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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112747-01
Application #
8267826
Study Section
Special Emphasis Panel (ZHL1-CSR-B (O1))
Program Officer
Harabin, Andrea L
Project Start
2012-05-15
Project End
2016-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$460,292
Indirect Cost
$196,708
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Dalli, Jesmond; Colas, Romain A; Quintana, Carolina et al. (2017) Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes. Crit Care Med 45:58-68
Boudreault, Francis; Pinilla-Vera, Miguel; Englert, Joshua A et al. (2017) Zinc deficiency primes the lung for ventilator-induced injury. JCI Insight 2:
Lasky-Su, Jessica; Dahlin, Amber; Litonjua, Augusto A et al. (2017) Metabolome alterations in severe critical illness and vitamin D status. Crit Care 21:193
Putman, Rachel K; Hunninghake, Gary M; Dieffenbach, Paul B et al. (2017) Interstitial Lung Abnormalities Are Associated with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 195:138-141
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
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
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
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
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
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

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