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ABSTRACT: OBJECTIVE:: To determine the effect of peridural analgesia on long-term survival in patients who underwent surgical treatment of colorectal carcinoma. BACKGROUND:: Clinical and animal studies suggest a potential benefit of peridural analgesia on morbidity and mortality after cancer surgery. The effect of peridural analgesia on long-term outcome after surgery for colorectal cancer remains undefined. METHODS:: From 2003 to 2009, there were 749 patients who underwent surgery for colorectal carcinoma under general anesthesia with or without peridural analgesia. Clinical data were reviewed retrospectively and analyzed with multivariate analysis and Kaplan-Meier plots. RESULTS:: There were 442 patients who received peridural analgesia and 307 patients who did not receive peridural analgesia. A substantial survival benefit was observed in patients who received peridural analgesia (5-year survival rate: peridural analgesia, 62%; no peridural analgesia, 54%; P < 0.02). The hazard rate for death was decreased by 27% in patients who received peridural analgesia. When peridural analgesia was included simultaneously in a Cox model with the confounding factors age, American Society of Anesthesiologists classification, and stage, there was a significant survival benefit in patients who received peridural analgesia. In patients with America Society of Anesthesiologists classification 3 to 4, there was significantly greater survival with peridural analgesia than without peridural analgesia (P < 0.009). CONCLUSIONS:: Peridural analgesia may improve survival in patients underwent surgery for colorectal carcinoma. The survival benefit with peridural analgesia was greater in patients who had greater medical morbidity.
Annals of surgery 04/2013; · 7.90 Impact Factor
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ABSTRACT: Long-term ventilation in intensive care units (ICUs) is associated with several problems such as increased mortality, increased rates of ventilator-associated pneumonia (VAP), and prolonged time of hospitalization, and thus leads to enormous healthcare expenditure. While the influence of tracheostomy on VAP incidence, duration of ventilation, and time of hospitalization has already been analyzed in several studies, the timing of the tracheostomy procedure on patient's mortality is still controversial. The aim of our study was to investigate whether early tracheostomy improved outcome in critically ill patients.
Within 2 years, 100 critically ill, predominantly surgical patients entered this prospective randomized study. A percutaneous dilatational tracheostomy was performed either early (≤4 days, 2.8 days median) or late (≥6 days, 8.1 days median) after intubation.
We could demonstrate that mortality was not significantly reduced in the early tracheostomy (ET) group in contrast to the late tracheostomy (LT) group. ET was associated with decreased VAP incidence (ET 38% vs. LT 64%), decreased duration of ventilation (ET 367.5 h vs LT 507.5 h), and shorter time of hospitalization both in hospital (ET 31.5 days vs LT 68 days) and in ICU (ET 21.5 days vs LT 27 days).
Despite many advantages like reduced time of ventilation and hospitalization, early tracheostomy is not associated with decreased mortality in critically ill patients.
Langenbeck s Archives of Surgery 02/2012; 397(6):1001-8. · 1.81 Impact Factor
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ABSTRACT: In the nonsurgical treatment of anal incontinence, the combination of amplitude-modulated medium-frequency stimulation and electromyographic biofeedback (EMG-BF), known as triple-target treatment (3T), is superior to EMG-BF alone. The aim of this trial is to compare 3T with the standard treatment, low-frequency stimulation (LFS).
80 patients with anal incontinence of Grade I or higher who presented to physicians or centers specialized in coloproctology were enrolled in this multicenter randomized trial with blinded observer. The trial had an open parallel-group design. Randomization was performed centrally by telephone. The primary endpoint was the Cleveland Clinic Score (CCS) after self-training at home with either 3T or LFS in two 20-minute sessions per day for 6 months. The secondary endpoints included the proportion of patients regaining continence, and the patients' quality of life (QoL). On completion of the trial as planned, the results were evaluated with an intention-to-treat analysis. Study registration: DRKS00000138 (http://register.germanctr.de).
39 patients were randomized to 3T, and 41 to LFS. After 6 months of treatment, the CCS (mean ± standard deviation) was 3.1 ± 4.2 in the 3T group and 9.6 ± 3.9 in the LFS group. The median improvement in the CCS at 6 months compared to baseline was 7 points greater in the 3T group than in the LFS group (95% CI: 5-9, p<0.001). Anal continence was regained by 54% of the 3T patients, but none of the LFS patients (95% CI for the difference: 37.18% - 69.91%, p<0.001). QoL scores were higher in all dimensions in the 3T group than in the LFS group. No major adverse effects occurred in either group.
3T is superior to LFS in the treatment of anal incontinence. The available evidence suggests that the success of 3T is based on the combined effect of biofeedback and medium-frequency stimulation. LFS of the type applied in this trial has no effect. 3T should be used in routine clinical practice instead of LFS.
09/2011; 108(39):653-60. · 2.92 Impact Factor
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ABSTRACT: Obstructed defecation syndrome is a multifactorial disorder of the defecation process. Stapled transanal rectal resection has been used to restore function in patients suffering from obstructed defecation syndrome.
The aim of this study was to use preoperative and postoperative dynamic pelvic floor MRI combined with clinical parameters to evaluate the outcome of stapled transanal rectal resection.
A prospective cohort study was conducted in a tertiary care center.
A group of 140 women with obstructed defecation syndrome were evaluated.
All 140 patients were initially treated conservatively with laxatives, increased fluid intake, pelvic floor exercises, and biofeedback. Stapled transanal rectal resection was performed in 30 patients with rectocele who did not show improvement in symptoms after at least 6 months of conservative treatment.
Preoperative diagnostic workup consisted of dynamic pelvic floor MRI, clinical examination, coloscopy, and clinical scores (Cleveland Clinic constipation score, German Working group on Coloproctology continence score, and SF-36 quality-of-life questionnaire). Postoperatively, patients were reevaluated at 3 months by means of dynamic pelvic floor MRI, clinical examination, and clinical scores; clinical scores were repeated at 6 months after the operation.
Postoperative dynamic pelvic floor MRI performed after a median of 3.4 months showed a decrease in rectocele size from 3.3 (interquartile range, 2.8-3.8) cm to 1.5 (1.2-2) cm (P < .001). The number of patients with intussusception decreased from 21 (70%) before the operation to none after the operation (P < .001). The size of cystoceles did not change. The number of patients with incomplete evacuation was significantly reduced (P < .001). With a mean follow-up of 18 ± 4 months, patients showed a significant improvement in the quality-of-life score (P < .001) but not in the continence scores.
Stapled transanal rectal resection is an effective treatment option for patients with obstructed defecation syndrome associated with rectocele and intussusception.
Diseases of the Colon & Rectum 04/2011; 54(4):412-7. · 3.13 Impact Factor
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ABSTRACT: The Symphony study showed superior 1-year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin-secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post-transplant. Tacr- compared with CsA-based immunosuppression was independently associated with increased IL-2 (P<0.0001, CD4 cells; P=0.014, CD8 cells) and CD4 cell IL-4 responses (P=0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL-10 responses (P=0.008), B-cell IL-6R expression (P<0.0001) and ISC formation [P=0.020, staphylococcus cowan strain I (SAC I); P=0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL-4 by Tacr, decreased CD4 cell IL-10 responses by MMF) and suppression of B-cell functions (MMF), whereas Tacr/Aza was associated with physiological IL-2 and IL-4 and stronger humoral responses which may reduce the risk of infectious disease complications.
Transplant International 03/2011; 24(6):596-609. · 2.92 Impact Factor
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ABSTRACT: Chronic allograft vasculopathy (CAV) is an important aspect of chronic allograft injury, which limits the long-term success of renal transplantation. The pathogenesis of CAV is ill defined, and no effective therapies exist. Acute rejection episodes are a major risk factor for CAV. Recently, we demonstrated that leukocytes, which strongly accumulate in allograft blood vessels during fatal acute rejection, produce acetylcholine (ACh), which has the potential to provoke CAV. Herein, we test the hypothesis that ACh is also produced by leukocytes during the development of CAV.
Kidneys were transplanted in the Fischer 344 to Lewis rat strain combination, an established experimental model for CAV. Isografts were performed in Lewis rats. The capacity of intravascular graft leukocytes to synthesize ACh was investigated during reversible acute rejection on day 9 posttransplantation and during the process of vascular remodeling on day 42. Furthermore, allograft recipients were treated with rivastigmine, which blocks enzymatic degradation of ACh.
The protein expression of the high-affinity choline transporter-1 and choline acetyltransferase was increased in leukocytes from allografts on day 9 and 42 posttransplantation. In addition, leukocytes accumulating in the lumina of allograft blood vessels were by far more numerous compared with isografts. In line with our hypothesis, ACh itself was detected by high-pressure liquid chromatography in graft leukocytes but not in leukocytes from untreated kidneys. Treatment with rivastigmine drastically exacerbated CAV compared with placebo.
We suggest that endogenous ACh contributes to the pathogenesis of CAV and may be a promising target for novel therapies preventing CAV.
Transplantation 02/2011; 91(3):263-70. · 4.00 Impact Factor
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ABSTRACT: Dimethylarginines are inhibitors of NO synthesis and are involved in the pathogenesis of vascular diseases. In this study, we ask the question if asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels change during fatal and reversible acute rejection, and contribute to the pathogenesis of chronic vasculopathy.
The Dark Agouti to Lewis rat strain combination was used to investigate fatal acute rejection. Fischer 344 kidneys were transplanted to Lewis rats to study reversible acute rejection episode and the process of chronic rejection. Isograft recipients and untreated Lewis rats were used as controls. l-arginine derivatives were determined by HPLC, and ADMA-metabolizing enzymes were studied by quantitative RT-PCR and western blotting.
Renal transplantation transiently increased dimethylarginine levels independent of acute rejection. ADMA plasma levels did not importantly differ between recipients undergoing fatal or reversible acute rejection, whereas SDMA was even lower in recipients of Fisher 344 grafts. In comparison to isograft recipients, ADMA and SDMA levels were slightly elevated during reversible, but not during the process of chronic rejection. Increased dimethylarginine levels, however, did not block NO synthesis. Interestingly, protein methylation, but not ADMA degradation, was increased in allografts.
Our data do not support the concept that renal allografts are protected from fatal rejection by dimethylarginines. Dimethylarginines may play a role in triggering chronic rejection, but a contribution to vascular remodelling itself is improbable. In contrast, differential arginine methylation of yet unknown proteins by PRMT1 may be involved in the pathogenesis of acute and chronic rejection.
Nephrology Dialysis Transplantation 01/2011; 26(1):124-35. · 3.40 Impact Factor
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ABSTRACT: During acute rejection, numerous pro-inflammatory and cytotoxic monocytes accumulate in the vasculature of experimental renal allografts. Arrestins (ARRBs) are cellular regulators of inflammation, but nothing is known about their expression during rejection. Intravascular mononuclear graft leukocytes were isolated 4 days after kidney transplantation. ARRB1 and ARRB2 mRNA expression was reduced in blood leukocytes from allografts undergoing acute rejection, whereas on the protein level only ARRB2 was changed. Flow cytometry and confocal microscopy revealed ARRB1 and ARRB2 expression by monocytes and T cells, with a selective decrease in ARRB2 expression in monocytes during acute rejection. I-κB directly interacted with ARRB2 and the levels of both proteins strongly correlated. Concomitantly, the mRNA expression of NF-κB targeted genes increased. Our results suggest that activation of blood monocytes in renal isografts is dampened by high ARRB2 levels. During acute rejection, ARRB2 levels are reduced and classical monocyte activation is enabled via NF-κB activation.
Immunobiology 12/2010; 216(7):854-61. · 3.20 Impact Factor
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ABSTRACT: In the lung, epidermal fatty acid-binding protein (E-FABP) is expressed by alveolar macrophages (AM) and alveolar epithelial cells type II (AEII). E-FABP may regulate macrophage activation and is involved in the metabolism of surfactant phospholipids. As macrophage activation and surfactant dysfunction are associated with rejection, we hypothesize that E-FABP expression is changed during acute rejection of pulmonary grafts. Orthotopic left lung transplantations were performed in the Dark Agouti to Lewis and in the isogeneic Lewis to Lewis rat strain combinations. E-FABP expression was analyzed in the lung by immunohistochemistry, immunoblotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR). Alveolar leukocytes obtained by bronchoalveolar lavage were analyzed by RT-PCR. Immunohistochemistry of isografts revealed strong E-FABP immunoreactivity in AEII and a moderate immunoreactivity in AM. In allografts undergoing acute rejection, AM exhibiting increased E-FABP immunoreactivity accumulated. Immunoblots revealed a single band at 15 kDa, which corresponds to the expected molecular mass of E-FABP. The levels of E-FABP mRNA were higher in allografts than in isografts and control lungs. Furthermore, alveolar leukocytes isolated by bronchoalveolar lavage from allografts displayed higher E-FABP mRNA expression levels than leukocytes from isografts and controls. In conclusion, we demonstrate for the first time upregulation of E-FABP expression in AM during severe inflammation.
Apmis 10/2010; 118(10):791-800. · 1.99 Impact Factor
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ABSTRACT: During self-limiting acute rejection preceding chronic vasculopathy, large amounts of leukocytes, predominantly monocytes, interact with the endothelium of renal allografts. We aim to characterize them and to identify targets for functional and interventional studies. Leukocytes were harvested by vascular perfusion from Fischer 344 to Lewis renal allografts or Lewis isografts, followed by flow cytometry, quantitative RT-PCR and genome-wide transcriptional profiling. Leukocyte accumulation peaked in allografts on day 9. The percentage of monocytes expressing MHC class II and CD161 was increased whereas CD4, CD11a, CD43, and CD71 expression remained unchanged. IFN-γ, IL-1β, IL-2, IL-10, TNF-α, and iNOS mRNA increased in allograft leukocytes but IL-4, IL-6, IL-12, TGF-β, and tissue factor did not. During acute rejection, 1783 genes were differentially expressed. In conclusion, graft blood leukocytes display a unique state of partial activation during self-limiting rejection. Numerous differentially expressed genes deserve further investigation as potential factors in deciding the fate of the allograft.
Immunobiology 09/2010; 216(5):613-24. · 3.20 Impact Factor
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ABSTRACT: This study was designed to analyze the efficacy of the Surgisis Anal Fistula Plug for the closure of transsphincteric anorectal fistulas.
Patients with single transsphincteric anorectal fistulas were prospectively enrolled. Setons were used in all tracts for at least eight weeks before surgery. Continence, surgical variables, complications, and healing rates were recorded. Surgery was performed in a standardized manner. The fistula tract and external opening were debrided, the tract was irrigated, and the plug was placed. The external opening was left open. Success was defined as the absence of drainage and closure of the external opening. Follow-up examinations were performed at 2 days, 2, 4, 6, and 12 weeks, and 6 and 12 months after surgery.
Sixty patients were enrolled. Seventeen patients were smokers, and ten had diabetes mellitus. The mean surgical time was 23 (range, 13-50) minutes; no morbidity occurred. The overall success rate after 12 months was 62%. Nineteen fistulas recurred, and four fistulas never completely healed. The success rate was significantly lower in smokers and diabetics. Two patients had a plug dislodgement, and plugs were successfully replaced. No change in continence was observed.
Because there is still no standard for the treatment of high transsphincteric fistulas and because recurrence rates are high for all procedures performed, new techniques are needed for this complex disease. Our success rate of 62% is promising because this technique can be used as a first approach to close the fistula tract without destruction of the sphincter muscle.
Diseases of the Colon & Rectum 10/2009; 52(9):1578-83. · 3.13 Impact Factor
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ABSTRACT: Widely differing surgical methods have been propagated to correct symptomatic rectocele. With transvaginal rectal repair (TVRR), we evaluate a method to reestablish the continuity of the rectal muscle wall, strengthen the weakened tunica muscularis, and restore normal rectal capacity and function.
Between 1997 and 2003, 102 female patients were treated by TVRR in cases of symptomatic rectocele. Patients without improvement following a stringent conservative treatment for a minimum of 3-6 months were selected for TVRR procedure. Patients with intussusception and slow-transit constipation were excluded from the study. To achieve optimal stabilization of the rectal wall, a transverse gathering of the rectocele was performed by a transvaginal access.
Average patient age was 60.9 years (47-76 years), operation time was 36.5 minutes (29-67 min.), in-hospital treatment lasted 4.1 days (2-7 days), and follow-up was 18.1 months (3-48 months). We observed complications in 11% of cases. Three months after the operation, 81% of the patients were symptom-free or improved. Following an average observation time of 18.1 months (3-48 months), 70% were still symptom-free or improved.
TVRR allows easy access for rectocele repair with a low rate of complications.
International Journal of Colorectal Disease 09/2009; 24(12):1429-34. · 2.38 Impact Factor
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ABSTRACT: Monocytes and macrophages play an important role in acute pulmonary allograft rejection. Acetylcholine has been shown to exert anti-inflammatory effects on these cells via nicotinic acetylcholine receptors. The aim of this study was to test for the hypothesis that a global nicotinic stimulation of pulmonary allograft recipients attenuates acute rejection.
Orthotopic left lung transplantation was performed in the Fischer 344-Wistar Kyoto rat strain combination. Graft recipients treated with nicotine added to the drinking water were compared with untreated allograft recipients. Graft histopathology, leukocytic infiltration, expression of inducible nitric oxide (NO) synthase and cytokine expression were analyzed during the process of acute rejection on Day 7 post-transplantation using quantitative reverse transcript-polymerase chain reaction (RT-PCR), enzyme-linked immunoassay (ELISA) and immunohistochemistry. The right native lung of the experimental animals was included as an internal control.
Nicotine treatment resulted in a marked reduction in lung allograft infiltration by CD68-like antigen(+) alveolar and tissue macrophages, whereas resident mature macrophages (CD163(+)) and T cells remained unchanged. Concomitantly, inducible NO synthase expression, which was predominantly localized in alveolar macrophages of control allografts, decreased in response to nicotine. In contrast, cytokine mRNA and peptide levels were only marginally affected by nicotine.
Stimulation of nicotinic acetylcholine receptors results in a marked attenuation of important hallmarks of pulmonary allograft rejection, indicating that cholinergic therapies may be beneficial for lung allograft recipients.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 06/2009; 28(5):493-500. · 3.54 Impact Factor
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ABSTRACT: Data on a protective role of fumarate in acute ischemia of the rat heart led to the obvious hypothesis that addition of fumarate to the preservation solution for kidney transplantation may have beneficial value. This study was designed to test this hypothesis. Kidneys of Lewis or Fischer 344 rats were flushed with University of Wisconsin (UW) solution or UW solution containing 5 mM fumarate. Grafts were immediately transplanted to Lewis recipients or stored at 4 °C for 5 h before transplantation. Renal function was assessed on d 10 and monthly for 6 mo. One group of isografts was removed on d 10 post-transplantation, the other groups of isografts and allografts after 6 mo. We detected a modest protective effect regarding proteinuria 10 d after isogeneic transplantation, and exclude the possibility that fumarate exerts acute nephrotoxicity. Surprisingly, fumarate strongly promoted intimal hyperplasia of allograft arteries, thickening of the arterial media of isografts and allografts, tubulo-interstitial allograft damage, and allograft infiltration by macrophages on the long run. To date, we do not know the mechanism resulting in fumarate-induced chronic graft damage. We suggest, however, that addition of fumarate to the conservation fluid does not improve graft outcome.
Journal of Surgical Research 06/2009; 166(2):306-13. · 2.25 Impact Factor
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Andreas Hecker,
Zbigniew Mikulski,
Katrin S Lips,
Uwe Pfeil,
Anna Zakrzewicz,
Sigrid Wilker,
Petra Hartmann, Winfried Padberg,
Ignaz Wessler,
Wolfgang Kummer,
Veronika Grau
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ABSTRACT: During acute rejection, large numbers of leukocytes accumulate in the blood vessels of experimental renal allografts. About 70% of them are activated, cytotoxic monocytes that appear to be involved in allograft destruction. ACh exerts anti-inflammatory effects upon monocytes/macrophages and has been proposed to be a key player in neuroimmunological interactions. Its short half-life, however, makes it unlikely that neuronal ACh affects blood leukocytes. Renal transplantation was performed in the allogeneic DA to LEW and in the isogeneic LEW to LEW rat strain combination. Intravascular leukocytes were harvested after 4 days, and the expression of CHT1, cChAT, pChAT, and nAChR subunits was investigated by RT-PCR, immunoblotting, and immunohistochemistry. Monocytes were identified by double-labeling with ED1-antibody, directed to a CD68-like antigen. ACh content was measured by HPLC. [Ca(2+)](i) was monitored by Fura-2. Intravascular graft leukocytes express CHT1 and cChAT mRNA and protein and pChAT protein. Their expression is strongly up-regulated in vivo during acute allograft rejection. Immunohistochemistry revealed CHT1, cChAT, and pChAT protein in ED1-positive monocytes. The ACh content of allograft intravascular leukocytes was sixfold higher than that of isografts. Intravascular leukocytes express nAChR subunits, and an ATP-induced increase in [Ca(2+)](i) was augmented in vitro by a nAChR inhibitor in allograft but not isograft leukocytes. Intravascular graft leukocytes, among them monocytes, up-regulate non-neuronal ACh synthesis and develop auto-/paracrine cholinergic attenuation of ATP signaling during acute allograft rejection.
Journal of leukocyte biology 03/2009; 86(1):13-22. · 4.99 Impact Factor
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ABSTRACT: Interleukin-21 (IL-21), a member of the type I cytokine family, regulates central functions of immunity. Within this family, signaling is mediated via a receptor complex consisting of a high-affinity receptor chain and the common gamma-chain (IL-2Rgamma, CD132). We analyze the mRNA expression of IL-21, IL-21 receptor-alpha (IL-21Ralpha) and family members IL-15, IL-2Rgamma, IL-21Ralpha, IL-15Ralpha, IL-2/15Rbeta, as well as IL-2Ralpha (CD25) in leukocytes isolated by vascular perfusion of rat renal allografts. Mononuclear leukocytes expressed increased amounts of IL-21Ralpha mRNA and protein during acute rejection. Most IL-21Ralpha-positive cells were monocytes. Furthermore, IL-21 and IL-2Ralpha mRNA expression was strongly increased. No changes in IL-2Rgamma, IL-2/15Rbeta, IL-15, and IL-15Ralpha mRNA expression levels were seen. In conclusion, we demonstrate that IL-21Ralpha expression is induced in intravascular monocytes in vivo in response to allogeneic transplantation. The function of the IL-21/IL-21R system in monocytes and during acute allograft rejection remains to be established.
Immunobiology 02/2009; 214(1):41-9. · 3.20 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY), a classical sympathetic comediator, regulates immunological functions including T cell activation and migration of blood leukocytes. A NPY-mediated neuroimmune cross-talk is well conceivable in sympathetically innervated tissues. In denervated, e.g., transplanted organs, however, leukocyte function is not fundamentally disturbed. Thus, we hypothesized that NPY is expressed by blood leukocytes themselves and regulated during inflammation. NPY mRNA and peptide expression were analyzed in mononuclear leukocytes isolated from the blood vessels of healthy rat kidneys, as well as from the blood vessels of isogeneic and allogeneic renal grafts transplanted in the Dark Agouti to Lewis or in the Fischer 344 to Lewis rat strain combination. Depending on the donor strain, acute allograft rejection is either fatal or reversible but both experimental models are characterized by massive accumulation of intravascular leukocytes. Leukocytes, predominantly monocytes, isolated from the blood vessels of untreated kidneys and isografts expressed high amounts of NPY mRNA and peptide, similar to expression levels in sympathetic ganglia. During acute allograft rejection, leukocytic NPY expression drastically dropped to approximately 1% of control levels in both rat strain combinations. In conclusion, NPY is an abundantly produced and tightly regulated cytokine of mononuclear blood leukocytes.
The Journal of Immunology 12/2008; 181(10):6906-12. · 5.79 Impact Factor
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ABSTRACT: After transplantation, passenger leukocytes move to lymphoid organs of the recipient. These cells appear to initiate allograft rejection, but they also might be involved in tolerance induction.
Orthotopic left lung transplantation was performed in the Dark Agouti to Lewis rat strain combination with no immunosuppression. Recipient spleens were removed at intervals of 24 h until day 6 after transplantation. For comparison, spleens from renal allograft recipients were analysed. Donor-derived major histocompatibility complex (MHC) class II antigens were detected by monoclonal antibody OX76. In double-staining experiments with antibodies specific for leukocyte subpopulations, their localisation and identity was analysed.
OX76-positive leukocytes were already detected in recipient spleens on day 1 post-transplantation. They increased in number until day 3 and decreased in number thereafter. Most of them were localised in splenic follicles and expressed the B cell variant of CD45R and IgG. Cell surface antigens typical for other leukocyte subpopulations were not detected. In the spleens of renal allograft recipients, only few donor-derived cells were seen.
After lung transplantation, numerous MHC class II-positive B cells migrate to the splenic follicles of the recipient. These cells might, in part, be responsible for immunologic differences observed between renal and pulmonary allografts.
Langenbeck s Archives of Surgery 04/2008; 393(2):219-26. · 1.81 Impact Factor
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ABSTRACT: Lung allografts are threatened by primary graft dysfunction, infections, and rejection. Novel therapies protecting pulmonary allografts are badly needed. Keratinocyte growth factor (KGF) protects the lung against a variety of injurious stimuli and exerts anti-inflammatory effects. The aim of the study was to test the potential of recombinant truncated KGF (DeltaN23-KGF, palifermin) to attenuate pulmonary allograft rejection.
Intratracheal instillation of 5 mg/kg DeltaN23-KGF was performed twice in donor rats on days 3 and 2 before explantation of the lung. In control animals, an equivalent volume of vehicle was instilled. Left lungs were transplanted in the fully allogeneic Dark Agouti to Lewis rat strain combination and in the less stringent Fischer 344 to Wistar Kyoto combination. Allograft recipients were additionally treated with DeltaN23-KGF post-transplantation. Graft outcome, leukocytic infiltration, and major histocompatibility complex (MHC) class II antigen expression was analyzed.
In both rat strain combinations, DeltaN23-KGF treatment did not improve pulmonary allograft outcome. Graft infiltration by macrophages and T lymphocytes remained unchanged. In addition, we demonstrated that MHC class II antigens were more abundant in KGF-treated allografts compared to control-treated grafts, which probably results in an increased alloreactivity.
In conclusion, intratracheal DeltaN23-KGF treatment is not effective to prevent acute pulmonary allograft rejection.
Langenbeck s Archives of Surgery 03/2008; 394(1):133-41. · 1.81 Impact Factor
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Sonja Blöcher,
Sigrid Wilker,
Jochen Sucke,
Uwe Pfeil,
Hartmut Dietrich,
Rolf Weimer,
Klaus Steger,
Andreas Kaufmann,
Markus Hirschburger,
Christian Plötz, Winfried Padberg,
Veronika Grau
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ABSTRACT: Leukocytes interacting with endothelia of lung allografts probably play a seminal role in acute rejection, but have not been characterized before. Transplantation was performed in the Lewis to Lewis and in the Dark Agouti to Lewis rat strain combinations. DNA replication was detected in T-cells on day 2 after pulse-labelling in vivo with 5-bromo-2'-deoxyuridine (BrdU). On day 5, leukocytes were isolated by intensive perfusion the graft, subject to flow cytometry and to quantitative RT-PCR. About 34 million leukocytes accumulated in allograft vessels, but only 10 and 6 million cells in isografts and control lungs, respectively. During rejection, IFN-gamma, IL-1beta and IL-10 mRNA expression increased, IL-12 mRNA decreased, whereas IL-2, IL-6, TNF-alpha, and TGF-beta mRNA did not change. The phenotype of graft monocytes was partially activated and intravascular T-cells proliferated. In conclusion, during rejection, monocytes with unusual properties accumulate and T-lymphocytes are activated in lung allograft blood vessels.
Clinical Immunology 08/2007; 124(1):98-108. · 4.05 Impact Factor
