The inflammasome has recently been described as an important protein complex in which a non-NFkB- mediated signaling pathway leads to up-regulation of key pro-inflammatory cytokines, including interleukin (IL)- 1b and IL-18. Members of our group recently reported that the inflammasome plays a critical role in pro- inflammatory response in murine sepsis, and this response is dependent upon mitochondrial integrity and an intact autophagy response to injury. We now present data supporting an important role for the inflammasome in predicting severity and mortality during human infection-related ALI/ARDS. Moreover, our preliminary animal studies demonstrate that statins exacerbate lung injury and inflammation via activation of the inflammasome. We therefore hypothesize that activation of the inflammasome plays a critical role in the development of infection-related ALI/ARDS and that statin administration may increase inflammasome-related downstream cytokines during lung injury. In particular, our collaboration with the ARDSnet SAILS trial investigators (a randomized trial of statins vs. placebo in infection-related ALI/ARDS) in this Ancillary Studies in Clinical Trials RFA (HL-12-012) provides a unique opportunity to obtain additional collection of key human samples to address these important processes. We therefore propose:
Specific Aim 1 : To determine gene expression and protein levels of the inflammasome during infection-related ALI/ARDS using prospectively collected blood (n=100) and banked plasma samples (n=600) from placebo- and statin-treated SAILS subjects. Gene expression and protein levels of the inflammasome will be correlated with 60-day mortality and additional SAILS trial secondary outcomes. We hypothesize that circulating inflammasome levels will serve as a biomarker of severity and mortality of infection-related ALI/ARDS and that inflammasome levels in statin-treated subjects will correlate with clinical outcomes.
Specific Aim 2 : To determine the cellular localization of expression of the inflammasome complex and role of inflammasome activation on cellular responses and function, using primary neutrophils and monocytes isolated from prospectively enrolled placebo- and statin-treated SAILS subjects (n=100), as well as primary cells isolated from control ICU subjects (n=100). We hypothesize that determining which circulating cells are the predominant source of inflammasome activation will increase sensitivity of the correlation of inflammasome levels with clinical outcomes and that localized activation of the inflammasome will result in mitochondrial dysfunction that will be enhanced in the presence of statin administration.
Although the mechanism of ALI/ARDS is intensively studied no biomarkers are currently available to predict disease severity and survival in among critically ill ALI/ARDS patients. This study will attempt to identify new molecules which can serve as potential biomarker(s) to predict severity of disease and mortality in ALI/ARDS.
|Shrime, Mark G; Ferket, Bart S; Scott, Daniel J et al. (2016) Time-Limited Trials of Intensive Care for Critically Ill Patients With Cancer: How Long Is Long Enough? JAMA Oncol 2:76-83|
|Englert, Joshua A; Macias, Alvaro A; Amador-Munoz, Diana et al. (2015) Isoflurane Ameliorates Acute Lung Injury by Preserving Epithelial Tight Junction Integrity. Anesthesiology 123:377-88|
|Moon, Jong-Seok; Lee, Seonmin; Park, Mi-Ae et al. (2015) UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis. J Clin Invest 125:665-80|
|Langley, Raymond J; Tipper, Jennifer L; Bruse, Shannon et al. (2014) Integrative ""omic"" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes. Am J Respir Crit Care Med 190:445-55|
|Lai, P S; Mita, C; Thompson, B T (2014) What is the clinical significance of pulmonary hypertension in acute respiratory distress syndrome? A review. Minerva Anestesiol 80:574-85|
|Rogers, Angela J; McGeachie, Michael; Baron, Rebecca M et al. (2014) Metabolomic derangements are associated with mortality in critically ill adult patients. PLoS One 9:e87538|
|Li, Yongsheng; Dalli, Jesmond; Chiang, Nan et al. (2013) Plasticity of leukocytic exudates in resolving acute inflammation is regulated by MicroRNA and proresolving mediators. Immunity 39:885-98|
|Nakahira, Kiichi; Kyung, Sun-Young; Rogers, Angela J et al. (2013) Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 10:e1001577; discussion e1001577|
|Langley, Raymond J; Tsalik, Ephraim L; van Velkinburgh, Jennifer C et al. (2013) An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 5:195ra95|