The Immune Response: Targets for the Treatment of Severe Sepsis
Doaa Abdel-Moneim Saeed Mansour El-Okda;
Abstract
Sepsis is one of the oldest and most elusive syndromes in medicine. Severe sepsis and septic shock are clinical manifestations of a dysregulated immune response to invasive pathogens in which a careful balance between pro-inflammatory and anti-inflammatory responses is vital.
Toll-like receptors, inflammasomes and other PRRs initiate the immune response after recognition of danger signals derived from microorganisms, so-called PAMPs or derived from the host, so-called DAMPS.
The pro-inflammatory response is enhanced by activation of leukocytes, complement, and the coagulation system. The anti-inflammatory immune suppressive response depends on impaired function of immune cells, neuroendocrine regulation, and inhibition of pro-inflammatory gene transcription. Importantly, direction, extent, and duration of the septic response is determined by both host factors, such as genetic composition, age, co-morbidity, and medication, and pathogen factors, including microbial load and virulence.
During sepsis a global reprioritization of the leukocyte transcriptome affects >80% of the cellular functions and pathways, which has been called a truly “genomic storm”.
The hyper-inflammatory phase has been termed a “cytokine storm” that is indicated by increased levels of TNF-α, IL-1β, and IL-9. Pro-inflammatory cytokines up-regulate adhesion molecules in neutrophils and endothelial cells. Although activated neutrophils kill microorganisms, they also injure endothelium by releasing mediators that increase vascular permeability, leading to the flow of protein-rich edema fluid into lung and other tissues. In addition, activated endothelial cells release NO, a potent vasodilator that acts as a key mediator of septic shock.
An important aspect of sepsis is the alteration of the procoagulant-anticoagulant balance, with an increase in procoagulant factors and a decrease in anticoagulant factors. LPS stimulates endothelial cells to up-regulate tissue factor, activating coagulation. Fibrinogen is then converted to fibrin, leading to the formation of microvascular thrombi and further amplifying injury.
Sepsis increases the synthesis of PAI-1. Sepsis also decreases the levels of protein C, protein S, antithrombin III, and TFPI. LPS and TNF-α decrease the synthesis of thrombomodulin and EPCR, thus decreasing the activation of protein C. Sepsis further disrupts the protein C pathway because sepsis also decreases the expression of EPCR, which amplifies the deleterious effects of the sepsis-induced decrease in levels of protein C. LPS and TNF-α also increase PAI-1 levels so that fibrinolysis is inhibited.
The clinical consequences of the changes in coagulation caused by sepsis are increased levels of markers of DIC and wide-spread organ dysfunction.
Patients may undergo a controlled anti-inflammatory response enabling them to return to immune homeostasis, or undergo uncontrolled anti-inflammatory response “immune-paralysis” which is mediated by:
o Predominance of Th2 producing and Treg responses over Th1, producing and T17 responses
o CD4 lymphopenia and B lymphocyte dysfunction
o Monocytes stimulated by PAMPs fail to produce adequate cytokines
o Decreased expression of HLA‐DR on monocytes
o Impaired neutrophils phagocytosis
In end-stage septic patients; apoptosis induces loss of cells of innate and adaptive immune system:
o CD4, CD8, T, B, dendritic cells
o When clonal expansion of lymphocytes should be occurring
Host immunosuppression has long been considered a factor in late death in patients with sepsis, since the sequelae of anergy, lymphopenia, hypothermia, and nosocomial infection all appear to be involved. Severe depletion of immune effector cells is a universal finding in sepsis.
The altered signaling pathways in sepsis ultimately lead to tissue injury and MOD. Cardiovascular dysfunction is characterized by circulatory shock and the redistribution of blood flow, with decreased vascular resistance, hypovolemia, and decreased myocardial contractility associated with increased levels of NO, TNF-α, IL-6, and other mediators. Respiratory dysfunction is characterized by increased microvascular permeability, leading to ALI. Renal dysfunction in sepsis, may be profound, contributing to morbidity and mortality.
Sepsis is now recognized as an overwhelmingly time-critical disease, requiring early initiation of care in the ED, with subsequent transfer to the ICU. The mortality and morbidity of severe sepsis can be improved by effective clinical interventions applied in a timely and systematic manner. Although time zero is defined differently in some hospitals, the SSC defines it as the time a septic patient is triaged in the ED. The guidelines recommend two bundles that should be completed within three hours and six hours of time zero.
Optimal management of sepsis requires EGDT, lung-protective ventilation, antimicrobial treatment within the first hour after diagnosis of severe sepsis, low-dose hydrocortisone for vasopressor-resistant septic shock and insulin therapy. Source control should be accomplished within the first 12 hours when the patient is able to tolerate it. Later in the course of sepsis, appropriate management necessitates organ support and prevention of nosocomial infection.
Recent studies focused on novel targets, mechanisms of action, and combination therapy may improve current treatment. Several types of therapy have proven ineffective. Anti-LPS therapy was ineffective, numerous therapies that block pro-inflammatory cytokines have failed. Ibuprofen, platelet-activating factor acetyl hydrolase, bradykinin antagonists and other therapies have not improved survival among patients with sepsis. Super-antigens and mannose may be potential therapeutic targets. Inhibition of tissue factor, a proximal target, might mitigate excessive procoagulant activity. Lipid emulsion may modulate innate immunity by inhibiting LPS.
Inhibition of apoptosis improved survival in an animal model of sepsis. Therapies that augment host immune responses as GM-CSF or G-CSF, IFN-γ and IL-7 can decrease mortality. Blocking PD-1/PD-L axis is a promising target for restoring immune function in sepsis.
Toll-like receptors, inflammasomes and other PRRs initiate the immune response after recognition of danger signals derived from microorganisms, so-called PAMPs or derived from the host, so-called DAMPS.
The pro-inflammatory response is enhanced by activation of leukocytes, complement, and the coagulation system. The anti-inflammatory immune suppressive response depends on impaired function of immune cells, neuroendocrine regulation, and inhibition of pro-inflammatory gene transcription. Importantly, direction, extent, and duration of the septic response is determined by both host factors, such as genetic composition, age, co-morbidity, and medication, and pathogen factors, including microbial load and virulence.
During sepsis a global reprioritization of the leukocyte transcriptome affects >80% of the cellular functions and pathways, which has been called a truly “genomic storm”.
The hyper-inflammatory phase has been termed a “cytokine storm” that is indicated by increased levels of TNF-α, IL-1β, and IL-9. Pro-inflammatory cytokines up-regulate adhesion molecules in neutrophils and endothelial cells. Although activated neutrophils kill microorganisms, they also injure endothelium by releasing mediators that increase vascular permeability, leading to the flow of protein-rich edema fluid into lung and other tissues. In addition, activated endothelial cells release NO, a potent vasodilator that acts as a key mediator of septic shock.
An important aspect of sepsis is the alteration of the procoagulant-anticoagulant balance, with an increase in procoagulant factors and a decrease in anticoagulant factors. LPS stimulates endothelial cells to up-regulate tissue factor, activating coagulation. Fibrinogen is then converted to fibrin, leading to the formation of microvascular thrombi and further amplifying injury.
Sepsis increases the synthesis of PAI-1. Sepsis also decreases the levels of protein C, protein S, antithrombin III, and TFPI. LPS and TNF-α decrease the synthesis of thrombomodulin and EPCR, thus decreasing the activation of protein C. Sepsis further disrupts the protein C pathway because sepsis also decreases the expression of EPCR, which amplifies the deleterious effects of the sepsis-induced decrease in levels of protein C. LPS and TNF-α also increase PAI-1 levels so that fibrinolysis is inhibited.
The clinical consequences of the changes in coagulation caused by sepsis are increased levels of markers of DIC and wide-spread organ dysfunction.
Patients may undergo a controlled anti-inflammatory response enabling them to return to immune homeostasis, or undergo uncontrolled anti-inflammatory response “immune-paralysis” which is mediated by:
o Predominance of Th2 producing and Treg responses over Th1, producing and T17 responses
o CD4 lymphopenia and B lymphocyte dysfunction
o Monocytes stimulated by PAMPs fail to produce adequate cytokines
o Decreased expression of HLA‐DR on monocytes
o Impaired neutrophils phagocytosis
In end-stage septic patients; apoptosis induces loss of cells of innate and adaptive immune system:
o CD4, CD8, T, B, dendritic cells
o When clonal expansion of lymphocytes should be occurring
Host immunosuppression has long been considered a factor in late death in patients with sepsis, since the sequelae of anergy, lymphopenia, hypothermia, and nosocomial infection all appear to be involved. Severe depletion of immune effector cells is a universal finding in sepsis.
The altered signaling pathways in sepsis ultimately lead to tissue injury and MOD. Cardiovascular dysfunction is characterized by circulatory shock and the redistribution of blood flow, with decreased vascular resistance, hypovolemia, and decreased myocardial contractility associated with increased levels of NO, TNF-α, IL-6, and other mediators. Respiratory dysfunction is characterized by increased microvascular permeability, leading to ALI. Renal dysfunction in sepsis, may be profound, contributing to morbidity and mortality.
Sepsis is now recognized as an overwhelmingly time-critical disease, requiring early initiation of care in the ED, with subsequent transfer to the ICU. The mortality and morbidity of severe sepsis can be improved by effective clinical interventions applied in a timely and systematic manner. Although time zero is defined differently in some hospitals, the SSC defines it as the time a septic patient is triaged in the ED. The guidelines recommend two bundles that should be completed within three hours and six hours of time zero.
Optimal management of sepsis requires EGDT, lung-protective ventilation, antimicrobial treatment within the first hour after diagnosis of severe sepsis, low-dose hydrocortisone for vasopressor-resistant septic shock and insulin therapy. Source control should be accomplished within the first 12 hours when the patient is able to tolerate it. Later in the course of sepsis, appropriate management necessitates organ support and prevention of nosocomial infection.
Recent studies focused on novel targets, mechanisms of action, and combination therapy may improve current treatment. Several types of therapy have proven ineffective. Anti-LPS therapy was ineffective, numerous therapies that block pro-inflammatory cytokines have failed. Ibuprofen, platelet-activating factor acetyl hydrolase, bradykinin antagonists and other therapies have not improved survival among patients with sepsis. Super-antigens and mannose may be potential therapeutic targets. Inhibition of tissue factor, a proximal target, might mitigate excessive procoagulant activity. Lipid emulsion may modulate innate immunity by inhibiting LPS.
Inhibition of apoptosis improved survival in an animal model of sepsis. Therapies that augment host immune responses as GM-CSF or G-CSF, IFN-γ and IL-7 can decrease mortality. Blocking PD-1/PD-L axis is a promising target for restoring immune function in sepsis.
Other data
| Title | The Immune Response: Targets for the Treatment of Severe Sepsis | Other Titles | الاستجابة المناعية: أهداف لعلاج تسمم الدم الشديد | Authors | Doaa Abdel-Moneim Saeed Mansour El-Okda | Issue Date | 2016 |
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