Assessing Taper Geometry, Head Size, Head Material, and Their Interactions in Taper Fretting Corrosion of Retrieved Total Hip Arthroplasty Implants.

BACKGROUND: Decreased fretting and corrosion damage at the taper interface of retrieved ceramic-on-polyethylene total hip arthroplasty (THA) implants has been consistently reported; however, resultant fretting corrosion as a function of femoral head size and taper geometry has not been definitively explained. METHODS: Eight cohorts were defined from 157 retrieved THA implants based on femoral head composition (n = 95, zirconia-toughened alumina, ZTA vs n = 62, cobalt-chromium alloy, CoCr), head size (n = 56, 32mm vs n = 101, 36mm), and taper geometry (n = 84, 12/14 vs n = 73, V40). THA implants were evaluated and graded for taper fretting and corrosion. Data were statistically analyzed, including via a 23 factorial modeling. RESULTS: Factorial-based analysis indicated the significant factors related to both resultant (summed) fretting and corrosion damage were head material and taper geometry; head material-taper geometry interaction was also a significant factor in resultant corrosion damage. Lower rates of moderate-to-severe fretting and corrosion damage were exhibited on ZTA heads (ZTA = 13%, CoCr = 38%), smaller heads (32mm = 18%, 36mm = 26%), and 12/14 tapers (12/14 = 13%, V40 = 35%). ZTA+32mm heads demonstrated the lowest rates of moderate-to-severe fretting and corrosion damage (12/14 = 2%, V40 = 7%), whereas CoCr heads with V40 tapers demonstrated the greatest rates of moderate-to-severe damage (32mm = 47%, 36mm = 59%). CONCLUSION: In this series, retrieved implants with ZTA, 32-mm heads paired with 12/14 tapers exhibited lower rates of moderate-to-severe damage. Factorial analysis showed head material, taper geometry, and their interactions were the most significant factors associated with resultant damage grades. Isolating implant features may provide additional information regarding factors leading to fretting and corrosion damage in THA. LEVEL OF EVIDENCE: IV (case series).

Does Taper Design Affect Taper Fretting Corrosion in Ceramic-on-Polyethylene Total Hip Arthroplasty? A Retrieval Analysis.

BACKGROUND: Ceramic-on-polyethylene (CoP) implants have exhibited lower fretting and corrosion scores than metal-on-polyethylene implants. This study aims at investigating the effect of taper design on taper corrosion and fretting in modular CoP total hip arthroplasty (THA) systems. METHODS: Under an institutional review board--approved protocol, a query of an implant retrieval library from 2002 to 2017 identified 120 retrieved CoP THA systems with zirconia toughened alumina femoral heads. Femoral stem trunnions were visually evaluated and graded for fretting, corrosion, and damage at the taper interface. Medical records were reviewed for patient demographics and implant characteristics. Data were statistically analyzed using Spearman correlation and rank-sum tests with a Dunn's post hoc test, with a significance level of α = 0.05. RESULTS: Four different taper designs were evaluated: 11/13 (n = 18), 12/14 (n = 53), 16/18 (n = 21), and V40 (n = 28). There were no statistically significant demographic differences between taper groups for duration of implantation, laterality, patient age, and patient sex, but patients with 16/18 tapers had a higher body mass index than V40 tapers (P = .012). Duration of implantation had a weak positive correlation with both trunnion fretting (ρ = 0.224, P = .016) and corrosion (ρ = 0.253, P = .006). Summed fretting and corrosion scores were significantly greater on the V40 and 16/18 tapers compared with the 12/14 tapers (all P ≤ .001). CONCLUSION: Taper fretting and corrosion were observed in CoP THA implants and were greatest with V40 and 16/18 tapers and lowest with 12/14 tapers. Differences in taper design characteristics may lead to greater micromotion at the taper-head interface, leading to increased fretting and corrosion.

Poor Outcomes of Irrigation and Debridement in Acute Periprosthetic Joint Infection With Antibiotic-Impregnated Calcium Sulfate Beads.

BACKGROUND: One proposed strategy to increase the success of irrigation and debridement with implant retention for the treatment of acute periprosthetic joint infection (PJI) is the use of dissolvable antibiotic-impregnated calcium sulfate beads to provide a local depot of antibiotics. The purpose of this study was to evaluate the outcome of such an approach. METHODS: Thirty-two patients with acute hematogenous (18 patients; 1 bilateral) or acute postoperative (14 patients) PJIs who underwent irrigation and debridement with implant retention and addition of antibiotic-impregnated calcium sulfate beads were retrospectively reviewed. PJI followed 27 total knee arthroplasties and 6 total hip arthroplasties. The most common infecting organisms were methicillin-sensitive Staphylococcus aureus (13 of 33) and Streptococcus (9 of 33). The primary outcome parameter was recurrence of infection according to the Musculoskeletal Infection Society criteria. Patients were followed up for a minimum of 3 months or until failure. RESULTS: At a mean of 12.7 months (range, 3-30 months), 16 of the 33 patients failed (48%). Acute hematogenous and acute postoperative PJI had similar failure rates at 47% and 50%, respectively (P = .88). Seven failures required a 2-stage exchange, while 8 patients were treated with chronic antibiotic suppression, being unwilling or unable to undergo further surgical intervention. CONCLUSION: The addition of antibiotic-impregnated calcium sulfate beads does not appear to improve outcomes of irrigation and debridement with implant retention in the setting of acute hematogenous or acute postoperative PJI. Given the short follow-up in this report, this represents a best-case scenario and the overall failure rate may be higher with further follow-up.

Changes and regulation of the C5a receptor on neutrophils during septic shock in humans.

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.

Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.

Successful LCL reconstruction and PCL repair for LCL tear and PCL avulsion following total knee arthroplasty.

Total knee arthroplasty represents a well-established and successful procedure; however, ligament incompetence is known to negatively affect surgical outcomes. Here we present an unusual case of early total knee arthroplasty failure secondary to femoral posterior cruciate ligament (PCL) avulsion and associated lateral collateral ligament (LCL) tear, treated successfully with primary PCL repair and LCL reconstruction. For LCL reconstruction, a peroneus longus allograft was passed through an anterior to posterior bony tunnel in the fibular head and docked into a horizontal femoral tunnel. Level of evidence Case report, Level IV.

Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.

Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary deposition of IgG immune complexes. A zonulin antagonist (AT-1001) and a related peptide with permeability agonist activities (AT-1002) were employed and given intratracheally or intravenously. Also, zonulin was blocked in lung with a neutralizing antibody. In a dose-dependent manner, AT-1001 or zonulin neutralizing antibody attenuated the intensity of ALI (as quantitated by albumin leak, neutrophil accumulation, and proinflammatory cytokines). A similar pattern was found using the bacterial lipopolysaccharide model of ALI. Using confocal microscopy on sections of injured lungs, staining patterns for TJ proteins were discontinuous, reduced, and fragmented. As expected, the leak of blood products into the alveolar space confirmed the passage of 3 and 20 kDa dextran, and albumin. In contrast to AT-1001, application of the zonulin agonist AT-1002 intensified ALI. Zonulin both in vitro and in vivo induced generation of complement C3a and C5a. Collectively, these data suggest that zonulin facilitates development of ALI both by enhancing albumin leak and complement activation as well as increased buildup of neutrophils and cytokines during development of ALI.

Generation of C5a in the absence of C3: a new complement activation pathway.

Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.

Phagocyte-derived catecholamines enhance acute inflammatory injury.

It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways. We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes. Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha2-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha2-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.

Molecular intercommunication between the complement and coagulation systems.

The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin-antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.

A new experimental polytrauma model in rats: molecular characterization of the early inflammatory response.

BACKGROUND: The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. METHODS: Male Wistar rats (250 g, 6-10/group) were anesthetized and exposed to chest trauma (ChT), closed head injury (CHI), or Tib/Fib fracture including a soft tissue trauma (Fx + STT) or to the following combination of injuries: (1) ChT; (2) ChT + Fx + STT; (3) ChT + CHI; (4) CHI; (5) polytrauma (PT = ChT + CHI + Fx + STT). Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of "key" inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL) fluid samples. RESULTS: Polytraumatized (PT) rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. CONCLUSION: This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.

Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways.

Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcgammaR was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcgammaRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRgamma-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4(-/-) mice. Unexpectedly, TLR4 mut and TLR4(-/-) mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcgammaRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcgammaRIII signaling via FcRgamma-subunit activation.

Targeted modulation of the neuroinflammatory response after spinal cord injury: the ongoing quest for the "holy grail".

This Commentary discusses the role of inflammation after spinal cord injury.

Molecular mechanisms of inflammation and tissue injury after major trauma--is complement the "bad guy"?

Trauma represents the leading cause of death among young people in industrialized countries. Recent clinical and experimental studies have brought increasing evidence for activation of the innate immune system in contributing to the pathogenesis of trauma-induced sequelae and adverse outcome. As the "first line of defense", the complement system represents a potent effector arm of innate immunity, and has been implicated in mediating the early posttraumatic inflammatory response. Despite its generic beneficial functions, including pathogen elimination and immediate response to danger signals, complement activation may exert detrimental effects after trauma, in terms of mounting an "innocent bystander" attack on host tissue. Posttraumatic ischemia/reperfusion injuries represent the classic entity of complement-mediated tissue damage, adding to the "antigenic load" by exacerbation of local and systemic inflammation and release of toxic mediators. These pathophysiological sequelae have been shown to sustain the systemic inflammatory response syndrome after major trauma, and can ultimately contribute to remote organ injury and death. Numerous experimental models have been designed in recent years with the aim of mimicking the inflammatory reaction after trauma and to allow the testing of new pharmacological approaches, including the emergent concept of site-targeted complement inhibition. The present review provides an overview on the current understanding of the cellular and molecular mechanisms of complement activation after major trauma, with an emphasis of emerging therapeutic concepts which may provide the rationale for a "bench-to-bedside" approach in the design of future pharmacological strategies.

Complement C3 serum levels in anorexia nervosa: a potential biomarker for the severity of disease?

BACKGROUND: Anorexia nervosa carries the highest mortality rate of any psychiatric disorder. Even the most critically ill anorexic patients may present with normal 'standard' laboratory values, underscoring the need for a new sensitive biomarker. The complement cascade, a major component of innate immunity, represents a driving force in the pathophysiology of multiple inflammatory disorders. The role of complement in anorexia nervosa remains poorly understood. The present study was designed to evaluate the role of complement C3 levels, the extent of complement activation and of complement hemolytic activity in serum, as potential new biomarkers for the severity of anorexia nervosa. PATIENTS AND METHODS: This was a prospective cohort study on 14 patients with severe anorexia nervosa, as defined by a body mass index (BMI) <14 kg/m2. Serum samples were obtained in a biweekly manner until hospital discharge. A total of 17 healthy subjects with normal BMI values served as controls. The serum levels of complement C3, C3a, C5a, sC5b-9, and of the 50% hemolytic complement activity (CH50) were quantified and correlated with the BMIs of patients and control subjects. RESULTS: Serum C3 levels were significantly lower in patients with anorexia nervosa than in controls (median 3.7 (interquartile range (IQR) 2.5-4.9) vs 11.4 (IQR 8.9-13.7, P <0.001). In contrast, complement activation fragments and CH50 levels were not significantly different between the two groups. There was a strong correlation between index C3 levels and BMI (Spearman correlation coefficient = 0.71, P <0.001). CONCLUSIONS: Complement C3 serum levels may represent a sensitive new biomarker for monitoring the severity of disease in anorexia nervosa. The finding from this preliminary pilot study will require further investigation in future prospective large-scale multicenter trials.

Pathophysiology of septic encephalopathy--an unsolved puzzle.

The exact cellular and molecular mechanisms of sepsis-induced encephalopathy remain elusive. The breakdown of the blood-brain barrier (BBB) is considered a focal point in the development of sepsis-induced brain damage. Contributing factors for the compromise of the BBB include cytokines and chemokines, activation of the complement cascade, phagocyte-derived toxic mediators, and bacterial products. To date, we are far from fully understanding the neuropathology that develops as a secondary remote organ injury as a consequence of sepsis. However, recent studies suggest that bacterial proteins may readily cross the functional BBB and trigger an inflammatory response in the subarachnoid space, in absence of a bacterial invasion. A better understanding of the pathophysiological events leading to septic encephalopathy appears crucial to advance the clinical care for this vulnerable patient population.

Stress radiograph to detect true extent of symphyseal disruption in presumed anteroposterior compression type I pelvic injuries.

BACKGROUND: The differentiation between anteroposterior compression (APC)-I and APC-II pelvic fracture patterns is critical in determining operative versus nonoperative treatment. We instituted a protocol in which a stress examination was performed for patients presenting with an APC-I injury diagnosed with static radiographs to reveal the true extent of the injury. METHODS: During a 4-year study period, we performed 22 stress radiographs in patients with a presumed APC-I injury, which showed symphyseal diastasis ≥ 1.0 cm but <2.5 cm on initial anteroposterior (AP) radiographs of the pelvis or on axial images of the pelvis on computed tomography (CT) scans. In the operating room, a radiopaque marker of known diameter was placed on the skin over the pubic symphysis. A direct AP load was manually applied to both anterior superior iliac spines, and diastasis of the pubic symphysis was measured on stress fluoroscopic images. RESULTS: The mean distance of symphyseal diastasis was 1.8 cm on the AP radiographs, 1.4 cm on the CT scans, and 2.5 cm on fluoroscopic images under a stress examination. Six of 22 patients (27.2%) demonstrated a symphyseal diastasis of >2.5 cm during the stress examination, which changed their treatment from nonoperative to operative. CONCLUSIONS: Measurements of symphyseal diastasis can significantly vary depending on the radiographic modality (CT vs. plain films) and during application of a stress force. The use of stress examination under general anesthesia in the acute setting of pelvic injury can be beneficial in accurately diagnosing the severity of injury and choosing appropriate treatment.

Traction table-related complications in orthopaedic surgery.

Traction tables are used in numerous procedures about the hip and femur, including fracture fixation, hip arthroscopy, and less invasive arthroplasty. The use of a traction table is not without risks, however, and significant complications have been described, including injury to the perineal integument and soft tissues, neurologic impairment, and iatrogenic compartment syndrome of the well leg. The orthopaedic surgeon who uses a traction table for the surgical management of femur fracture must be familiar with the associated potential dangers and risks and must develop a plan to avoid traction table-associated complications, such as use of a radiolucent flat-top operating table for obese patients, adequate patient positioning, and the minimum possible surgical time.

Absence of the complement regulatory molecule CD59a leads to exacerbated neuropathology after traumatic brain injury in mice.

BACKGROUND: Complement represents a crucial mediator of neuroinflammation and neurodegeneration after traumatic brain injury. The role of the terminal complement activation pathway, leading to generation of the membrane attack complex (MAC), has not been thoroughly investigated. CD59 is the major regulator of MAC formation and represents an essential protector from homologous cell injury after complement activation in the injured brain. METHODS: Mice deleted in the Cd59a gene (CD59a-/-) and wild-type littermates (n = 60) were subjected to focal closed head injury. Sham-operated (n = 60) and normal untreated mice (n = 14) served as negative controls. The posttraumatic neurological impairment was assessed for up to one week after trauma, using a standardized Neurological Severity Score (NSS). The extent of neuronal cell death was determined by serum levels of neuron-specific enolase (NSE) and by staining of brain tissue sections in TUNEL technique. The expression profiles of pro-apoptotic (Fas, FasL, Bax) and anti-apoptotic (Bcl-2) mediators were determined at the gene and protein level by real-time RT-PCR and Western blot, respectively. RESULTS: Clinically, the brain-injured CD59a-/- mice showed a significantly impaired neurological outcome within 7 days, as determined by a higher NSS, compared to wild-type controls. The NSE serum levels, an indirect marker of neuronal cell death, were significantly elevated in CD59a-/- mice at 4 h and 24 h after trauma, compared to wild-type littermates. At the tissue level, increased neuronal cell death and brain tissue destruction was detected by TUNEL histochemistry in CD59a-/- mice within 24 hours to 7 days after head trauma. The analysis of brain homogenates for potential mediators and regulators of cell death other than the complement MAC (Fas, FasL, Bax, Bcl-2) revealed no difference in gene expression and protein levels between CD59a-/- and wild-type mice. CONCLUSION: These data emphasize an important role of CD59 in mediating protection from secondary neuronal cell death and further underscore the key role of the terminal complement pathway in the pathophysiology of traumatic brain injury. The exact mechanisms of complement MAC-induced secondary neuronal cell death after head injury require further investigation.

Functions of the complement components C3 and C5 during sepsis.

Activation of the complement system is a key event in the pathogenesis of sepsis. Nevertheless, the exact mechanisms remain inadequately understood. In the current study, we examined the role of complement C3 and C5 in sepsis in wild-type and C3- or C5-deficient mice induced by cecal ligation and puncture. When compared to wild-type mice, C5(-/-) showed identical survival, and C3(-/-) presented significantly reduced survival. Interestingly, this was associated with significant decreases in plasma levels of proinflammatory mediators. Moreover, although septic C3(-/-) animals displayed a 10-fold increase of blood-borne bacteria, C5(-/-) animals exhibited a 400-fold increase in bacteremia when compared to wild-type mice. These effects were linked to the inability of C5(-/-) mice to assemble the terminal membrane attack complex (MAC), as determined by complement hemolytic activity (CH-50). Surprisingly, although negative control C3(-/-) mice failed to generate the MAC, significant increases of MAC formation was found in septic C3(-/-) mice. In conclusion, our data corroborate that hemolytic complement activity is essential for control of bacteremia in septic mice. Thus, during sepsis, blockade of C5a or its receptors (rather than C5) seems a more promising strategy, because C5a-blockade still allows for MAC formation while the adverse effects of C5a are prevented.