New approaches to the study of sepsis

Abstract

Models of sepsis have been instructive in understanding the sequence of events in animals and, to an extent, in humans with sepsis. Events developing early in sepsis suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance. Development of immunosuppression and degraded innate and adaptive immune responses are well-established complications of sepsis. In addition, there is robust activation of the complement system, which contributes to the harmful effects of sepsis. These events appear to be associated with development of multiorgan failure. The relevance of animal models of sepsis to human sepsis and the failure of human clinical trials are discussed, together with suggestions as to how clinical trial design might be improved.

Figure 1. Intrinsic (DAMPs) and extrinsic (PAMPs) signals develop during an infectious condition (e.g. bacterial pneumonia) that causes inflammation and sepsis which is often associated with development of SIRS, buildup of ROS and RNS in tissues, multiorgan failure (MOF) and lethality

Receptors (PRRs) for these signals engage both TLRs and NOD-like receptors. The listings of ligands that interact with TLRs and NOD receptors is somewhat artificial. For instance, while HMGB1 (considered to be a DAMP) interacts with TLR4, it also interacts with TLR2 and with the receptor for advanced glycation products (RAGE). Heat shock proteins (DAMPs) react with TLR2, TLR4 and with receptors on antigen presenting cells (CD36, a scavenger receptors). ‘Sterile’ inflammation occurs after hemorrhagic shock, polytrauma, ischemia/reperfusion and is not usually associated with the presence of an infectious agent. In all cases, the same cascade of downstream events seems to occur.

Figure 2. Evidence of hyperinflammatory responses developing in the setting of sepsis

The early event is appearance of ROS and RNS in tissues together with numerous proinflammatory cytokines and chemokines in plasma (SIRS), accompanied by other manifestations of a robust inflammatory response (appearance of activation markers on PMNs, such as CD11b/CD18), increased levels of adhesion molecules (ICAM-1, VCAM-1) on endothelial cells, and elevated levels of chemokine receptors on PMNs, all of which implies a ‘gain of function’, resulting in a buildup in tissues of PMNs, monocytes, lymphocytes and dendritic cells in tissues. Development of activation molecules as well as chemokine receptors on leukocytes and adhesion molecules on endothelial cells would facilitate leukocyte buildup, perhaps contributing to the damage of multiple organs by facilitating the recruitment of inflammatory cells, which may be linked to MOF.

Figure 3. Molecular models of C5a and C5aR in which its ligand, C5a, is also shown

1. C5a is a rather oxidant-resistant glycosylated peptide with antiparallel helical structures.

2. The interaction of C5a with C5aR (CD88) triggers series of responses initiated by interaction of the cytoplasmic tail of C5aR with G-proteins, followed by engagement and activation of the signalling molecules, RAS, RAF-1, MEK1/2 and ERK1/2. An important response is activation of NADPH oxidase (NOX2) which is linked to the translocation of cytosolic subunits of NOX2 to the plasma membrane where NOX2 is assembled, facilitating electron transport and production of superoxide anion () and generation of H₂O₂, which accounts for the major bactericidal activity of activated PMNs. The presence of activated PMNs would result in inflammatory injury of organs.