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Biomedical subjects

N Zimmermann

Publications and source records attributed to N Zimmermann.

At least 19 recordsLinked to original sources
PubMed2006

The alpha4bbeta7-integrin is dynamically expressed on murine eosinophils and involved in eosinophil trafficking to the intestine.

BACKGROUND: Of the numerous adhesion molecules expressed by eosinophils, the alpha4-integrin has been identified as critically involved in eosinophil trafficking in the lung. Most studies have focused on the role of the alpha4beta1-adhesion complex, but eosinophils also express the alpha4beta7-integrin complex. OBJECTIVE: To investigate the role of alpha4beta7, by assessing its membrane expression on eosinophils from different compartments using allergen-challenged mice and IL-4/IL-5 bi-transgenic mice. In addition, we aim to determine the impact of beta7-integrin deficiency on eosinophil recruitment to the lungs and intestine in specific experimental allergic models. RESULTS: Evaluation of alpha4beta7 expression on bronchoalveolar lavage fluid (BALF) and lung tissue eosinophils revealed a down-regulation of this integrin as eosinophils migrate through the lungs. Indeed eosinophils isolated from the BALF and lung of allergic mice had low expression of the alpha4beta7-complex. While expression of the alpha4-chain remained unchanged, a significant decrease in beta7-surface expression was observed. Intestinal eosinophils, isolated from Peyer's patches, also displayed a down-regulation of the alpha4beta7-integrin, albeit only modest. In contrast, circulating eosinophils, isolated from the blood and spleen, expressed high levels of the alpha4beta7-integrin. However, eosinophil trafficking into the lungs of beta7-integrin-deficient mice was not significantly impaired in response to respiratory allergen challenges. In contrast, beta7-deficient mice had impaired eosinophil recruitment to the intestine. CONCLUSION: Taken together, these results identify differential expression of the alpha4beta7-integrin on eosinophils and its critical role in regulating eosinophil responses in the intestine.

Animals↗
PubMed2005

Ventricular constraint in dilated cardiomyopathy: a new, compliant textile mesh exerts prophylactic and therapeutic properties.

BACKGROUND: Dilated cardiomyopathy is associated with a progressive decrease in cardiac function, leading to end-stage heart failure. We aimed to stop this process by mechanically constraining the heart with a new, compliant textile mesh. METHODS: In 16 male Munich minipigs (50 +/- 7 kg), dilated cardiomyopathy with congestive heart failure was induced through 4 weeks of rapid ventricular pacing (220 beats/min). In the early-mesh group (n = 8), a polyvinylidene fluoride mesh was positioned around both ventricles before pacing was started. In the other group (n = 8), experimental dilated cardiomyopathy through rapid pacing was induced (no mesh). After mesh grafting, rapid pacing was continued (late mesh). RESULTS: Rapid pacing in the no-mesh group (control group) significantly decreased both systolic (cardiac output, peak systolic pressure, and the derivative of pressure increase [dP/dt(max)]) and diastolic (minimum rate of pressure rise [dP/dt(min)] and left ventricular end-diastolic pressure) variables, whereas these variables remained almost unchanged in the early-mesh group. In the late-mesh group the passive-elastic constraint not only prevented further deterioration but even exerted reverse remodeling to some extent (dP/dt(max) and left ventricular end-diastolic pressure, P < .05). CONCLUSIONS: Ventricular constraint with the new mesh seems to be a prophylactic and therapeutic option in cardiac insufficiency caused by ventricular dilation. This passive-elastic cardioplasty induced reverse remodeling of dilated hearts and significantly improved diastolic and systolic ventricular function.

Animals↗
PubMed2003

Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery.

BACKGROUND: Aspirin inhibits platelet activation and reduces atherothrombotic complications in patients at risk of myocardial infarction and stroke. However, a sufficient inhibition of platelet function by aspirin is not always achieved. The causes of this aspirin resistance are unknown. METHODS AND RESULTS: Patients undergoing coronary artery bypass grafting (CABG) have a high incidence of aspirin resistance. To evaluate functional and biochemical responses to aspirin, platelet-rich plasma was obtained before and at days 1, 5, and 10 after CABG. Thromboxane formation, aggregation, and alpha-granule secretion were effectively inhibited by 30 or 100 micromol/L aspirin in vitro before CABG, but this inhibition was prevented or attenuated after CABG. Whereas the inhibition of thromboxane formation and aggregation by aspirin in vitro partly recovered at day 10 after CABG, oral aspirin (100 mg/d) remained ineffective. The inducible isoform of cyclooxygenase in platelets, COX-2, has been suggested to confer aspirin resistance. In fact, immunoreactive COX-2 was increased 16-fold in platelets at day 5 after CABG, but the COX-2 selective inhibitor celecoxib did not alter aspirin-resistant thromboxane formation. By contrast, the combined inhibitor of thromboxane synthase and thromboxane receptor antagonist terbogrel equally prevented thromboxane formation of platelets obtained before (control) and after CABG. CONCLUSIONS: Platelet aspirin resistance involves an impairment of both in vivo and in vitro inhibition of platelet functions and is probably due to a disturbed inhibition of platelet COX-1 by aspirin.

Arachidonic Acid↗
PubMed2003

[Current diagnosis and therapy of non-occlusive mesenteric ischemia].

PURPOSE: Non-occlusive mesenteric ischemia (NOMI) is a life threatening disease. Therapy and prognosis depend upon the length of time elapsed between primary clinical manifestation and the time of definitive diagnosis and treatment. MATERIALS AND METHODS: NOMI was diagnosed by intraarterial selective angiography in four patients. After a bolus administration of 20 g Alprostadil (Prostavasin) into the superior mesenteric artery, intraarterial perfusion was continued with 60 microg Alprostadil/day via the catheter for three days. RESULTS: The mesenteric ischemia resolved in all patients. One patient recovered completely. Three patients recovered from mesenteric ischemia, but died subsequently due to complications of their primary diseases. CONCLUSION: When NOMI without perforation or necrosis of the bowel wall is suspected clinically, immediate intraarterial angiography is the diagnostic method of choice. If NOMI is confirmed, the appropriate treatment is the intraarterial application of potent vasodilators for several days. The diagnostic work-up in suspected NOMI and the impact of different radiological examinations are explained. The literature is reviewed.

Aged↗
PubMed2001

A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation.

Although eosinophils have been implicated in the pathogenesis of gastrointestinal disorders, their function has not been established. Using a murine model of oral antigen-induced eosinophil-associated gastrointestinal disease, we report the pathological consequences of eosinophilic inflammation and the involvement of eotaxin and eosinophils. Exposure of mice to enteric-coated antigen promotes an extensive T helper 2-associated eosinophilic inflammatory response involving the esophagus, stomach, small intestine and Peyer's patches as well as the development of gastric dysmotility, gastromegaly and cachexia. Electron microscopy shows eosinophils in proximity to damaged axons, which indicated that eosinophils were mediating a pathologic response. In addition, mice deficient in eotaxin have impaired eosinophil recruitment and are protected from gastromegaly and cachexia. These results establish a critical pathological function for eotaxin and eosinophils in gastrointestinal allergic hypersensitivity.

Administration, Oral↗
PubMed2001

Long-term follow-up of left ventricular pacing via a posterior cardiac vein after mechanical tricuspid valve replacement.

Permanent cardiac pacing was recommended in a 66-year-old woman with mechanical prosthetic mitral and tricuspid valves. To avoid a thoracotomy, a conventional endocardial lead was inserted with a steerable stylet (Locator) into the posterior cardiac vein via the right cephalic vein. Four weeks later, lead dislodgement required reoperation. The lead position remained stable up to 29 months.

Aged↗
PubMed2001

IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism.

BACKGROUND: IL-13 induces several characteristic features of asthma, including airway eosinophilia, airway hyperresponsiveness, and mucus overproduction; however, the mechanisms involved are largely unknown. OBJECTIVE: We hypothesized that IL-13-induced inflammatory changes in the lung were dependent in part on IL-5 and eotaxin, two eosinophil-selective cytokines. METHODS: Recombinant murine IL-13 was repeatedly administered to the lung by intranasal delivery until the characteristic features of asthma developed. To analyze the role of IL-5 and eotaxin, we subjected eotaxin gene-targeted, IL-5 gene-targeted, eotaxin/IL-5-double-deficient, IL-5 transgenic, and wild-type mice of the Balb/C background to the experimental regime. RESULTS: The induction of IL-13-mediated airway eosinophilia was found to occur independently of eosinophilia in the blood or bone marrow, indicating that IL-13-induced airway inflammation is primarily mediated by local effects of IL-13 in the lung. Eosinophil recruitment into both the lung tissue and bronchoalveolar lavage fluid was markedly attenuated in IL-5-deficient mice in comparison with wild-type controls. Accordingly, IL-13 delivery to IL-5 transgenic mice resulted in a large increase in airway eosinophils in comparison with wild-type mice. Interestingly, IL-13-induced eosinophilia in the bronchoalveolar lavage fluid of eotaxin-deficient mice was not impaired; however, these same mice failed to mount a significant tissue eosinophilia in response to IL-13. Finally, IL-13-induced mucus production was not affected by the presence of IL-5 or eotaxin, suggesting that IL-13-induced mucus secretion is mechanistically dissociated from airway eosinophilia. CONCLUSION: Selective components of the IL-13-induced asthma phenotype--airway eosinophilia but not mucus secretion--are differentially regulated by IL-5 and eotaxin. IL-5 is required for IL-13 to induce eosinophilia throughout the lung, whereas eotaxin regulates the distribution of airway eosinophils.

Animals↗
PubMed2000

Murine eotaxin-2: a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression.

The generation of tissue eosinophilia is governed in part by chemokines; initial investigation has identified three chemokines in the human genome with eosinophil selectivity, referred to as eotaxin-1, -2, and -3. Elucidation of the role of these chemokines is dependent in part upon analysis of murine homologues; however, only one murine homologue, eotaxin-1, has been identified. We now report the characterization of the murine eotaxin-2 cDNA, gene and protein. The eotaxin-2 cDNA contains an open reading frame that encodes for a 119-amino acid protein. The mature protein, which is predicted to contain 93 amino acids, is most homologous to human eotaxin-2 (59.1% identity), but is only 38.9% identical with murine eotaxin-1. Northern blot analysis reveals three predominant mRNA species and highest constitutive expression in the jejunum and spleen. Additionally, allergen challenge in the lung with Aspergillus fumigatus or OVA revealed marked induction of eotaxin-2 mRNA. Furthermore, eotaxin-2 mRNA was strongly induced by both transgenic over-expression of IL-4 in the lung and administration of intranasal IL-4. Analysis of eotaxin-2 mRNA expression in mice transgenic for IL-4 but genetically deficient in STAT-6 revealed that the IL-4-induced expression was STAT-6 dependent. Recombinant eotaxin-2 protein induced dose-dependent chemotactic responses on murine eosinophils at concentrations between 1-1000 ng/ml, whereas no activity was displayed on murine macrophages or neutrophils. Functional analysis of recombinant protein variants revealed a critical role for the amino terminus. Thus, murine eotaxin-2 is a constitutively expressed eosinophil chemokine likely to be involved in homeostatic, allergen-induced, and IL-4-associated immune responses.

Administration, Intranasal↗
PubMed2000

Optimal method to achieve consistently low defibrillation energy requirements.

Reduction of the defibrillation energy requirement offers the opportunity to decrease implantable cardioverter defibrillator (ICD) size and to increase device longevity. Therefore, the purpose of this prospective study was to obtain confirmed defibrillation thresholds (DFTs) of < or = 15 J in each patient with an endocardial dual-coil lead system incorporating an active pectoral pulse generator (TRIAD lead system: RV- --> SVC+ + CAN+). According to our previous clinical and experimental studies, we tried to lower DFTs that were > 15 J by repositioning the distal coil of the endocardial lead system in the right ventricle. A total of 190 consecutive patients requiring ICDs for ventricular fibrillation and/or recurrent ventricular tachycardia were investigated at the time of ICD implantation (42 women, 148 men; mean age 61.9 +/- 12.0 years; mean left ventricular ejection fraction 42.7 +/- 16.6%). Coronary artery disease was present in 139 patients; nonischemic dilated cardiomyopathy in 34 patients; and other etiologies in 17 patients; 47 patients had undergone previous cardiac surgery. Regardless of optimal pacing and sensing parameters, for patients having DFTs > 15, we repositioned the distal coil of the endocardial lead system toward the intraventricular septum to include this part of both ventricles within the electrical defibrillating field. In 177 of 190 patients, induced ventricular fibrillation was successfully terminated with < or = 15 J (group I) using the initial lead position. Repositioning of the endocardial lead was necessary in 13 patients whose DFT(plus) (DFT(plus) = second additional success at lowest energy level) were > 15 J (group II). In all patients, repositioning was successful within a 15 J energy level (100% success). The mean DFT(plus) was 7.3 +/- 3.5 J (group I) and 11.0 +/- 4.5 J (group II; p<0.005). The mean DFT(plus) of all patients enrolled in the study was 7.6 +/- 3.7 J (range: 2 to 15 J). In 87% of all patients, DFT(plus) of < or = 10 J was achieved. Repositioning of the endocardial lead in the right ventricle is a simple and effective method to reduce intraoperative high DFTs. As a result of this procedure, ICDs with a 20 J output should be sufficient for the vast majority (87%) of our patients. Furthermore, we were able to avoid additional subcutaneous or epicardial electrodes in all patients.

Aged↗
PubMed2000

Analysis of the CC chemokine receptor 3 gene reveals a complex 5' exon organization, a functional role for untranslated exon 1, and a broadly active promoter with eosinophil-selective elements.

To understand the regulation of CC chemokine receptor 3 (CCR3) expression, its gene structure and promoter have been characterized. The CCR3 gene contains 4 exons that give rise to multiple messenger RNA (mRNA) species by alternative splicing. Exon 1 is present in all transcripts, whereas exon 2 or 3 is present at low frequency (< 10%). Exon 4 contains the open reading frame and 11 bp of the 5' untranslated region. Northern analysis revealed 4 species of CCR3 mRNA. Direct sequencing revealed that the first 1 kb of the promoter and exon 1 contained only one mutation in 19 individuals, indicating that the CCR3 promoter and exon 1 are conserved between individuals. The first 1.6 kb of the 5' flanking region of exon 1 contained promoter elements including a TATA box and motifs for myeloid transcription factors and had strong promoter activity in eosinophilic, lymphoid, myeloid, and respiratory epithelial cell lines. Deletion analysis revealed differential regulation of the CCR3 promoter in eosinophilic and epithelial cells suggesting the presence of lineage-specific elements. Interestingly, exon 1 enhanced the activity of the promoter and this effect was especially prominent in eosinophilic cells. Thus, the human CCR3 gene has a complex 5' exon structure, a conserved promoter with strong activity in multiple cell types, and a functional 5' untranslated exon.

Alternative Splicing↗
PubMed2000

PDGF-induced Akt phosphorylation does not activate NF-kappa B in human vascular smooth muscle cells and fibroblasts.

A recent report suggested that platelet-derived growth factor (PDGF) activates nuclear factor-kappa B (NF-kappa B) by phosphorylation of the protein kinase Akt [Romashkova and Makarov, Nature 401 (1999) 86-90]. The present study investigates the role of Akt in the activation of NF-kappa B by tumor necrosis factor-alpha (TNF alpha, 10 ng/ml) and PDGF-BB (20 ng/ml) in human vascular smooth muscle cells (SMC), skin and foreskin fibroblasts. TNF alpha stimulated serine phosphorylation and degradation of the inhibitory protein I kappa B alpha and strongly induced nuclear NF-kappa B translocation and binding activity. PDGF did not induce serine phosphorylation or degradation of I kappa B alpha and did not enhance binding activity of NF-kappa B. In contrast, stimulation with PDGF resulted in a marked phosphorylation of Akt, but no Akt phosphorylation occurred after stimulation with TNF alpha. These data suggest that Akt phosphorylation is not involved in NF-kappa B activation in human SMC and fibroblasts.

Becaplermin↗
PubMed2000

Molecular analysis of CCR-3 events in eosinophilic cells.

CCR-3 is a major receptor involved in regulating eosinophil trafficking. Initial analysis of chemokine receptors has demonstrated unique receptor events in different cell types, indicating the importance of investigating CCR-3 events in eosinophilic cell lines. We now report that the eosinophilic cell line, acute myelogenous leukemia (AML) 14.3D10, expresses eosinophil granule proteins and eotaxin, but has no detectable expression of eosinophil chemokine receptors. Treatment of the cell line with butyric acid and IL-5 results in a dose-dependent synergistic induction of CCR-3 and, to a lesser extent, CCR-1 and CCR-5. Interestingly, using a luciferase reporter construct under the control of the hCCR-3 promoter, the uninduced and induced cells display high, but comparable, levels of promoter activity. Differentiated AML cells developed enhanced functional activation, as indicated by adhesion to respiratory epithelial cells and chemokine-induced transepithelial migration. Chemokine signaling did not inhibit adenylate cyclase activity even though calcium transients were blocked by pertussis toxin. Additionally, chemokine-induced calcium transients were inhibited by pretreatment with PMA, but not forskolin. Eotaxin treatment of differentiated AML cells resulted in marked down-modulation of CCR-3 expression for at least 18 h. Receptor internalization was not dependent upon chronic ligand exposure and was not accompanied by receptor degradation. Thus, CCR-3 is a late differentiation marker on AML cells and uses a signal transduction pathway involving rapid and prolonged receptor internalization, calcium transients inhibitable by protein kinase C but not protein kinase A, and the paradoxical lack of inhibition of adenylate cyclase activity.

Adenylate Cyclase Toxin↗
PubMed2000

Enantioselective hydrogenation of olefins with phosphinooxazoline-iridium catalysts.

Cationic iridium complexes with chiral phosphinooxazoline ligands are efficient catalysts for the enantioselective hydrogenation of olefins. The complexes are readily prepared, air-stable, and easy to handle. In contrast to chiral rhodium- and ruthenium-phosphine catalysts, they do not require the presence of a polar coordinating group near the C=C bond. In the hydrogenation of unfunctionalized trisubstituted 1,2-diaryl-olefins, high enantioselectivities of >95% ee with full conversion and turnover frequencies of >7,000 h-1 can be achieved, using 0.1 mol% of catalyst with tetrakis[3, 5-bis(trifluoromethyl)phenyl]borate (TFPB or BARF) as the counterion. The corresponding hexafluorophosphate or tetrafluoroborate salts give low conversion due to deactivation of the catalyst during the reaction. Substrates with polar substituents such as allylic alcohols, on the other hand, afford better results with the hexafluorophosphate salts.

Journal Article↗
PubMed2000

Inotropic effects of diadenosine monophosphate (AP1A) in isolated human cardiac preparations.

Dependent on the number of phosphate residues, diadenosine polyphosphates (APnP) exert divergent inotropic effects in the human heart. We studied the inotropic effects of the smallest member of this family, diadenosine monophosphate (AP1A). Force of contraction was measured in an isometric setup in isolated electrically driven (0.5 Hz) preparations from human atria. AP1A exerted a concentration-dependent negative inotropic effect. The IC50 value was 20.2 microM and the IC50 value was 3.1 microM (n = 5-8). At 100 microM AP1A, force of contraction declined to 50% of the predrug value after 2.5 +/- 0.5 min of incubation (n = 8). AP1A antagonized the positive inotropic effect of the beta-adrenoceptor agonist isoprenaline (10 nM). For 100 microM AP1A, the time to 50% of the predrug force in the presence of isoprenaline amounted to 2.3 +/- 0.2 min (n = 5). The positive inotropic and lusitropic effects of isoprenaline were antagonized by AP1A. The direct (AP1A alone) and indirect (AP1A in the presence of isoprenaline) negative inotropic effects of AP1A were blocked by the A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX, 0.3 microM). The inotropic effect of AP1A was not blocked by adenosine deaminase. In conclusion, AP1A exerts indirect and direct negative inotropic effects in the human heart through A1-adenosine receptors. These effects might protect the heart against excessive beta-adrenergic stimulation.

Adenosine Deaminase↗
PubMed1999

CC chemokine receptor-3 undergoes prolonged ligand-induced internalization.

CC chemokine receptor-3 (CCR-3) is a major receptor involved in regulating eosinophil trafficking; therefore, elucidation of ligand-induced CCR-3 events has important implications in understanding the biological and pathological properties of eosinophils. Previous studies have demonstrated that unique receptor events occur in different cell types supporting investigation of CCR-3-mediated events in eosinophilic cells. We now report biochemical characterization of CCR-3 internalization following exposure of eosinophils to CCR-3 ligands. Treatment of freshly isolated human eosinophils with CCR-3 ligands resulted in marked and differential internalization of CCR-3 in a dose-dependent manner. Exposure to 100 ng/ml eotaxin reduced surface expression to 43, 43, and 76% at 15 min, 1 h, and 3 h, respectively. RANTES (reduced on activation T cell expressed and secreted) treatment induced more significant and prolonged internalization of CCR-3 than eotaxin; following 100 ng/ml of RANTES, 29, 24, and 47% of the receptor was expressed at 15 min, 3 h, and 18 h, respectively. Confocal microscopy demonstrated that receptor modulation involved receptor internalization by an endocytic pathway shared with the transferrin receptor. Receptor internalization was accompanied by partial degradation of CCR-3, and reexpression of CCR-3 was dependent in part upon de novo protein synthesis. Internalization was not blocked by pretreatment of eosinophils with pertussis toxin. Furthermore, staurosporine did not inhibit internalization although it blocked phorbol 12-myristate 13-acetate-induced CCR-3 down-modulation. These results demonstrate that CCR-3 ligands induce differential receptor internalization that is not dependent upon Gi-protein coupling, calcium transients, or protein kinase C.

Cell Line↗
PubMed1999

Regional expression of phospholamban in the human heart.

BACKGROUND: Several independent lines of evidence indicate that phospholamban (PLB) expression correlates positively with depression of force of contraction and duration of contraction in isolated cardiac preparations of several animal species. Here, we studied whether PLB levels correlate with attenuation of contractility and enhancement of contractile time parameters in different parts of the human heart. METHODS: Force of contraction was measured in isolated electrically driven atrial and ventricular preparations from human hearts. Ca(2+)-uptake by human atrial and ventricular homogenates was assayed at different ionized Ca(2+)-concentrations. Protein expression of PLB and the sarcoplasmic Ca(2+)-ATPase (SERCA) was measured in homogenates by quantitative immunoblotting using specific antibodies. PLB mRNA expression was quantified in human cardiac preparations by Northern blot analysis. RESULTS: The duration of contraction in isolated preparations of human right ventricle (RV) was double that found in right atrial preparations (RA) (620 +/- 25 ms versus 308 +/- 15 ms). In RA, PLB expression was reduced by 44% at the protein level and by 34% at the mRNA level compared to RV. In contrast, the SERCA protein content was increased by 104% in RA compared to RV. Ca(2+)-uptake at low ionized Ca(2+)-concentration, where the inhibiting effect of PLB is maximal, amounted to 1.39 +/- 0.28 nmol Ca2+/mg protein in RA and to 0.62 +/- 0.09 nmol Ca2+/mg protein in RV (n = 6 both). CONCLUSIONS: It is suggested that duration of contraction is shorter in human atrium versus ventricle due to the combined effect of decreased PLB levels (which inhibits SERCA function) and increased SERCA levels. The lower relative ratio of PLB to SERCA leads to less inhibition of SERCA and increased Ca(2+)-uptake which enhances relaxation and contraction in human atrium.

Atrial Natriuretic Factor↗