Christoph W. Strey

The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration

Complement has been implicated in liver repair after toxic injury. Here, we demonstrate that complement components are essential for liver regeneration, and mediate their effect by interacting with key signaling networks that promote hepatocyte proliferation. C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy. Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution. Interception of C5a receptor signaling resulted in suppression of IL-6/TNFα induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor–κB/STAT-3 activation after hepatectomy. These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration.

Increased C5a receptor expression in sepsis

Excessive production of the complement activation product C5a appears to be harmful during the development of sepsis in rodents. Little is known about the role of the C5a receptor (C5aR) and its presence in different organs during sepsis. Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice. C5aR mRNA expression in these organs was also significantly increased during sepsis. Immunohistochemical analysis revealed patterns of increased C5aR expression in parenchymal cells in all four organs following CLP. Mice injected at the start of CLP with a blocking IgG to C5aR (alphaC5aR) showed dramatically improved survival when compared with animals receiving nonspecific IgG, as did mice injected with alphaC5a. In alphaC5aR-treated mice, serum levels of IL-6 and TNF-alpha and bacterial counts in various organs were significantly reduced during CLP when compared with control CLP animals. These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis.

C3a and C3b Activation Products of the Third Component of Complement (C3) Are Critical for Normal Liver Recovery after Toxic Injury

Although the complement system has been implicated in liver regeneration after toxic injury and partial hepatectomy, the mechanism or mechanisms through which it participates in these processes remains ill-defined. In this study, we demonstrate that complement activation products (C3a, C3b/iC3b) are generated in the serum of experimental mice after CCl4 injection and that complement activation is required for normal liver regeneration. Decomplementation by cobra venom factor resulted in impaired entry of hepatocytes into S phase of the cell cycle. In addition, livers from C3-deficient (C3−/−) mice showed similarly impaired proliferation of hepatocytes, along with delayed kinetics of both hepatocyte hyperplasia and removal of injured liver parenchyma. Restoration of hepatocyte proliferative capabilities of C3−/− mice through C3a reconstitution, as well as the impaired regeneration of C3a receptor-deficient mice, demonstrated that C3a promotes liver cell proliferation via the C3a receptor. These findings, together with data showing two waves of complement activation, indicate that C3 activation is a pivotal mechanism for liver regeneration after CCl4 injury, which fulfills multiple roles; C3a generated early after toxin injection is relevant during the priming of hepatocytes, whereas C3 activation at later times after CCl4 treatment contributes to the clearance of injured tissue.

Dysregulation of Stathmin, a Microtubule-Destabilizing Protein, and Up-Regulation of Hsp25, Hsp27, and the Antioxidant Peroxiredoxin 6 in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Gain-of-function mutations of the Cu/Zn superoxide dismutase (SOD1) gene cause dominantly inherited familial amyotrophic lateral sclerosis. The identification of differentially regulated proteins in spinal cords of paralyzed mice expressing SOD1(G93A) may contribute to understanding mechanisms of toxicity by mutant SOD1. Protein profiling showed dysregulation of Stathmin with a marked decrease of its most acidic and phosphorylated isoform, and up-regulation of heat shock proteins 25 and 27, peroxiredoxin 6, phosphatidylinositol transfer protein-alpha, apolipoprotein E, and ferritin heavy chain. Stathmin accumulated in the cytoplasm of 30% of spinal cord motor neurons with fragmented Golgi apparatus. Overexpression of Stathmin in HeLa cells was associated with collapse of microtubule networks and Golgi fragmentation. These results, together with the decrease of one Stathmin isoform, suggest a role of the protein in Golgi fragmentation. Mutant SOD1 co-precipitated and co-localized with Hsp25 in neurons and astrocytes. Mutant SOD1 may thus deprive cells of the anti-apoptotic and other protective activities of Hsp25. Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant. The up-regulation of peroxiredoxin 6 probably constitutes a defense to oxidative stress induced by SOD1(G93A). Direct effects of SOD1(G93A) or sequential reactions triggered by the mutant may cause the protein changes.

The Regulation of Liver Cell Survival by Complement

Complement effectors are known to contribute to host cell injury in several inflammatory diseases. Contrary to this paradigm, in this study utilizing surgical liver resection (partial hepatectomy) in various complement-deficient mice as a model, we have demonstrated that complement anaphylatoxins C3a and C5a are required for the survival of liver cells during regeneration. The mechanisms of these cytoprotective functions of complement were related to the regulation of IL-6 and TNF production or release after liver resection. Disturbances in the cytokine milieu, induced by a loss of complement activity, were found to alter prosurvival signaling, including the IL-6/STAT3 and PI3K/Akt/mammalian target of rapamycin pathways. In conclusion, this study documents functions of complement proteins as prosurvival factors that, through their interactions with cytokines, inhibit apoptotic signaling in proliferating cells of epithelial origin.

Benefit of a clipping device in use in intestinal bleeding and intestinal leakage

BACKGROUND The over-the-scope clip (OTSC) system was first used to close the access route in natural orifice transluminal endoscopic surgery and is increasingly used for other indications. OBJECTIVE We analyzed the use of the OTSC in intestinal bleeding and in closure of GI tract leaks. DESIGN Analysis of a consecutive series of patients. SETTING University hospital. PATIENTS Nineteen patients (group A: closure of GI leak site, n = 12; group B: complex GI bleeding, n = 7) were retrospectively enrolled in this study. We analyzed outcome and follow-up (6-68 weeks; group A: mean 37 weeks, standard deviation 24) in terms of treatment success (closure of the GI tract leak/durable hemostasis). INTERVENTION Endoscopic application of OTSCs. MAIN OUTCOME MEASUREMENTS Resolution of leaks, closure of fistula (group A), or stopping bleeding (group B). RESULTS In group A, durable closure was achieved in 8 of 12 patients. Sealing a postoperative/postinterventional leak was successful in 6 patients and failed in 3. A gastrocutaneous fistula was primarily closed successfully in 2 patients, but recurred in 1 of these patients. A gastric wall dehiscence in necrotizing pancreatitis was successfully closed in another patient. Group B patients had previous endoscopic treatment failure in 4 of 7 patients (through-the-scope clips, injection of Suprarenin or fibrin glue, others) and were deemed not treatable by through-the-scope clips in 3 of 7 patients. The primary success rate was 100% (7 of 7 patients); durable hemostasis was achieved in 4 of 7 patients, whereas surgery or angiography was necessary in the remaining patients. LIMITATIONS Retrospective analysis. CONCLUSIONS Leaks and fistulae are reliably closed with OTSCs in tissue flexible enough to be sucked into the attached cap (eg, in lesions caused <1 week before). GI bleeding may be stopped by OTSCs with reliable transient hemostasis, but durable hemostasis is less frequent.

Triple-Step Laparoscopic Incisional Hernia Repair: Midline Suture Closure Supported by Dorsal Component Separation and Intraperitoneal Onlay Mesh Reinforcement

Abstract Incisional hernias remain a surgical challenge when balancing surgical morbidity, functional restoration, and risk of recurrence. Laparoscopic intraperitoneal onlay mesh (IPOM) placement reduces postoperative wound infections and allows fast patient recovery. Yet, current IPOM techniques do not achieve closure of the midline hernia gap, thereby increasing the risk of persistent mesh bulging with poor abdominal wall function. We propose a novel triple-step hernia repair technique that includes tension-free midline reconstruction. It is achieved through laparoscopic dorsal component separation and laparoscopic suture closure of the midline with a 1.0 polydioxanone suture sling. Combining dorsal abdominal wall component separation, a midline closure with adequate suture strength, and IPOM reinforcement merges the benefits of open and laparoscopic hernia repair. This triple-step technique allows static and functional laparoscopic abdominal wall reconstruction.

Chirurgische Therapie des hepatozellulären Karzinoms

ZusammenfassungDie chirurgische Therapie des hepatozellulären Karzinoms (HCC) mit vollständiger Entfernung des Tumors oder die Lebertransplantation kann eine langfristige Heilung ermöglichen. Beide Verfahren sind primär oder im Rahmen neoadjuvanter Konzepte durchführbar. In bestimmten Fällen kann ein lokoregionäres Verfahren mit kurativer Zielsetzung angewandt werden. Die Zuordnung des Patienten zu einer primär chirurgisch kurativen, neoadjuvanten oder palliativen Vorgehensweise ist, neben der hepatischen und extrahepatischen Tumorausdehnung, von der vorbestehenden chronischen Leberschädigung abhängig. Die individuelle Grenze der Resektabilität ergibt sich aus der notwendigen Radikalität und dem für eine suffiziente postoperative Leberfunktion erforderlichen Parenchymrest. Aus diesem Grund ist das Ausmaß der zirrhotischen Leberschädigung für die Auswahl und die Sequenz der Therapiemaßnahmen entscheidend.AbstractSurgical treatment with complete resection of the hepatocellular carcinoma and liver transplantation can lead to a long term cure. If needed both surgical approaches can be incorporated into a neoadjuvant concept. In certain cases locoregional tumor treatment with curative intent can establish tumor control. Patients with established diagnosis are assigned to the corresponding surgical curative, neoadjuvant or palliative therapeutic approach according to the tumor stage and degree of parenchymal liver damage. The individual resection requirements to achieve tumor control and the acceptable limit of remnant liver volume to maintain liver function, define the individual feasibility of liver resection. For this reason sequence and choice of the therapeutic measures are determined by the extent of chronic functional impairment of the liver.