R Koczulla

Philipps University of Marburg, Marburg, Hesse, Germany

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Publications (28)51 Total impact

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    ABSTRACT: The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator-activated receptor [PPAR]γ-induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human α1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5-154.6] versus 76.8 [54.8-98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1α, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein.
    The Journal of Immunology 04/2014; · 5.52 Impact Factor
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    ABSTRACT: Background: It has been observed that patients with allergic asthma/rhinitis have increased apoptosis of peripheral blood cells. This study was designed to explore the idea that the markers of apoptosis may help predict the response of allergen immunotherapy. Methods: The Allergy Department of University Hospital, Malmö, Sweden, recruited a total of 58 young adults ( Results: In patients receiving immunotherapy plasma gelsolin levels were higher relative to those without immunotherapy (the median level was 23.97 μg/mL [range, 18‐35.8 μg/mL] versus 21.2 μg/mL [range, 13.9‐29.8 μg/mL]; p = 0.012) and were similar to those of healthy controls (24.7 μg/mL [range, 17.4‐35.3 μg/mL]). Plasma levels of sFas, Fas-L, CCL17, and TIMP-1 did not differ between study groups. Only in controls did the plasma gelsolin levels inversely correlate to the levels of soluble Fas. Conclusion: Allergen-specific immunotherapy increases plasma levels of gelsolin, an antioxidant and antiapoptotic protein.
    American journal of rhinology & allergy 01/2014; 28(3). · 1.74 Impact Factor
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    ABSTRACT: A major problem associated with COPD is exacerbation. Symptoms include increased shortness of breathing, coughing, wheezing and sputum production. The frequency and severity of exacerbations are associated with a higher mortality risk. Early recognition and treatment have been shown to reduce severity of exacerbations, consecutive morbidity and hospital admissions. Telemonitoring of (nocturnal) lungsounds, oxygen saturation and frequency of breathing may offer the opportunity to detect symptoms of exacerbations very early. Therefore further research is needed to clarify precisely the role of telemonitoring in patients with COPD and exacerbations.
    DMW - Deutsche Medizinische Wochenschrift 04/2013; 138(16):837-41. · 0.65 Impact Factor
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory lung disease that affects a large number of patients and has significant impact. One hallmark of the disease is the presence of bacteria in the lower airways. The aim of this study was to analyze the detailed structure of microbial communities found in the lungs of healthy individuals and patients with COPD. Nine COPD patients as compared and 9 healthy individuals underwent flexible bronchoscopy and BAL was performed. Bacterial nucleic acids were subjected to terminal restriction fragment (TRF) length polymorphism and clone library analysis. Overall, we identified 326 T-RFLP band, 159 in patients and 167 in healthy controls. The results of the TRF analysis correlated partly with the data obtained from clone sequencing. Although the results of the sequencing showed high diversity, the genera Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera, Veillonella, Staphylococcus, and Streptococcus constituted the major part of the core microbiome found in both groups. A TRF band possibly representing Pseudomonas sp. monoinfection was associated with a reduction of the microbial diversity. Non-cultural methods reveal the complexity of the pulmonary microbiome in healthy individuals and in patients with COPD. Alterations of the microbiome in pulmonary diseases are correlated with disease.
    PLoS ONE 01/2013; 8(7):e68302. · 3.53 Impact Factor
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    ABSTRACT: The importance of rare disease is appreciated by all parties and tremendous effort is made to increase the knowledge about the individual disorders and improve the care of affected patients. Political initiatives on a European level aim to improve the structure of medical care for patients with rare diseases in each member state. The provided incentives for the development of medicines for orphan diseases have led to increased research activities and numbers of licensed Orphan Drugs. Patients are organized nationally and internationally in various patient organizations and umbrella organizations. They are involved in health care policy, support the detection and research of rare diseases and offer support to affected patients and families with educational meetings and materials as well as options for discussions. Many experts are engaged in national and international networks and registries that generate and publish high quality research data on rare diseases. A well developed infrastructure is in place to support the search for qualified partners that can be of assistance with specific questions in a rare lung disease.
    Pneumologie 06/2012; 66(7):437-41.
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    ABSTRACT: ABSTRACT: BACKGROUND: Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) alpha1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD. METHODS: Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and "normal" MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR. RESULTS: A total of 162 genes were found to be differentially expressed (p-value [less than or equal to] 0.05 and |FC| [greater than or equal to] 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Kruppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy. CONCLUSIONS: These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.
    Orphanet Journal of Rare Diseases 05/2012; 7(1):29. · 4.32 Impact Factor
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    ABSTRACT: Purpose/Objective: The objective of our study was to evaluate whether the frequency of B and T lymphocytes and of natural killer cells in peripheral blood is influenced by moderate exercise in competitive athletes and in non-athletes, respectively. Material and methods: Blood samples from 11 competitive athletes and 6 non-athletes were obtained before, directly after, and 1 h after moderate exercise. Peripheral blood mononuclear cells (PBMCs) were isolated by density centrifugation and analysed by four-colour flow cytometry. Results: Whereas the frequency distribution of B lymphocyte subpopulations (CD19+ cells, class-switched/non class-switched memory cells, plasmablasts) was maintained in both groups, we found considerable differences in the T cell subpopulations: While T cell subpopulations in the athletes group did not change compared to pre-exercise baseline, we found a significant induction of cytotoxic T cells (Tc; CD3+CD8+; p < 0.05, compared to pre-exercise baseline), activated Tc (CD3+CD8+CD69+; p < 0.05), and natural killer T cells (NKT; CD3+CD56+; p < 0.05) in the non-athletes group directly after exercise, which returned to baseline within 1 h. In contrast, numbers of T helper cells (Th; CD3+CD4+; p < 0.01) and regulatory T cells (Treg; CD3+CD4+CD25+CD127-; p < 0.05) were reduced 1 h after exercise in non-athletes. Interestingly, even at baseline level Treg numbers in athletes were significantly reduced compared to non-athletes (p < 0.001). The frequency of natural killer cells (NK; CD3-CD16+CD56+Nkp46+; p < 0.01) increased in athletes and non-athletes after exercise. However, the increase in NK numbers was significantly alleviated in athletes compared to non-athletes (p < 0.01). Conclusion: We found significant temporary changes in the frequency of Tc, Th, Treg, NKT, and NK cells in PBMCs from non-athletes, whereas cell frequencies in athletes, except for NK cells, did not change. Reduced Treg numbers in athletes imply a putative role of Treg cells in the immune regulation during chronic exercise and might contribute to the increased susceptibility to infections in competitive athletes.
    3. European Congress of Immunology, Glasgow; 01/2012
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    ABSTRACT: Fragestellung: B1-Zellen produzieren bereits beim Feten und Neugeborenen spontan Immunglobuline der Klasse M, die häufig gegen Polysaccharid- und Lipid- Antigene von Mikroorganismen gerichtet sind und als „angeborene Antikörper“ bezeichnet werden. Kürzlich wurden anhand funktioneller Studien die B1-Zellen beim Menschen neu definiert (B1: CD20+,CD27+,CD43+,CD69-; alte Definition: CD19+,CD5+). Unser Ziel war es, die B1-Zellen im fetalen und adulten zu quantifizieren. Material und Methoden: Aus Nabelschnurblut (NSB) von 10 gesunden Reifgeborenen und aus peripherem Blut von 10 gesunden Erwachsenen wurden die mononukleären Zellen mit Ficoll-Gradient aufgereinigt, mit fluoreszierenden Antikörpern gefärbt und im Durchflusszytometer analysiert. Ergebnisse: Der Anteil von B1-Zellen an CD20+ B-Zellen betrug im NSB 1,1 ± 0,2% und bei Erwachsenen 1,6 ± 0,3% (n.s.). Naive B-Zellen (CD27-,IgD+, IgM+) machten mit 50,0 ± 4,6% (NSB) bzw. 42,0 ± 3,9% (Erwachsene, n.s.) den größten Anteil an B-Zellen aus. Unreife B-Zellen (CD27-,IgD-,IgM-), Maginalzonen-ähnliche B-Zellen (CD27+, IgD+, IgM+), IgM-Gedächtnis-B-Zellen (CD27+,IgD-,IgM+), Plasmablasten (CD38++,IgM-), Transitionale B-Zellen (CD21+,CD38+,IgM+), sowie klassengewechselte Gedächtnis-B-Zellen (CD27+,IgD-,IgM-) waren im fetalen gegenüber adulten Blut seltener (p< 0,05). Diskussion: Während nach der alten Definition mehr B1 Zellen im fetalen als im adulten Blut vorkamen, war die neu definierte B1-Zellpopulation in beiden Gruppen gleich häufig. Die alte am Mausmodell orientierte Definition umfasst beim Menschen keine einheitliche Zellpopulation, was z.T. widersprüchliche Ergebnisse zur Häufigkeit und Funktion der B1-Zellen erklärt. Weitere Untersuchungen sollten den molekulargenetischen Vergleich fetaler und adulter B1-Zellen umfassen.
    Jahrestagung der Deutschen Gesellschaft für Kinderheilkunde und Jugendmedizin, Hamburg; 01/2012
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    ABSTRACT: Volatile organic compounds (VOCs) can be used as biomarkers in exhaled air. VOC profiles can be detected by an array of nanosensors of an electronic nose. These profiles can be analysed using bioinformatics. It is, however, not known whether different devices of the same model measure identically and to which extent different set-ups and the humidity of the inhaled air influence the VOC profile. Three different measuring set-ups were designed and three healthy control subjects were measured with each of them, using four devices of the same model (Cyranose 320™, Smiths Detection). The exhaled air was collected in a plastic bag. Either ambient air was used as reference (set-up Leipzig), or the reference air was humidified (100% relative humidity) (set-up Marburg and set-up Munich). In the set-up Marburg the subjects inhaled standardised medical air (Aer medicinalis Linde, AGA AB) out of a compressed air bottle through a demand valve; this air (after humidification) was also used as reference. In the set-up Leipzig the subjects inhaled VOC-filtered ambient air, in the set-up Munich unfiltered room air. The data were evaluated using either the real-time data or the changes in resistance as calculated by the device. The results were clearly dependent on the set-up. Apparently, humidification of the reference air could reduce the variance between devices, but this result was also dependent on the evaluation method used. When comparing the three subjects, the set-ups Munich and Marburg mapped these in a similar way, whereas not only the signals but also the variance of the set-up Leipzig were larger. Measuring VOCs with an electronic nose has not yet been standardised and the set-up significantly affects the results. As other researchers use further methods, it is currently not possible to draw generally accepted conclusions. More systematic tests are required to find the most sensitive and reliable but still feasible set-up so that comparability is improved.
    Pneumologie 03/2011; 65(8):465-70.
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    ABSTRACT: The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status.
    Respiratory research 03/2011; 12:31. · 3.64 Impact Factor
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    ABSTRACT: α1-Antitrypsin (AAT) is the archetype member of the serine protease inhibitor (SERPIN) supergene family. The AAT deficiency is most often associated with the Z mutation, which results in abnormal Z AAT folding in the endoplasmic reticulum of hepatocytes during biogenesis. This causes intra-cellular retention of the AAT protein rather than efficient secretion with consequent deficiency of circulating AAT. The reduced serum levels of AAT contribute to the development of chronic obstructive pulmonary disease (COPD) and the accumulation of abnormally folded AAT protein increases risk for liver diseases. In this review we show that with the discovery of AAT deficiency in the early 60s as a genetically determined predisposition to the development of early-onset emphysema, intensive investigations of enzymatic mechanisms that produce lung destruction in COPD were pursued. To date, the role of AAT in other than lung and liver diseases has not been extensively examined. Current findings provide new evidence that, in addition to protease inhibition, AAT expresses anti-inflammatory, immunomodulatory and antimicrobial properties, and highlight the importance of this protein in health and diseases. In this review co-occurrence of several diseases with AAT deficiency is discussed.
    Respiratory medicine 02/2011; 105(8):1129-39. · 2.33 Impact Factor
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    International Journal for Ion Mobility Spectrometry 01/2011; 14.
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    ABSTRACT: Analysis of exhaled breath condensate (EBC) is a non-invasive method for studying the acidity (pH) of airway secretions in patients with inflammatory lung diseases. To assess the reproducibility of EBC pH for two commercially available devices (portable RTube and non-portable ECoScreen) in healthy controls, patients with asthma or COPD, and subjects suffering from an acute cold with lower-airway symptoms. In addition, we assessed the repeatability in healthy controls. EBC was collected from 40 subjects (n = 10 in each of the above groups) using RTube and ECoScreen. EBC was collected from controls on two separate occasions within 5 days. pH in EBC was assessed after degasification with argon for 20 min. In controls, pH-measurements in EBC collected by RTube or ECoScreen showed no significant difference between devices (p = 0.754) or between days (repeatability coefficient RTube: 0.47; ECoScreen: 0.42) of collection. A comparison between EBC pH collected by the two devices in asthma, COPD and cold patients also showed good reproducibility. No differences in pH values were observed between controls (mean pH 8.27; RTube) and patients with COPD (pH 7.97) or asthma (pH 8.20), but lower values were found using both devices in patients with a cold (pH 7.56; RTube, p < 0.01; ECoScreen, p < 0.05). We conclude that pH measurements in EBC collected by RTube and ECoScreen are repeatable and reproducible in healthy controls, and are reproducible and comparable in healthy controls, COPD and asthma patients, and subjects with a common cold.
    Respiratory research 08/2009; 10:78. · 3.64 Impact Factor
  • Pneumologie 07/2009; 63(6):335-41; quiz 342-3.
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is defined as a progressive, usually only partially reversible, obstruction of the airways The disease is associated with an inflammatory response of the lungs to noxious particles, particularly cigarette smoke. Numerous epidemiological studies have shown a significant association between impaired lung function and the presence of cardiovascular, metabolic or other extrapulmonary comorbidities. Systemic inflammation may be the missing link between COPD and its extrapulmonary manifestations, although the exact mechanism of this relationship remains unclear. The development and validation of score systems that classify COPD severity, not only by changes in lung function, is an important step. The BODE score (body-mass index, airways obstruction, dyspnea, exercise capacity) is such a system. Based on the concept of COPD as a systemic disease, a concept is needed which describes in detail the pharmacological treatment of the pulmonary and extrapulmonary manifestations of the disease. In addition, the part of the disease that is treatable with physiotherapy and rehabilitation must be fully taken into account. Such multimodal treatment regimens have so far not been implemented into clinical guidelines.
    DMW - Deutsche Medizinische Wochenschrift 06/2009; 134(23):1231-5. · 0.65 Impact Factor
  • Pneumologie 01/2009; 63.
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    ABSTRACT: BACKGROUND: alpha-1-Antitrypsin deficiency (AATD) is a rare condition with a prevalence of about 1/4000 individuals in Germany. The clinical manifestations are the early development of pulmonary emphysema or of liver cirrhosis. The low prevalence of AATD suggested the establishment of a registry with the aim to learn more details about the natural history and the quality of care for these patients. METHODS, PATIENTS, RESULTS: Since 2004 the German registry for individuals with AATD is maintained in Marburg. Up to May 2008, 548 individuals were registered, 455 with the genotype PiZZ and 46 with PiSZ. The age range of the registered individuals extends from 2 to 82 years (mean 55, SD 20; men 54 [SD 19] years, women 55 [SD 21] years). Most patients are affected by chronic obstructive pulmonary disease (COPD, distribution to the GOLD stages: GOLD I = 16 %, GOLD II = 30 %, GOLD III = 33 %, GOLD IV = 21 %). Currently 109 subjects are under substitution therapy. The time period between the first symptom and the establishment of the correct diagnosis was on average 5.6 years. CONCLUSIONS: The data of the registry allow a detailed characterisation of the natural course of the disease and the levels of the patient care.
    Pneumologie 11/2008; 62(11):655-8.
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    ABSTRACT: Cancer development can be viewed as dysregulated repair. Antimicrobial peptides (AMPs) are effector molecules of the innate immune system with direct antimicrobial activity. Beside this host defence function several AMPs play a role in the regulation of inflammation and tissue repair. The aim of the present study was to investigate whether the human cathelicidin AMP LL-37/hCAP-18 is involved in the biology of lung cancer. Human cancer cell lines were found to express the human cathelicidin LL-37/hCAP-18 mRNA and peptide at different levels. Immunohistochemistry of human lung cancers showed that the peptide is expressed mostly in adenocarcinoma and squamous cell carcinoma. Application of exogenous LL-37 at low concentrations of 5ng/ml to cancer cell lines increased proliferation and growth of anchorage-independent colonies. At the molecular level, LL-37 induced phosphorylation of the epidermal growth factor receptor (EGFR) and activation of downstream MAP kinase signalling pathways. Lung cancer cell lines that stably overexpress the peptide by means of a doxycycline-regulated promoter system also showed a faster growth. When these cell lines were injected subcutaneously into nude mice, cathelicidin overexpression resulted in increased tumourigenicity and the formation of significantly larger tumours. In conclusion, cathelicidin is expressed in human lung cancers. The peptide activates tumour cells resulting in increased cell growth in vitro and in an animal model. The host defence peptide cathelicidin LL-37/hCAP-18 acts as growth factor for human lung cancer.
    Lung Cancer 02/2008; 59(1):12-23. · 3.39 Impact Factor
  • Pneumologie 01/2008; 62(11):655-658.
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    ABSTRACT: Alpha-1-antitrypsin deficiency (AATD) is significantly underdiagnosed. The early detection of AATD would enable affected persons to make lifestyle changes such as quitting smoking. It was the aim of the study to determine whether the combination of an awareness program with the offer of a cost-free diagnostic test results in the identification of a significant number of individuals with severe AATD. We combined a series of measures to promote awareness with the offer of a diagnostic test at no charge. Test blood was applied to a filter paper and sent to our laboratory. The level of AAT was measured by nephelometry, the presence of the S- or Z-allele was determined by PCR, and phenotyping was performed by isoelectric focusing. During 37 months 17688 testing kits were distributed and 2722 were sent back to our laboratory. We identified 335 patients with severe AATD including 16 individuals with rare genotypes. Prescreening by determining the AAT serum levels by the submitting physician increased the detection rate as compared to similar programs that screened unselected individuals. These data show that the combination of an awareness program with the offer of free diagnostic testing results in the identification of a large number individuals with severe AATD.
    Respiratory Medicine 09/2007; 101(8):1708-14. · 2.59 Impact Factor

Publication Stats

568 Citations
51.00 Total Impact Points

Institutions

  • 1970–2013
    • Philipps University of Marburg
      • Faculty of Medicine
      Marburg, Hesse, Germany
  • 2012
    • Hannover Medical School
      • Institute for Pathology
      Hanover, Lower Saxony, Germany
  • 2006–2011
    • Universitätsklinikum Gießen und Marburg
      Marburg, Hesse, Germany
  • 2009
    • Leiden University Medical Centre
      • Department of Pulmonology
      Leiden, South Holland, Netherlands