Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity.

INTRODUCTION: Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. METHODS: 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. RESULTS: Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. CONCLUSION: Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

Polypropylene mesh implantation for hernia repair causes myeloid cell-driven persistent inflammation.

Polypropylene meshes that are commonly used for inguinal hernia repair may trigger granulomatous foreign body reactions. Here, we show that asymptomatic patients display mesh-associated inflammatory granulomas long after surgery, which are dominated by monocyte-derived macrophages expressing high levels of inflammatory activation markers. In mice, mesh implantation by the onlay technique induced rapid and strong myeloid cell accumulation, without substantial attenuation for up to 90 days. Myeloid cells segregated into distinct macrophage subsets with separate spatial distribution, activation profiles, and functional properties, showing a stable inflammatory phenotype in the tissue surrounding the biomaterial and a mixed, wound-healing phenotype in the surrounding stromal tissue. Protein mass spectrometry confirmed the inflammatory nature of the foreign body reaction, as characterized by cytokines, complement activation, and matrix-modulating factors. Moreover, immunoglobulin deposition increased over time around the implant, arguing for humoral immune responses in association with the cell-driven inflammation. Intravital multiphoton microscopy revealed a high motility and continuous recruitment of myeloid cells, which is partly dependent on the chemokine receptor CCR2. CCR2-dependent macrophages are particular drivers of fibroblast proliferation. Thus, our work functionally characterizes myeloid cell-dependent inflammation following mesh implantation, thereby providing insights into the dynamics and mechanisms of foreign body reactions to implanted biomaterials.

[Deep Veins: Hybrid Procedure for Treatment of Iliofemoral Obstruction]. / Tiefes Venensystem: Hybridverfahren zur Therapie der iliofemoralen chronischen venösen Obstruktionen.

Background Endovascular recanalisation of chronic obstruction of iliofemoral or caval veins gives very good patency. However, patency decreases if the common femoral vein and its side branches are also involved. Endophlectomy during a hybrid procedure can improve outcome and avoid early reocclusion due to restored inflow. The review presents the technical details and the published results of this technique. Results The hybrid procedure combines venous recanalisation and stent angioplasty with endophlebectomy. There have only been 4 studies with more than 10 patients and follow-up between 6 and 24 months. Primary and secondary patency ranges from 0 to 70% and 30 to 93%, respectively, but most patients showed clinical benefit. Conclusion Although there have only been a few studies on the hybrid procedure with endophlebectomy, this technique seems to improve the outcome of venous recanalisation if femoral inflow is disturbed.

Aspirin, but Not Tirofiban Displays Protective Effects in Endotoxin Induced Lung Injury.

BACKGROUND: Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. Recruitment of neutrophils into the lungs, regarded as a key mechanism in progression of ALI, depends on signaling between neutrophils and platelets. Consequently we explored the effect of platelet-targeted aspirin and tirofiban treatment in endotoxin induced acute lung injury. METHODS: C57Bl/6 mice were exposed to aerosolized LPS (500µg/ml) for 30min and treated with Aspirin (100µg/g bodyweight via intraperitoneal injection, 30 min before or 1 hour after LPS inhalation) or Tirofiban (0.5µg/ g bodyweight via tail vein injection 30 min before or 1 hour after LPS inhalation). The count of alveolar, interstitial, and intravascular neutrophils was assessed 4h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and protein content in the BAL fluid. RESULTS: Aspirin both before and after LPS inhalation reduced neutrophil influx into the lung and lung permeability indicating the protective role of Aspirin in ALI. Tirofiban, however, did not alter neutrophil recruitment after LPS inhalation. Release of platelet-derived chemokines CCL5 and PF4 and neutrophil extracellular traps was reduced by Aspirin but not by Tirofiban. CONCLUSION: Aspirin, but not Tirofiban reduces neutrophil recruitment and displays protective effects during endotoxin induced lung injury.

Vascular anatomy of the small intestine-a comparative anatomic study on humans and pigs.

BACKGROUND: Porcine models are well established for studying intestinal anastomotic healing. In this study, we aimed to clarify the anatomic differences between human and porcine small intestines. Additionally, we investigated the influences of longitudinal and circular sutures on human small intestine perfusion. METHODS: Intestines were obtained from human cadavers (n = 8; small intestine, n = 51) and from pigs (n = 10; small intestine, n = 60). Vascularization was visualized with mennige gelatin perfusion and high-resolution mammography. Endothelial cell density was analyzed with immunohistochemistry and factor VIII antibodies. We also investigated the influence of suture techniques (circular anastomoses, n = 19; longitudinal sutures, n = 15) on vascular perfusion. RESULTS: Only human samples showed branching of mesenteric vessels. Compared to the pig, human vessels showed closer connections at the entrance to the bowel wall (p = 0.045) and higher numbers of intramural anastomoses (p < 0.001). Porcine main vessels formed in multifilament-like vessel bundles and displayed few intramural vessel anastomoses. Circular anastomoses induced a circular perfusion defect at the bowel wall; longitudinal anastomoses induced significantly smaller perfusion defects (p < 0.001). Both species showed higher vascular density in the jejunum than in the ileum (p < 0.001). Human samples showed similar vascular density within the jejunum (p = 0.583) and higher density in the ileum (p < 0.001) compared to pig samples. CONCLUSION: The results showed significant differences between human and porcine intestines. The porcine model remains the standard for studies on anastomotic healing because it is currently the only viable model for studying anastomosis and wound healing. Nevertheless, scientific interpretations must consider the anatomic differences between humans and porcine intestines.

Chronological evaluation of inflammatory mediators during peritoneal adhesion formation using a rat model.

PURPOSE: The inflammatory response to peritoneal injury is considered to be of particular importance in adhesion formation. The aim of this study was to investigate the dynamics of inflammatory mediators in peritoneal adhesions. METHODS: In 60 male rats, a peritoneal defect was performed using a standardized cecal abrasion model. On days 3, 5, 14, 30, 60, and 90, ten animals were sacrificed. The expression of five integral mediators for the cellular immune response (macrophages, T lymphocytes), inflammation (COX-2), cell differentiation, and proliferation (ß-catenin, c-myc) in visceral and parietal adhesions were analyzed. RESULTS: A distinct infiltration of macrophages was observed in all animals up to the 90th postoperative day with a peak on day 3 for visceral adhesions (26.3 ± 5.6%) and on day 14 for parietal adhesions (5.1 ± 1.1%). Compared to parietal adhesions, macrophage levels were significantly higher on day 3 (p = 0.001) and 5 (p = 0.002) but significantly lower on days 30, 60, and 90 in visceral adhesions (p = 0.041; p = 0.001; p = 0.017). T lymphocytes were detected over time with the highest levels on day 3 (visceral 4.0 ± 0.7%; parietal 6.7 ± 2.9%). High levels of COX-2 expression could be detected for the whole observation period. Positive expression of both ß-catenin and c-myc was detected in persistent adhesions; however, no expression of c-myc was observed in parietal adhesions. CONCLUSIONS: The inflammatory reaction in adhesions is not limited to the early postoperative phase. Macrophages may be fundamental in triggering adhesions, and the presence of T cells indicates an additional role of the adoptive immune system. Identification of chemokines and chemokine receptors that trigger the cellular immune response might be a potential option to minimize adhesion formation.

Balancing zinc deficiency leads to an improved healing of colon anastomosis in rats.

BACKGROUND: In colorectal surgery, anastomotic leakage is a relevant complication. The aim of this study was to investigate whether intraperitoneally (i.p.) administered zinc improves the healing of colon anastomosis in rats. MATERIALS AND METHODS: Male Wistar rats (66) received zinc-deficient diet for 21 days. To determine the effective dose of zinc which is necessary to compensate this deficiency, preliminary analysis in 30 rats were performed. In these rats, analysis by atom-absorption spectrophotometry revealed a dose of 1.0 mg zinc aspartate/kg body weight to be the compensatory dosage. In the remaining zinc-deficient rats (n= 36), a transverse colonic anastomosis was performed. Eighteen rats received either a zinc supplementation i.p. or 0.9% NaCl i.p. (n = 18; control group). On postoperative days 3, 5, and 14, the surface of the mucosal villi, expression of MMP 2, MMP 8, MMP 13, TIMP 1, as well as the collagen types I/III ratio were analyzed. RESULTS: Protein expression of MMP 2 and MMP 8 was significantly higher in the anastomosis of the zinc group on day 3 and on day 5. The collagen types I/III ratio was significantly increased in the zinc group on days 5 and 14. CONCLUSION: Balancing zinc deficiency benefits wound healing of colonic anastomosis qualitatively due to an increased collagen type I/III ratio. Surprisingly, these zinc supplements, however, increased the expression of MMP 2 and MMP 8 that are supposed to impair wound healing in case of an over-expression. Thus, further investigations are needed to elucidate the influence of zinc supplementation on regulation of MMPs.

Surgical technique for gastroesophageal reflux disease.

AIMS: Laparoscopic fundoplication is the standard surgical therapy for managing gastroesophageal reflux disease. According to the pre-existing esophageal motility of the patient, tailoring antireflux surgery has been proposed in order to avoid postoperative dysphagia. Thus, the aim of this study is to evaluate the long-term results following this tailored concept. METHODS: One-hundred sixty patients were included in this prospective study. A 360° Nissen fundoplication (NF) was performed on n = 127 patients with a normal esophageal peristalsis, whereas a 270° Toupet fundoplication (TF) was conducted on n = 33 patients having an esophageal motility disorder. Before surgery, all the patients were subjected to pH-metry, manometry, gastroscopy, and they had to respond to a standardized questionnaire. Postoperatively, pH-metry, and manometry were performed. In addition to the questionnaire, side effects and complications were evaluated. RESULTS: The NF cohort and the TF cohort were each followed up for an average of 39 ± 13 months and 43 ± 12 months, respectively. Dysphagia was significantly reduced after NF (p = .033). The TF, however, decreased the intensity but not the incidence of dysphagia (p = .884). Heartburn was significantly diminished in both cohorts. The DeMeester score was significantly reduced after NF, whereas it was not significantly reduced following TF with a still evident, pathological acid reflux occurring postoperatively. CONCLUSION: Our data indicate that tailoring antireflux surgery to the esophageal motility of the patient seems unnecessary. In summary, technical surgical aspects appear to be more important for clinical outcome.