Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

Abstract

Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins

Integrated Inflammatory Stress (ITIS) Model

“…The main contributors to the acute inflammatory response are the phagocytic cells and cytokines, and the HPA axis consists of hypothalamus, pituitary and the adrenal secreting hormones. The interaction between the systems is that cytokines activates the HPA axis, while the hormone cortisol has an anti-inflammatory effect endotoxins (e.g., lipopolysaccharides, LPS) which is found in the outer membrane of gram-negative bacteria and known to activate the immune response (Amersfoort et al 2003;Vedder et al 1999). It is of importance that the inflammation is tightly regulated, since a too extensive response can cause further tissue damage and chronic inflammation, while an insufficient response can lead to serious infections and sepsis (Beishuizen and Thijs 2003;Sternberg 2006).…”

“…When phagocytic cells recognize bacterial components (such as endotoxin), the acute inflammatory response is initiated (Amersfoort et al 2003;Cavaillon 1994). As long as endotoxin is present in the model, the activated phagocytic cells are further up-regulated by the pro-inflammatory TNF-α (Tracey 2002) …”

“…The secretion of CRH results in a secretion of ACTH leading to a secretion of cortisol which in turn inhibits further up-regulation of CRH and ACTH (Beishuizen and Thijs 2003;Sternberg 2006). When an endotoxin challenge is introduced to the system, the phagocytic cells are activated to eliminate the threat (Amersfoort et al 2003;Tracey 2002). Endotoxin stimulates Toll-like receptors primarily on the surface of the macrophages or T-lymphocytes.…”

“…Some cytokines act as chemokines attracting T-lymphocytes responsible for inactivation of the bacteria producing the endotoxin while others (interleukines) activate the production of cytokines from neighboring leukocytes initiating a spreading of the inflammatory process (Dinarello 2000;Opal and DePalo 2000;Scheller et al 2011). Macrophages which are phagocytic cells specifically release TNF-α as a response to endotoxin exposure (Amersfoort et al 2003). Furthermore, activated TNF-α stimulates the HPA axis by up-regulating the production of CRH and ACTH (Beishuizen and Thijs 2003;Silverman et al 2005).…”

“…This results in an anti-inflammatory response modulated by TGF-β caused by the increased secretion of cortisol (John and Buckingham 2003;Sternberg 2006;Tracey 2002). Cortisol inhibits several inflammatory processes such as cytokine production (Amersfoort et al 2003). When the endotoxin challenge is eliminated, the system returns to a steady state.…”