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Gene Silencing in Severe Systemic Inflammation

¹ Sections of Molecular Medicine and Infectious Diseases, Department of Internal Medicine, and ² Division of Surgical Sciences, Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Correspondence and requests for reprints should be addressed to Charles E. McCall, M.D., Section of Molecular Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1042. E-mail: chmccall{at}wfubmc.edu

ABSTRACT

This critical care perspective appraises reprogramming of gene expression in inflammatory diseases as an emerging concept of clinical importance. We emphasize gene reprogramming that "silences" acute proinflammatory genes during severe systemic inflammation, wherein in the systemic inflammatory response syndrome (SIRS) exists as a continuum during severe sepsis, septic shock, and the multiorgan dysfunction and failure phenotypes without infection. In contrast, silencing of acute proinflammatory genes is not apparent in sites of localized inflammatory processes like rheumatoid arthritis. We discuss in three parts the clinical context and the translational basic science associated with gene silencing during the SIRS continuum of severe systemic inflammation: (1) reprogramming of acute proinflammatory genes; (2) a "nuclear factor-B paradox," coupled with RelB expression, that combine to silence genes using an epigenetic (inherited and reversible) signature on the nucleosome; and (3) the potential clinical importance of compartmentalization in gene silencing. Our emergent understanding of these physiologic processes may provide a novel framework for developing treatments.

Key Words: compartmentalization • epigenetic • gene silencing • reprogramming

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