Sepsis-induced acute respiratory distress syndrome (ARDS) is a leading cause of acute respiratory failure in critical illness. Morbidity and mortality are high and there are no proven pharmacologic therapies other than antimicrobials. Increased permeability of the pulmonary microvascular endothelium is a defining pathogenic feature that leads to acute pulmonary edema and lung dysfunction in sepsis-associated ARDS. Although the mechanisms that regulate microvascular permeability are an area of intensive research effort, the proximal triggers of increased pulmonary microvascular permeability in sepsis-associated ARDS are not well understood. There is a vital need to identify these early triggers of increased microvascular permeability in sepsis, both to enhance our understanding of pathophysiology, and critically, to identify new therapeutic targets for prevention and early treatment of sepsis-induced ARDS. Our recent translational studies in patients, the isolated perfused human lung, and mouse models of sepsis have identified cell-free hemoglobin (CFH) as a key proximal mediator of increased microvascular permeability that (1) is released into the circulation in over 80% of patients with severe sepsis, (2) is independently associated with mortality in patients with severe sepsis, (3) has potent effects on pulmonary microvascular permeability across our model systems, (4) can be oxidized in clinical and experimental sepsis to highly reactive ferryl (4+) hemoglobin, a potent oxidant, and (5) can be mechanistically targeted by the hemoprotein reductant acetaminophen. Furthermore, preliminary studies suggest that oxidant-mediated mitochondrial injury and activation of apoptosis in endothelial cells are key mechanisms through which CFH mediates its effects on microvascular permeability. The studies in this proposal will build on this preliminary work to characterize the mechanisms by which CFH triggers increased pulmonary microvascular permeability in sepsis. Our primary goal is to translate these findings to new targeted therapies that will be tested in our novel human lung model as preparation for rapid translation to clinical trials in sepsis.
In Aim 1, we will study the cellular and physiologic mechanisms by which CFH increases microvascular permeability and acute lung injury in the isolated human lung and clinically relevant models of sepsis-induced ARDS.
In Aim 2 we will study primary pulmonary microvascular endothelial cells along with our in vivo models to define the molecular mechanisms by which CFH induces endothelial apoptosis.
In Aim 3, we will test the therapeutic potential of targeting oxidized CFH with acetaminophen in pulmonary microvascular endothelial cells and clinically relevant models of human and murine sepsis-induced ARDS. The studies proposed in these aims have the potential for major and sustained scientific impact. Targeting CFH for early prevention and treatment of ARDS in sepsis is a new approach that could have a major impact on clinical outcomes. Furthermore, the focus on acetaminophen as a targeted therapy for increased microvascular permeability due to oxidized CFH could repurpose an inexpensive, and safe compound for treatment of sepsis.
Acute respiratory distress syndrome (ARDS) is a common and life-threatening condition that is most frequently caused by sepsis, has a 30-50% death rate, and has no disease-specific therapies. Hemoglobin that has escaped from red blood cells is a potential proximal trigger for sepsis-induced ARDS and is a prime target for specific therapies to prevent ARDS in sepsis. This translational proposal will define the mechanisms of the injurious effects of hemoglobin in sepsis to move our findings ?from bench to bedside? by validation of new pharmacological targets that could lead to new therapies for sepsis and ARDS.
| Van Driest, Sara L; Jooste, Edmund H; Shi, Yaping et al. (2018) Association Between Early Postoperative Acetaminophen Exposure and Acute Kidney Injury in Pediatric Patients Undergoing Cardiac Surgery. JAMA Pediatr 172:655-663 |
| Kuck, Jamie L; Bastarache, Julie A; Shaver, Ciara M et al. (2018) Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin. Biochem Biophys Res Commun 495:433-437 |
| Shaver, Ciara M; Wickersham, Nancy; McNeil, J Brennan et al. (2018) Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury. JCI Insight 3: |
