The inflammatory response in sepsis

Abstract

The pathophysiology of sepsis and its accompanying systemic inflammatory response syndrome (SIRS) and the events that lead to multiorgan failure and death are poorly understood. It is known that, in septic humans and rodents, the development of SIRS is associated with a loss of the redox balance, but SIRS can also develop in noninfectious states. In addition, a hyperinflammatory state develops, together with impaired innate immune functions of phagocytes, immunosuppression, and complement activation, collectively leading to septic shock and lethality. Here, we discuss recent insights into the signaling pathways in immune and phagocytic cells that underlie sepsis and SIRS and consider how these might be targeted for therapeutic interventions to reverse or attenuate pathways that lead to lethality during sepsis.

Figure 1

Sepsis-induced defects in redox balance and anti-oxidant enzymes. In sepsis, an excessive oxidant state (presence of elevated levels of ROS, RNS) leads to reduced ubiquitination and nuclear translocation of the transcription factor, Nrf2, which in turn leads to reduced activation of genes that encode for anti-oxidant enzymes [19, 20, 22]. This imbalance intensifies the SIRS response and enhances development of MOF and lethality. Restoration of the redox balance by inducers of Nrf2 may reduce the intensity of SIRS and downstream events that would otherwise be lethal, at least based on studies in CLP mice. Dietary products, such as sulforaphane, cause of induction of Nrf2 and may be candidates for reversal of the redox imbalance in sepsis [18].

Figure 2

Sepsis-induced defects in redox system and depletion of cellular ATP. The nuclear hormone peroxisome proliferator activity receptors (PPARs) participate in responses to oxidative stresses, resulting in preservation of mitochondrial function and containment of inflammation [20, 26-30]. Sepsis causes reduced levels of PPARs accompanied by defective mitochondrial function as well as reductions in mitochondrial ATP, and reduced ability to restrain inflammatory responses such as SIRS. The two insets are transmission electron micrographs showing swollen mitochondria (in liver) during sepsis (X12,500). Several agonists for PPARs have been developed [27, 32, 33]. Sepsis and increased ROS and RNS also trigger DNA single strand breaks, which results in activation of poly ADP-ribose polymerase (PARP) for repair of DNA [17]. In the process, depletion of NAD⁺ levels can occur, accompanied by reductions in cellular and mitochondrial ATP. Inhibitors for PARP have been developed, which may preserve mitochondrial ATP during sepsis.

Figure 3

C5a and C5a receptors as targets in sepsis. In sepsis, C5a, and its receptors (C5aR, C5L2), are involved in a series of responses that promote development of SIRS, MOF, septic shock and lethality. Early in sepsis, robust activation of complement occurs, generating C5a which interacts with its receptors to promote development of ROS, RNS and onset of SIRS. C5aR and C5L2 are expressed in large amounts by neutrophils, at lower levels in macrophages and monocytes and non-myeloid cells (endothelial cells, alveolar epithelial cells, Kupffer cells, cardiomyocytes, etc.) [35, 36]. Development of SIRS and its complications (immunosuppression, defective innate and adaptive immune responses, consumptive coagulopathy) results in a sequence of events that is often lethal. In vivo neutralization of C5a with antibodies or blockade of C5a receptors (C5aR, C5L2) suppresses this cascade of adverse events and improves survival in CLP rodents. In vivo, blockade of C5a with neutralizing antibody in CLP rodents greatly improves survival, even if given up to 12 h after CLP [8].

Figure 4

Role of the parasympathetic and sympathetic nervous systems (PNS, SNS, respectively) in sepsis. a) The PNS, also referred to as the cholinergic system, acts via the vagus nerve to release acetylcholine from T cells, suppressing proinflammatory mediator release form activated macrophages and T cells [38]. b) Depending on which adrenergic receptor is in play, the SNS pathway may either intensify [45] or suppress the lung inflammatory response [46]. The cholinergic pathway can be activated by vagal nerve stimulation or use by chemical antagonists of the acetylcholine receptor, α7nAchR, resulting in suppressed release of proinflammatory mediators from macrophages. The SNS pathways can suppress the inflammatory response in the presence of β₂AR agonists (formoterol, albuterol). Alternatively, agonists (epinephrine, norepinephrine) of β₂ARs will intensify the lung inflammatory response [45]. Thus there are several strategies to target the PNS or SNS that may be used to suppress inflammatory responses and reduce ROS/RNS formation, the intensity of SIRS and other adverse events in sepsis.

Figure 5

Sepsis-induced immunosuppression and defective phagocytes. Sepsis leads to immunosuppression and defective phagocytosis, caused by depletion or functional deficiencies in macrophages and DCs, apoptosis of T and B cells, and tissue expression of inhibitory ligands and receptors that suppress immune responses, mostly by targeting T cells. Immunosuppression and defective phagocyte function, leads to failure to contain commensal and invading bacteria and fungi. The immunostimulant, IL-7, which promotes T and B cell proliferation and which has antiapoptotic effects, may be a candidate for clinical trials in humans to reverse the immunosuppression of sepsis [52].