The acute respiratory distress syndrome (ARDS) is a common and devastating complication of severe sepsis carrying a very high mortality. ARDS lacks any effective pharmacotherapy. We previously described a functional genetic variant in the interleukin-1 receptor antagonist gene, encoding the protein IL1RA, which associates with reduced ARDS risk, improved sepsis survival, and with higher plasma IL1RA. A recombinant form of IL1RA (anakinra) has been suggested as a possible therapy for severe sepsis, the most common precipitant of ARDS, though the effect was modest and predictors of anakinra response are lacking. Our preliminary data raises the possibility that anakinra would be a helpful therapy in ARDS. This application will address whether anakinra may show promise as a preventative agent or a therapy in ARDS and whether response to anakinra may be predicted by genetic or molecular profiles.
In aim 1, we will infer the causality of early plasma IL1RA level for ARDS susceptibility, and the causality of interleukin-1 beta (IL1) for ARDS mortality, using genotype as an instrumental variable that explains a large proportion of each plasma marker's variance. If these markers seem to be causal for ARDS or mortality, then targeting them with anakinra is a logical next step.
In aim 2, we identify the functional genetic determinants of evoked plasma IL1RA using a human endotoxin model to stimulate inflammatory stress, and test functional variants for association with sepsis-associated ARDS.
In aim 3, we molecularly characterize plasma stored from the last randomized controlled trial of anakinra in severe sepsis, to test whether plasma cytokine level or genotype can define a subgroup of patients who had reduced mortality with anakinra. This proposal uses 3 novel human populations to address the role of IL1RA in sepsis-associated ARDS: a large cohort of critically ill subjects with severe sepsis monitored for ARDS; an experimental human volunteer pool given intravenous endotoxin as a stimulus for inflammatory stress; and a completed clinical trial population with severe sepsis who were randomized to receive placebo or anakinra. Completion of this project will yield new knowledge regarding the potential role of recombinant IL1RA to prevent or treat ARDS, and may identify an ideal clinical trial population for future testing of personalized IL1RA therapy.

Public Health Relevance

Sepsis-associated acute respiratory distress syndrome (ARDS) claims the lives of over 40,000 Americans each year, and has no effective drug therapy. This project will evaluate the causality of the cytokines interleukin-1 beta and its antagonist, interleukin-1 receptor antagonist, in the development of ARDS or mortality from ARDS, while also elucidating the genetic regulation of these markers during inflammation and sepsis. Finally, we will assess whether genetic markers or cytokine levels identify septic patients likely to benefi from therapy with exogenous interleukin-1 receptor antagonist, which would be a novel and personalized therapy for this potentially devastating syndrome.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Harabin, Andrea L
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Bime, Christian; Pouladi, Nima; Sammani, Saad et al. (2018) Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor. Am J Respir Crit Care Med 197:1421-1432
Meyer, Nuala J; Reilly, John P; Anderson, Brian J et al. (2018) Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration. Crit Care Med 46:21-28
Reilly, John P; Wang, Fan; Jones, Tiffanie K et al. (2018) Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis. Intensive Care Med 44:1849-1858
Meyer, Nuala J; Reilly, John P; Feng, Rui et al. (2017) Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome. JCI Insight 2:
Reilly, John P; Christie, Jason D; Meyer, Nuala J (2017) Fifty Years of Research in ARDS. Genomic Contributions and Opportunities. Am J Respir Crit Care Med 196:1113-1121