P. aeruginosa pneumonia secondary to hemorrhagic shock as a more clinically relevant format to evaluate potential neutrophil-targeted therapeutic strategies. ?2 integrins are adhesion receptors that regulate neutrophil trafficking, and must become activated to bind to their ligands expressed on endothelium or extracellular matrix. Our previous studies suggest a strategy of attenuating ?2 integrin activation to promote neutrophil emigration from the pulmonary vasculature and recruitment into the airspaces during acute respiratory P. aeruginosa infection in mice with a fully competent innate immune response. In the second part of this study, we will use the new mouse model to evaluate the efficacy of XVA143, a small molecule antagonist that prevents ?2 integrins from achieving their highest ligand-binding affinity. We will additionally assess the effects of modulating neutrophil recruitment on lung injury and pulmonary edema, as neutrophils are also mediators of bystander tissue damage that can lead to acute respiratory distress syndrome. These studies may identify regulators of ?2 integrin activation as effective therapeutics for promoting host defense of the lung against secondary bacterial pneumonia while maintaining tissue protection.
Infectious complications of hemorrhagic shock in hospitalized trauma patients are a significant cause of death due to a compromised immune system. To better understand how neutrophils, a critical subset of innate immune cells, are involved in this increased susceptibility to infection, we propose studies that will establish an animal model of bacterial pneumonia secondary to hemorrhagic shock. We also address a potential therapeutic strategy to promote certain aspects of the inflammatory response (neutrophil recruitment) to improve outcome to secondary pneumonia.
| Lee, Kayla; Cohen, Joshua T; Wilson, Zachary S et al. (2018) Hemorrhage Attenuates Neutrophil Recruitment in Response to Secondary Respiratory Infection by Pseudomonas Aeruginosa. Shock : |
