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Role of complement in multiorgan failure.

Rittirsch D, Redl H, Huber-Lang M - Clin. Dev. Immunol. (2012)

Bottom Line: Multiorgan failure (MOF) represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS) following severe trauma.Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems.In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.

View Article: PubMed Central - PubMed

Affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. drittirsch@googlemail.com

ABSTRACT
Multiorgan failure (MOF) represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS) following severe trauma. The underlying immune response is highly complex and involves activation of the complement system as a crucial entity of innate immunity. Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems. In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.

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Summarizing illustration on the effects of excessive complement activation on various organ systems and the development of organ failure. For details see text. MBL: mannose-binding lectin, CNS: central nervous system, BBB: blood brain barrier, PMN: polymorphonuclear neutrophils, ARDS: acute respiratory distress syndrome, ATIII: antithrombin III, RES: reticuloendothelial system, GFR: glomerular filtration rate, ATN: acute tubular necrosis, FX: coagulation factor X, FII: coagulation factor II, TF: tissue factor, DIC: disseminated intravascular coagulation.
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fig1: Summarizing illustration on the effects of excessive complement activation on various organ systems and the development of organ failure. For details see text. MBL: mannose-binding lectin, CNS: central nervous system, BBB: blood brain barrier, PMN: polymorphonuclear neutrophils, ARDS: acute respiratory distress syndrome, ATIII: antithrombin III, RES: reticuloendothelial system, GFR: glomerular filtration rate, ATN: acute tubular necrosis, FX: coagulation factor X, FII: coagulation factor II, TF: tissue factor, DIC: disseminated intravascular coagulation.

Mentions: Historically, the central nervous system (CNS) was defined as an “immunological privileged organ” because of its separation from peripheral circulation by the blood-brain barrier (BBB). However, it became evident that the CNS is a rich source of inflammatory mediators and complement proteins can be produced by neurons, astrocytes, microglia, and oligodendroglia [41–43]. Severe trauma and sepsis are associated with systemic inflammation that can lead to blood-brain barrier (BBB) dysfunction and cerebral edema, regardless of the presence of traumatic brain injury (TBI) [44]. The breakdown of the BBB is considered to be a key event in the development of septic encephalopathy, while the cellular and molecular mechanisms of sepsis-induced brain damage are still vastly unknown [45]. Interestingly, the direct contact between blood and cerebrospinal fluid leads to complement activation, and the extent of intrathecal complement activation is associated with BBB dysfunction [46]. In addition, intracerebral complement levels increase under pathological conditions due to leakage of serum-derived complement proteins into the subarachnoidal space after breach of the BBB as well as increased complement biosynthesis in the CNS [47]. C1q, C3a, and C5a contribute to intracranial inflammation by induction of BBB damage and increase in vascular permeability [47, 48]. Blood-derived leukocytes, predominantly PMN, are then able to transmigrate into the CNS and release proteases and free radicals resulting in tissue damage (Figure 1) [47, 49]. In line with this, in experimental sepsis blockade of C5a attenuated pathophysiological changes that are typically associated with septic encephalopathy [50]. C3 and its derivates seem to play a central role in the pathogenesis of CNS dysfunction. Accumulation of C3 fragments is related to neuronal cell death and intracerebral PMN infiltration [51]. Previous studies suggested that the alternative pathway activation is a leading mechanism for neuronal cell death after closed head injury [52, 53]. C5a can induce neuronal apoptosis via the interaction with its receptor (C5aR), which is abundantly expressed on various cell types in the CNS [54, 55]. Finally, inactivation of the complement regulatory proteins on neurons during inflammation pave the road for complement-mediated lysis of homologous cells by the membrane attack complex [56]. Despite the unambiguous involvement in various pathological mechanisms, the role of the complement system in the pathogenesis of CNS dysfunction appears to be a double-edged sword since it has been reported that C3a as well as C5a also may mediate neuroprotective and neuroregenerative effects [57, 58].


Role of complement in multiorgan failure.

Rittirsch D, Redl H, Huber-Lang M - Clin. Dev. Immunol. (2012)

Summarizing illustration on the effects of excessive complement activation on various organ systems and the development of organ failure. For details see text. MBL: mannose-binding lectin, CNS: central nervous system, BBB: blood brain barrier, PMN: polymorphonuclear neutrophils, ARDS: acute respiratory distress syndrome, ATIII: antithrombin III, RES: reticuloendothelial system, GFR: glomerular filtration rate, ATN: acute tubular necrosis, FX: coagulation factor X, FII: coagulation factor II, TF: tissue factor, DIC: disseminated intravascular coagulation.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3539671&req=5

fig1: Summarizing illustration on the effects of excessive complement activation on various organ systems and the development of organ failure. For details see text. MBL: mannose-binding lectin, CNS: central nervous system, BBB: blood brain barrier, PMN: polymorphonuclear neutrophils, ARDS: acute respiratory distress syndrome, ATIII: antithrombin III, RES: reticuloendothelial system, GFR: glomerular filtration rate, ATN: acute tubular necrosis, FX: coagulation factor X, FII: coagulation factor II, TF: tissue factor, DIC: disseminated intravascular coagulation.
Mentions: Historically, the central nervous system (CNS) was defined as an “immunological privileged organ” because of its separation from peripheral circulation by the blood-brain barrier (BBB). However, it became evident that the CNS is a rich source of inflammatory mediators and complement proteins can be produced by neurons, astrocytes, microglia, and oligodendroglia [41–43]. Severe trauma and sepsis are associated with systemic inflammation that can lead to blood-brain barrier (BBB) dysfunction and cerebral edema, regardless of the presence of traumatic brain injury (TBI) [44]. The breakdown of the BBB is considered to be a key event in the development of septic encephalopathy, while the cellular and molecular mechanisms of sepsis-induced brain damage are still vastly unknown [45]. Interestingly, the direct contact between blood and cerebrospinal fluid leads to complement activation, and the extent of intrathecal complement activation is associated with BBB dysfunction [46]. In addition, intracerebral complement levels increase under pathological conditions due to leakage of serum-derived complement proteins into the subarachnoidal space after breach of the BBB as well as increased complement biosynthesis in the CNS [47]. C1q, C3a, and C5a contribute to intracranial inflammation by induction of BBB damage and increase in vascular permeability [47, 48]. Blood-derived leukocytes, predominantly PMN, are then able to transmigrate into the CNS and release proteases and free radicals resulting in tissue damage (Figure 1) [47, 49]. In line with this, in experimental sepsis blockade of C5a attenuated pathophysiological changes that are typically associated with septic encephalopathy [50]. C3 and its derivates seem to play a central role in the pathogenesis of CNS dysfunction. Accumulation of C3 fragments is related to neuronal cell death and intracerebral PMN infiltration [51]. Previous studies suggested that the alternative pathway activation is a leading mechanism for neuronal cell death after closed head injury [52, 53]. C5a can induce neuronal apoptosis via the interaction with its receptor (C5aR), which is abundantly expressed on various cell types in the CNS [54, 55]. Finally, inactivation of the complement regulatory proteins on neurons during inflammation pave the road for complement-mediated lysis of homologous cells by the membrane attack complex [56]. Despite the unambiguous involvement in various pathological mechanisms, the role of the complement system in the pathogenesis of CNS dysfunction appears to be a double-edged sword since it has been reported that C3a as well as C5a also may mediate neuroprotective and neuroregenerative effects [57, 58].

Bottom Line: Multiorgan failure (MOF) represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS) following severe trauma.Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems.In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.

View Article: PubMed Central - PubMed

Affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. drittirsch@googlemail.com

ABSTRACT
Multiorgan failure (MOF) represents the leading cause of death in patients with sepsis and systemic inflammatory response syndrome (SIRS) following severe trauma. The underlying immune response is highly complex and involves activation of the complement system as a crucial entity of innate immunity. Uncontrolled activation of the complement system during sepsis and SIRS with in excessive generation of complement activation products contributes to an ensuing dysfunction of various organ systems. In the present review, mechanisms of the inflammatory response in the development of MOF in sepsis and SIRS with particular focus on the complement system are discussed.

Show MeSH
Related in: MedlinePlus