Inflammatory cytokines play a pivotal role in sepsis pathogenesis. The major proinflammatory cytokines, TNF-α and IL-1β, induce their hemodynamic and metabolic effects in concert with an expanding group of host-derived inflammatory mediators that work in a coordinated fashion to produce the systemic inflammatory response (see Table 42–2). The cytokine system functions as a network of communication signals between neutrophils, monocytes, macrophages, and endothelial cells. Autocrine and paracrine activation results in synergistic potentiation of the inflammatory response once it is activated by a systemic microbial challenge. Much of the inflammatory response is localized and compartmentalized in the primary region of initial inflammation. If left unchecked, the inflammatory response enters the systemic circulation, resulting in a generalized reaction culminating in diffuse endothelial injury, coagulation activation, and septic shock. The endocrine-like effect of systemic cytokine and chemokine release drives the inflammatory process and causes coagulation activation throughout the body.
Table 42–2Host-derived inflammatory mediators in septic shock. |Favorite Table|Download (.pdf) Table 42–2 Host-derived inflammatory mediators in septic shock.
|Proinflammatory Mediators ||Anti-Inflammatory Mediators |
Tumor necrosis factor-α
Complement components (C5a and C3a)
Mannose binding lectin
Reactive oxygen species
Granulocyte macrophage colony-stimulating factor
Macrophage inhibitory factor
High mobility group box I
Histamine, thrombin, other clotting factors
TREM-1 (triggering receptor expressed on myeloid cells)
Interleukin-1 receptor antagonist
Soluble tumor necrosis factor receptor
Soluble interleukin-1 receptor
Type II interleukin-1 receptor
Transforming growth factor-β
Granulocyte colony-stimulating factor
Anticoagulants (antithrombin, activated protein C, tissue factor pathway inhibitor)
The inflammatory cytokines and chemokines found in excess quantities in the bloodstream in patients with septic shock are matched by a group of anti-inflammatory mediators (see Table 42–2). The proinflammatory mediators tend to predominate locally and in the first 12 to 24 hours of sepsis, whereas the endogenous anti-inflammatory components often prevail systemically in the later phases. Monocyte-macrophage–generated cytokines and chemokines primarily promote sepsis early on; the lymphocyte-derived cytokines and interferons become important in the regulation of later phases of sepsis and may ultimately determine the outcome in septic shock.
Activated, yet uncommitted, T cells (TH0 cells) have four major pathways of functional differentiation (TH1, TH2, TH17, or Treg cells). TH0 cells exposed to IL-12 in the presence of IL-2 are driven toward a TH1-type functional development. These cells produce IFN-γ, TNF-α, and IL-2 and promote an inflammatory, cell-mediated immune response. TH0 cells exposed to IL-4 will preferentially develop into a TH2-type phenotype; TH2 cells secrete IL-4, IL-10, and IL-13, which promote humoral immune responses and attenuate T helper cells, and myeloid cell activity. Sepsis is often accompanied by a TH2-type response after an initial septic insult, likely due in part to the expression of adrenocorticotropic hormone, corticosteroids, and catecholamines that promote a TH2 response. CD4 cells are selectively depleted by apoptosis in sepsis further limiting cell-mediated immunity and T helper cell capacity.
A phase of relative immune refractoriness occurs in septic patients that place them at increased risk for secondary bacterial or fungal infection. Part of the pathophysiology of sepsis-induced immunosuppression is mediated by Th17 cells and regulatory T cells. Th17 cells are stimulated by dendritic cell-derived interleukin-23 to produce IL-17, chemokines, and antibacterial and antifungal peptides. Th17 cells are depleted in sepsis and might explain the propensity of septic patients to develop late, opportunistic bacterial and fungal infections. Regulatory T cells expand during sepsis and produce anti-inflammatory cytokines such as IL-10 and transforming growth factor beta contributing to T cell exhaustion. This pathophysiologic state is associated with endotoxin tolerance, anti-inflammatory cytokine synthesis, and deactivation of monocytes, macrophages, and neutrophils.
Activation of the coagulation cascade and generation of a consumptive coagulopathy and diffuse microthrombi are well-recognized events in sepsis. The tissue factor pathway (also known as the extrinsic pathway) is the predominant mechanism by which the coagulation system is activated. The contact factors in the intrinsic pathway are also activated, which helps perpetuate clotting and secondarily initiates vasodilation through bradykinin generation. Activation of intravascular coagulation results in microthrombi and contributes to microcirculatory dysfunction and the multiorgan failure that occur in septic patients. Depletion of coagulation factors and activation of plasmin, antithrombin III, and protein C may subsequently lead to a hemorrhagic diathesis. Depletion of these endogenous anticoagulants may secondarily lead to a procoagulant state and portend a poor prognosis.
Neutrophil–endothelial cell interactions
The recruitment of neutrophils to an area of localized infection is an essential component of the host inflammatory response. Localization and eradication of invading microbial pathogens at the site of initial infection is the principal objective of the immune response to microbial pathogens. This physiologic process becomes deleterious if diffuse neutrophil–endothelial cell interactions occur throughout the circulation in response to systemic inflammation.
Complex mechanisms govern the migration of neutrophils from the intravascular space into the interstitium, where invasive microorganisms may reside. Activated neutrophils degranulate, exposing endothelial surfaces and surrounding structures to reactive oxygen intermediates, nitric oxide, and a variety of proteases. This process contributes not only to microbial clearance but also to diffuse endothelial injury in the setting of systemic inflammation.
Nitric oxide is a highly reactive free radical that plays an essential role in the pathophysiology of septic shock. Its half-life of 1 to 3 seconds limits its activity to local tissues, where it is first generated by nitric oxide synthase. Full expression of inducible nitric oxide synthase requires TNF-α, IL-1, LPS, and probably other regulatory elements.
Nitric oxide is the major endothelial-derived relaxing factor that initiates the vasodilation and systemic hypotension observed in septic shock. Nitric oxide activates guanylate cyclase, which increases cyclic guanosine monophosphate levels inside vascular smooth muscle cells. This results in systemic vasodilation and decreased vascular resistance. Excessive and prolonged release of nitric oxide results in generalized vasodilatation and systemic hypotension.
Nitric oxide also helps increase intracellular killing of microbial pathogens and regulation of platelet and neutrophil adherence in septic patients. It is a highly diffusible gas that does not require specific receptors to cross cell membranes. In the presence of superoxide anion, nitric oxide leads to the formation of peroxynitrite and highly cytotoxic molecules, such as hydroxyl radicals and nitrosyl chloride, which then initiate lipid peroxidation and cause irreversible cellular damage. Nitric oxide inhibits a variety of key enzymes in the tricarboxylic acid pathway, the glycolytic pathway, DNA repair systems, electron transport pathways, and energy-exchange pathways. Because of its potent reactivity, nitric oxide alters the function of many metallo-enzymes, carrier proteins, and structural elements.
Late host-derived mediators
Macrophage migration inhibitory factor is a late mediator that activates immune cells, upregulates TLR4 expression, and contributes to lethal septic shock. This corticosteroid-regulated mediator promotes inflammation and has become a target for therapeutic agents in sepsis. The nuclear protein high-mobility group box–1 protein is released into the extracellular space with cell injury and necrosis and also participates in late-onset inflammatory phase of septic shock.
Pathogenesis: organ dysfunction
The diffuse endothelial injury accompanying septic shock results in organ dysfunction distant from the original site of the septic insult. The signal that results in diffuse endovascular injury is thought to be relayed by plasma factors (eg, inflammatory cytokines, complement, kinins, and other host-derived inflammatory mediators) or cellular signals from immune effector cells.
Inadequate tissue blood supply and repeated episodes of ischemia-reperfusion produces MODS. The failure of the microcirculation to support tissue maintenance may result from capillary bed hypoperfusion, blood flow redistribution within vascular beds, functional arteriovenous shunting, blood flow obstruction from microthrombi, platelet or white blood cell aggregates, or abnormal red blood cell deformability. Nitric oxide, reactive oxygen intermediates, inflammatory cytokines, and apoptosis inducers may directly damage endothelial surfaces. Endothelial swelling shifts intravascular fluid into extravascular and intracellular spaces, mechanically obstructing capillary lumens and further limiting microvascular blood flow.
Myocardial performance and pulmonary function also diminish over the course of septic shock and may contribute to the development of MODS. Myocardial contractility decreases in response to various myocardial depressant factors. TNF-α is a prominent cause of myocardial dysfunction; IL-1, IL-6, nitric oxide, and other host-derived inflammatory mediators may be contributing factors. Acute lung injury occurs in septic shock as a result of damage to pulmonary vascular circulation and excess permeability of alveolar capillary membranes. A supply-dependent dysoxia, along with altered capacity for oxidative phosphorylation (cytopathic hypoxia), likely contributes to tissue injury and multiorgan failure in sepsis.