-Review-

Novel Therapeutic Targets for Sepsis: Regulation of Exaggerated Inflammatory Responses

Akihisa Matsuda^1,2, Asha Jacob¹, Rongqian Wu¹, Monowar Aziz¹, Weng-Lang Yang¹, Takeshi Matsutani², Hideyuki Suzuki², Kiyonori Furukawa², Eiji Uchida² and Ping Wang¹

¹Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset and Laboratory of Surgical Research, the Feinstein Institute for Medical Research, Manhasset, NY, USA
²Department of Surgery, Nippon Medical School, Tokyo, Japan

Sepsis is a devastating and complex syndrome and continues to be a major cause of morbidity and mortality among critically ill patients at the surgical intensive care unit setting in the United States. The occurrence of sepsis and septic shock has increased significantly over the past two decades. Despite of highly dedicated basic research and numerous clinical trials, remarkable progress has not been made in the development of novel and effective therapeutics. The sepsis-induced physiologic derangements are due largely to the host responses to the invading microorganism in contrast to the direct effects of the microorganism itself. Sepsis, the systemic inflammatory response to infection, is marked by dysregulated production of pro-inflammatory cytokines. Although pro-inflammatory cytokine production is normally indispensable to protect against pathogens and promote tissue repair, the dysregulated and prolonged production of these cytokines can trigger a systemic inflammatory cascade mediated by chemokines, vasoactive amines, the complement and coagulation system, and reactive oxygen species (ROS), amongst others. These mediators collectively lead to multiple organ failure, and ultimately to death. In this regard, the role of inflammation in the pathophysiology of sepsis, although still incompletely understood, is clearly critical. Recent findings resulting from vigorous investigations have contributed to delineate various novel directions of sepsis therapeutics. Among these, this review article is focused on new promising mechanisms and concepts that could have a key role in anti-inflammatory strategies against sepsis, including 1) "inflammasome": a multiprotein complex that activates caspase-1; 2) "the cholinergic anti-inflammatory pathway": the efferent arm of the vagus nerve-mediated, brain-to-immune reflex; 3) "stem cells": unspecialized and undifferentiated precursor cells with the capacity for self-renewal and potential to change into cells of multiple lineages; 4) "milk fat globule-EGF factor VIII (MFG-E8)": a bridging molecule between apoptotic cells and phagocytes, which promotes phagocytosis of apoptotic cells.

J Nippon Med Sch 2012; 79: 4-18

Keywords
sepsis, inflammation, inflammasome, cholinergic pathway, stem cells, MFG-E8

Correspondence to
Ping Wang, MD, Laboratory of Surgical Research, the Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
pwang@nshs.edu

Received, July 25, 2011
Accepted, October 31, 2011