Liver-Dependent Lung Remodeling and Pneumonia Susceptibility During Endotoxemia

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Project Summary/Abstract Pneumonia is the leading global cause of infectious disease deaths and contributes to one of the greatest disease burdens worldwide. It is also the leading cause of sepsis, which in turn predisposes patients to secondary infections in the lungs and elsewhere. Indeed, patients with sepsis, trauma, or extra-pulmonary complications are exquisitely vulnerable to hospital-acquired pneumonias. Both diseases are growing public health concerns with limited treatments. Due to the integrated nature of pneumonia and sepsis, understanding intra- and extra-pulmonary pathways controlling pneumonia susceptibility in the wake of systemic inflammation or injury may reveal protective signaling hubs for targeted interventions. The hepatic acute phase response (APR), activated by both pneumonia and sepsis, is a coordinated response resulting in numerous blood protein changes that correlate with disease severity and modulate host outcome, albeit in ways that remain somewhat speculative. We have shown that a robust APR during pneumonia is coordinated by liver activation of the transcription factors STAT3 and RelA, and when one or both of these factors are eliminated, the APR is diminished or completely ablated, respectively. In an earlier study, we modeled the conditions of pneumonia susceptibility during sepsis/systemic inflammation by pre-challenging mice with endotoxemia prior to an intratracheal instillation of bacteria. These studies revealed substantially worsened pneumonia outcomes in mice lacking hepatocyte STAT3 (hepSTAT3-/-) compared to littermate controls under the same conditions. While mechanisms of liver- derived protection remain unclear, our prior and preliminary results together suggest the involvement of both cellular and innate humoral changes in the immune landscape of the lung. Such changes include airspace macrophage function as well as liver dependent remodeling of the lung transcriptome and airspace proteome. The latter corresponds with reduced hepatic synthesis and delivery of coagulation proteins to the alveolar compartment of hepSTAT3-/- mice. Based on these findings, we propose the central hypothesis that STAT3-dependent liver activation limits pneumonia susceptibility by reprogramming lung macrophages and dispatching coagulation proteins to infected airspaces. Aim 1 is designed to test the hypothesis that STAT3-dependent liver-activity remodels lung macrophages during endotoxemia followed by pneumonia, whereas the goal of aim 2 is to test the hypothesis that liver-derived coagulation proteins fortifies intrapulmonary bacterial killing and improves pneumonia outcome. These studies will provide important insights regarding the biological pathways connecting liver activation and pneumonia susceptibility, possibly revealing targetable clinical interventions for vulnerable patient populations.