Inflection points in sepsis biology: from local defense to systemic organ injury

Abstract

Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory-derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection.

Fig. 1.

Locally beneficial host defense mechanisms can become detrimental during the systemic spread of infection and inflammation. Local inflammatory mediators, including tumor necrosis factor (TNF) and interleukin (IL)-1β, lead to vasodilation, which recruits leukocytes to sites of infection and sets off a cascade of leukocyte activation, neutrophil extracellular trap (NET) formation, and coagulation. These mechanisms help contain and kill pathogens during localized infection. In contrast, the systemic spread of these same immune mechanisms leads to septic shock, acute organ injury, and potentially death. DIC, disseminated intravascular coagulation.

Fig. 2.

Early cellular and molecular events during infection. Molecular motifs specific to pathogens (PAMPs) are sensed by resident innate immune cells, which express Toll-like receptors (TLRs). TLRs signal via the nuclear factor (NF)-κB signaling cascade, leading to the expression of nitric oxide, which induces vasodilation and increases blood flow to sites of infection. TLR signaling also leads to inflammatory cytokine (TNF, IL-1β, IL-6) and chemokine [monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α] production, which recruits monocyte and neutrophil sites of infection. Local cytokine release and the effects of these cytokines on the endothelium increase the procoagulant properties of endothelial cells and induce platelet-neutrophil interactions that lead to the formation of NETs.

Fig. 3.

Sepsis is a numeric and geographic race between bacterial growth and host defense. A: after the initial inoculum, bacteria or other pathogens begin to propagate within local compartments. B: if the immune response is sufficiently fast, then the spread of pathogens is limited by defense mechanisms, including NET formation, local thromboses, and neutrophil and monocyte recruitment. C: in contrast, if invading pathogens are able to spread outside a single compartment and the inflection point where specific host defense mechanisms shift from benefit to detriment is crossed, then both infection and the inflammatory response to the infection become systemic, resulting in diffuse organ injury and shock.