A New Role for Statins in Sepsis
Ayman Salah El Din Altohamy;
Abstract
Sepsis is defined as the presence of probable or documented infection together with systemic manifestations of infection.
The inflammatory response is a central component of sepsis as it drives the physiological alterations that are recognized as the SIRS. Sepsis develops when the initial, appropriate host response to an infection becomes amplified, and then aberrant. Bacterial components reacting with specific toll receptors are believed to trigger monocytes, neutrophils, and endothelial cells (EC) to initiate an inflammatory cascade.
Gram-positive and gram-negative bacteria, viruses, and fungi bind to pattern-recognition receptors (toll-like receptors [TLRs]) on the surface of immune cells. Binding of TLR-2 and TLR-4 activates intracellular signal-transduction pathways that lead to the activation of cytosolic nuclear factor B (NF- B). Activated NF- B moves from the cytoplasm to the nucleus, binds to transcription initiation sites, and increases the transcription of cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β, and interleukin-10. TNF-α and interleukin-1 are proinflammatory cytokines that activate the adaptive immune response but also cause both direct and indirect host injury. Interleukin-10 is an anti-inflammatory cytokine that inactivates macrophages and has other anti-inflammatory effects.
Sepsis increases the activity of inducible nitric oxide synthase (iNOS), which increases the synthesis of nitricoxide (NO), a potent vasodilator. Cytokines activate endothelial cells by up-regulating adhesion receptors and injure endothelial cells by inducing neutrophils, monocytes, macrophages, and platelets to bind to endothelial cells. These effector cells release mediators such as proteases, oxidants, prostaglandins, and leukotrienes.
This mechanisms result in vascular tissue damage. Endothelial damage and death occurs during human sepsis and leads to organ dysfunction and failure: the multi-organ dysfunction syndrome (MODS). This pan-endothelial damage is particularly important within the pulmonary circulation and results in high permeability pulmonary edema that is clinically recognized as ARDS and necessitates mechanical ventilation.
In sepsis, cytokine-induced coagulopathy triggers increased activity of TF and PAI-1 and decreased levels of the natural anticoagulant protein C on mononuclear and EC.
There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes.
Evidences indicates that statins decrease C-reactive protein levels in just 6 weeks of treatment, independent of LDL cholesterol reduction, and suggests that statins possess anti-inflammatory actions.
Simvastatin reduces leukocyte rolling, adherence, and transmigration in a rodent model of NO deficiency and attenuates endothelial adhesion molecule and monocyte CD11b expression in the absence of lipid lowering.
Statins are well tolerated by most patients. The most common adverse effects are gastrointestinal disturbance and headache, are usually mild and transient. Hepatic and skeletal muscle toxicity are also bad adverse effects, but they are fortunately quite rare.
The reduction in signalling intensity affects the expression of cytokines, acute phase proteins, chemokines, adhesion molecules, and enzymes, and also modulates the coagulation system and leucocyte function.
The inflammatory response is a central component of sepsis as it drives the physiological alterations that are recognized as the SIRS. Sepsis develops when the initial, appropriate host response to an infection becomes amplified, and then aberrant. Bacterial components reacting with specific toll receptors are believed to trigger monocytes, neutrophils, and endothelial cells (EC) to initiate an inflammatory cascade.
Gram-positive and gram-negative bacteria, viruses, and fungi bind to pattern-recognition receptors (toll-like receptors [TLRs]) on the surface of immune cells. Binding of TLR-2 and TLR-4 activates intracellular signal-transduction pathways that lead to the activation of cytosolic nuclear factor B (NF- B). Activated NF- B moves from the cytoplasm to the nucleus, binds to transcription initiation sites, and increases the transcription of cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β, and interleukin-10. TNF-α and interleukin-1 are proinflammatory cytokines that activate the adaptive immune response but also cause both direct and indirect host injury. Interleukin-10 is an anti-inflammatory cytokine that inactivates macrophages and has other anti-inflammatory effects.
Sepsis increases the activity of inducible nitric oxide synthase (iNOS), which increases the synthesis of nitricoxide (NO), a potent vasodilator. Cytokines activate endothelial cells by up-regulating adhesion receptors and injure endothelial cells by inducing neutrophils, monocytes, macrophages, and platelets to bind to endothelial cells. These effector cells release mediators such as proteases, oxidants, prostaglandins, and leukotrienes.
This mechanisms result in vascular tissue damage. Endothelial damage and death occurs during human sepsis and leads to organ dysfunction and failure: the multi-organ dysfunction syndrome (MODS). This pan-endothelial damage is particularly important within the pulmonary circulation and results in high permeability pulmonary edema that is clinically recognized as ARDS and necessitates mechanical ventilation.
In sepsis, cytokine-induced coagulopathy triggers increased activity of TF and PAI-1 and decreased levels of the natural anticoagulant protein C on mononuclear and EC.
There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes.
Evidences indicates that statins decrease C-reactive protein levels in just 6 weeks of treatment, independent of LDL cholesterol reduction, and suggests that statins possess anti-inflammatory actions.
Simvastatin reduces leukocyte rolling, adherence, and transmigration in a rodent model of NO deficiency and attenuates endothelial adhesion molecule and monocyte CD11b expression in the absence of lipid lowering.
Statins are well tolerated by most patients. The most common adverse effects are gastrointestinal disturbance and headache, are usually mild and transient. Hepatic and skeletal muscle toxicity are also bad adverse effects, but they are fortunately quite rare.
The reduction in signalling intensity affects the expression of cytokines, acute phase proteins, chemokines, adhesion molecules, and enzymes, and also modulates the coagulation system and leucocyte function.
Other data
| Title | A New Role for Statins in Sepsis | Other Titles | دور جديد لعقار الستاتين في التقيح الدموي | Authors | Ayman Salah El Din Altohamy | Issue Date | 2014 |
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