Molecular mechanisms in the early phase of hemorrhagic shock

Hierholzer, Christian; Billiar, Timothy R.

doi:10.1007/s004230100242

Cited by 126 publications

(92 citation statements)

References 47 publications

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“…There is increasing evidence that the rapid activation of the coagulation cascade after trauma is accompanied by a very early onset of an uncontrolled, progressive inflammatory response with often lethal consequences (Hierholzer and Billiar 2001). Obviously, acute blood loss and tissue trauma activate the complement cascade in humans (Hecke et al 1997).…”

Section: Complement Systemmentioning

confidence: 99%

“…When reflecting a more philosophical consideration that "the end is in the beginning", the very early and rapid activation of both, the coagulation system and the complement system seem to be crucially involved in the initiation and progression of the systemic inflammatory response and also in the deathly escalation of posttraumatic organ failure (Hierholzer et al 2001). During experimental hemorrhagic shock, pretreatment of rats with carboxypeptidase N inhibitor (blocker of C5a clearance) turned out lethally (Younger et al 2001).…”

Section: Interaction Between the Coagulation And Complement Cascade Amentioning

confidence: 99%

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Interaction Between the Coagulation and Complement System

Amara

Rittirsch

Flierl

et al. 2008

Advances in Experimental Medicine and Biology

298

282

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The complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature. Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 (Huber-Lang et al. 2006) but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. These findings suggest that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.

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Section: Complement Systemmentioning

confidence: 99%

Section: Interaction Between the Coagulation And Complement Cascade Amentioning

confidence: 99%

Interaction Between the Coagulation and Complement System

Amara

Rittirsch

Flierl

et al. 2008

Advances in Experimental Medicine and Biology

298

282

View full text Add to dashboard Cite

show abstract

“…Severe traumatic injury and blood loss can lead to a cascade of detrimental signaling events, which can lead to shock, sepsis or multiple organ dysfunction (MOD) [8,10]. hemorrhagic shock following critical trauma is associated with high morbidity and mortality [23,24].…”

Section: Introductionmentioning

confidence: 99%

Establishment of an Experimental Mouse Model of Trauma-Hemorrhagic Shock

et al. 2012

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This study established an experimental mouse model of trauma-hemorrhagic shock (THS). THS-induced mice (C57BL/6J, n=33) were subjected to femoral fracture, ischemia for 90 min, and resuscitation for 15 min. The sham-operated mice (C57BL/6J, n=33) underwent the same anesthetic and surgical procedures, but neither trauma-hemorrhage nor fluid resuscitation were performed. Mean arterial pressure (MAP) and microvascular tissue perfusion over the small intestine, liver, and left kidney were longitudinally measured in all mice. Blood was collected for analysis at baseline and 3, 6, 12, and 24 h post resuscitation, and the small intestine, liver, and left kidney were resected for hematoxylin and eosin staining 24 h post resuscitation. Compared with the sham group, MAP and microvascular tissue perfusion over the small intestine, liver, and left kidney were all significantly reduced in the THS group at the end of hemorrhage. Following resuscitation, no significant differences were observed between the groups. THS induction was associated with significantly increased plasma concentrations of Cr, AST, CPK, IL-6, IL-10, and TNF-α from the baseline values by two-to three-fold after the hemorrhage phase, and THS-induced mice demonstrated significantly increased histological injury scores. The rapid drop in MAP and microvascular tissue perfusion observed following THS induction, and the gradual recovery post resuscitation, reflects the successful establishment of a THS experimental mouse model.

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“…The deleterious impact of femur fracture and associated soft tissue injury on remote organ function has been described in regard to splenocyte proliferation, intestinal permeability, and hepatic ischemia (37,51,60). Although many organs are affected by the systemic mediators released during trauma, the liver is a primary site of response (18).…”

mentioning

confidence: 99%

Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4

Levy¹,

Prince²,

Yang³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Extensive soft tissue injury and bone fracture are significant contributors to the initial systemic inflammatory response in multiply injured patients. Systemic inflammation can lead to organ dysfunction remote from the site of traumatic injury. The mechanisms underlying the recognition of peripheral injury and the subsequent activation of the immune response are unknown. Toll-like receptors (TLRs) recognize microbial products but also may recognize danger signals released from damaged tissues. Here we report that peripheral tissue trauma initiates systemic inflammation and remote organ dysfunction. Moreover, this systemic response to a sterile local injury requires toll-like receptor 4 (TLR4). Compared with wild-type (C3H/HeOuJ) mice, TLR4 mutant (C3H/HeJ) mice demonstrated reduced systemic and hepatic inflammatory responses to bilateral femur fracture. Trauma-induced nuclear factor (NF)-κB activation in the liver required functional TLR4 signaling. CD14−/− mice failed to demonstrate protection from fracture-induced systemic inflammation and hepatocellular injury. Therefore, our results also argue against a contribution of intestine-derived LPS to this process. These findings identify a critical role for TLR4 in the rapid recognition and response pathway to severe traumatic injury. Application of these findings in an evolutionary context suggests that multicellular organisms have evolved to use the same pattern recognition receptor for surviving traumatic and infectious challenges.

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Molecular mechanisms in the early phase of hemorrhagic shock

Cited by 126 publications

References 47 publications

Interaction Between the Coagulation and Complement System

Interaction Between the Coagulation and Complement System

Establishment of an Experimental Mouse Model of Trauma-Hemorrhagic Shock

Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4

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