1) The major scientific goal of this project is to determine the pathogenic mechanisms responsible for sepsis-induced acute lung injury (ALI), a leading clinical cause of the acute respiratory distress syndrome (ARDS). Laboratory investigation will be conducted in vivo to elucidate basic immunologic and inflammatory mechanisms of sepsis-related lung injury, including the role of mechanical ventilation in this process. The research program will place special emphasis on the roles of apoptosis, especially those mediated by Fas (CD95), and MyD88-dependent in ALl pathogenesis. 2) The major specific aims are: 1) to determine whether mechanical ventilation interacts with sepsis in vivo to synergistically induce ALI; 2) to determine if sepsis and mechanical ventilation promote pro-apoptotic responses in the lung that contribute to ALI; 3) to determine whether mechanical ventilation synergizes with sepsis to induce ALI via potentiation of MyD88-dependent pro-inflammatory mechanisms. 3) Experimental approach: Murine models of sepsis will be employed to address the specific aims. The relative roles of the Fas apoptotic and the MyD88-dependent pro-inflammatory will be assessed in experiments with lpr (Fas-deficient) and MyD88 -/- mice, respectively. 4) Expected results/significance: Sepsis alone is not expected to cause significant ALl but is anticipated to prime the lung for tissue injury in response to mechanical ventilation. Sepsis-induced/ventilator-associated ALI is expected to involve apoptosis of the lung epithelium and MyD88-dependent pro-inflammatory responses. The experimental approach is unique in that it utilizes a murine model of extra-pulmonary sepsis to study the pathogenesis of ALI and the modulating effects of concomitant mechanical ventilation. Results are expected to yield fundamental insights into the basic pathogenic mechanisms of sepsis-induced ALI and provide the basis for development of novel anti-apoptotic and anti-inflammatory therapeutic strategies for ALI/ARDS.
| Morrell, Eric D; O'Mahony, D Shane; Glavan, Bradford J et al. (2018) Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome. Am J Respir Cell Mol Biol 58:117-125 |
| Morrell, Eric D; Radella 2nd, Frank; Manicone, Anne M et al. (2018) Peripheral and Alveolar Cell Transcriptional Programs Are Distinct in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 197:528-532 |
| Esposito, Anthony J; Bhatraju, Pavan K; Stapleton, Renee D et al. (2017) Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. Crit Care 21:304 |
| Mikacenic, Carmen; Price, Brenda L; Harju-Baker, Susanna et al. (2017) A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis. Am J Respir Crit Care Med 196:1004-1011 |
| Skerrett, Shawn J; Braff, Marissa H; Liggitt, H Denny et al. (2017) Toll-like receptor 2 has a prominent but nonessential role in innate immunity toStaphylococcus aureuspneumonia. Physiol Rep 5: |
| Gharib, Sina A; Mar, Daniel; Bomsztyk, Karol et al. (2016) SYSTEM-WIDE MAPPING OF ACTIVATED CIRCUITRY IN EXPERIMENTAL SYSTEMIC INFLAMMATORY RESPONSE SYNDROME. Shock 45:148-56 |
| Mikacenic, Carmen; Hansen, Elizabeth E; Radella, Frank et al. (2016) Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome. Crit Care Med 44:496-502 |
| Altemeier, William A; Liles, W Conrad; Villagra-Garcia, Ana et al. (2013) Ischemia-reperfusion lung injury is attenuated in MyD88-deficient mice. PLoS One 8:e77123 |
| Bejan, Cosmin A; Vanderwende, Lucy; Wurfel, Mark M et al. (2012) Assessing pneumonia identification from time-ordered narrative reports. AMIA Annu Symp Proc 2012:1119-28 |
| Chaffin, Donald O; Taylor, Destry; Skerrett, Shawn J et al. (2012) Changes in the Staphylococcus aureus transcriptome during early adaptation to the lung. PLoS One 7:e41329 |
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