Neville Berkman

Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel

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Publications (90)409.88 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.
    Nature medicine 07/2015; DOI:10.1038/nm.3889 · 28.05 Impact Factor
  • Miri Assayag · Sara Goldstein · Amram Samuni · Neville Berkman
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    ABSTRACT: The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardant, hypotensive, anti-cancer and anti-teratogenic activities. Yet, these stable radicals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3-carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (~300mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of asthma. The present results demonstrate the therapeutic potential of nitroxides for the treatment of asthma. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 06/2015; DOI:10.1016/j.freeradbiomed.2015.06.031 · 5.71 Impact Factor
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    ABSTRACT: Background: The prevalence of asthma has increased in western countries towards the end of the last century, but recently seems to have stabilized. Objective: To evaluate trends in the prevalence and severity of asthma that occurred in Israel over the past decade. Methods: The medical records of 17-year-old boys, eligible for national service, between 1999 and 2008 were reviewed. National annual hospitalization and death rates for asthma were extracted. Results: Three hundred thousand medical records were reviewed. During the study period, lifetime asthma prevalence decreased from 9.7 to 8.1% (p = 0.002). The point prevalence of moderate-to-severe and mild persistent asthma decreased significantly from 0.88 and 3.41% to 0.36 and 2.44%, respectively, during this period. The prevalence of intermittent asthma and asthma in clinical remission for more than 3 years did not change significantly. The annual hospitalization rate for asthma decreased from 13.0 to 7.5 per 10,000 population (p < 0.0001), whilst the annual death rate due to asthma decreased between 1999 and 2008 from 2.1 to 1.4 per 100,000 population (p = 0.003). Conclusions: The prevalence of asthma in Israeli teenage boys decreased significantly over the last decade. In addition, asthma hospitalization and asthma-related death rates in the total population also decreased. © 2014 S. Karger AG, Basel.
    Respiration 11/2014; 89(1). DOI:10.1159/000368613 · 2.92 Impact Factor
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    ABSTRACT: Extra domain A-containing fibronectin (EDA-FN) is necessary for the development of allergen-induced lower airway fibrosis. The pathogenesis of fibrosis in allergic rhinitis has not been well studied. To determine whether EDA-fibronectin is necessary for the development of nasal remodeling in a murine model of chronic allergic rhinitis and in human allergic rhinitis. EDA(-/-) and wild-type (WT) C57Bl/6 mice were sensitized intraperitoneally and then challenged with inhaled ovalbumin (OVA) or saline for 2 and 5 weeks. Clinical signs of rhinitis and histological analysis of nasal tissue were evaluated. Immunohistological staining for EDA-FN was performed in human tissue of inferior nasal conchae from patients with allergic rhinitis and controls. After 2 weeks of allergen exposure, only goblet cell hyperplasia and perivascular eosinophilia were observed. After 5 weeks, goblet cell number, thickening of the subepithelial layer, and extent and area of collagen deposition were increased in the nasal tissue of WT OVA (ovalbumin)-challenged mice as compared with saline controls (P < .0001, P < .0001, P = .018, and P = .03, respectively). Clinical signs of rhinitis were observed only in WT OVA-challenged mice. In the EDA(-/-) mice exposed to OVA, collagen deposition, collagen area, and subepithelial thickness showed no increase and were similar to saline control mice, whereas goblet cell hyperplasia was similar to WT OVA-challenged mice. EDA-FN expression was prominent in inferior conchae from patients with allergic rhinitis but was absent in control patients. EDA-containing fibronectin is necessary for the development of nasal tissue fibrotic remodeling process in both murine and human allergic rhinitis.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 05/2013; 110(5):322-7. DOI:10.1016/j.anai.2013.03.002 · 2.75 Impact Factor
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    World Allergy Organization Journal 04/2013; 6(Suppl 1):P69-P69. DOI:10.1186/1939-4551-6-S1-P69
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    ABSTRACT: Abstract A new oscillatory device administers predetermined pressure oscillation sequences into the chest cavity over inhaled/exhaled air streams at low positive pressure. We assessed device safety and effect on 6MW performance, pulmonary function, and health-related quality-of-life (HRQOL) in moderate-to-very severe COPD in a randomized, double-blind, controlled, crossover study. Outcomes with an oscillatory device (Pulsehaler(TM), Respinova Ltd, Herzliya, Israel) and a "muted" sham device (control) of identical appearance that delivered continuous positive air pressure were compared in two groups receiving opposite treatment sequences: 2-week oscillatory device/control, 2-week washout, 2-week control/oscillatory device, 2-week washout. The clinical trial was registered ( www.clinicaltrials.gov , NCT00821418) and approved by the Hadassah-Hebrew University Medical Center Institutional Review Board (08-608). All participants signed informed consent; 22 patients completed the study with no marked differences in COPD exacerbations or side effects. A total of 91% of patients treated with the oscillatory device had a clinically significant improvement (increase >40 m) in 6MW performance. The 6MW distance with the oscillatory device increased significantly after 1 week of treatment (51.6 ± 7.6 m, +13.5 ± 2.3%, p < 0.001), and more after 2 weeks (61.8 ± 9.0 m, 16.3 ± 2.7%, p < 0.001). This increase with the oscillatory device was significantly greater (p < 0.001) than the 15.4 ± 10.4 m increase (4.2 ± 2.6%, NS) with control. FVC and inspiratory capacity (IC) improved significantly (p = 0.03 for each) with the oscillatory device but not with control. HRQL improved markedly (≥1 point) for dyspnea and mastery with the oscillatory device (p = 0.02) but not control. Treatment with a new oscillatory device appears to be safe, and to improve 6MW performance, pulmonary function, and HRQL in COPD. Further evaluation is warranted.
    COPD Journal of Chronic Obstructive Pulmonary Disease 12/2012; 9(6). DOI:10.3109/15412555.2012.748625 · 2.62 Impact Factor
  • Neville Berkman · Avraham Abutbul · Julia Kheifits · Miri Assayag
    American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: Asthma is characterized by bronchial hyperreactivity and airway remodeling. Subepithelial fibrosis, a feature of remodeling, is accompanied by activation of fibroblasts to myofibroblasts, with excessive proliferation and increased collagen, extracellular matrix protein, and profibrogenic cytokine production. Mast cells are important in the development of asthma and its fibrotic changes. In this study, we aimed to investigate the direct effect of the drugs most frequently used in asthma, that is, glucocorticosteroids (dexamethasone) and shortacting β(2)-agonists (salbutamol), on human lung fibroblast proliferation when unstimulated or activated by mast cells or eotaxin. Subconfluent human fetal lung or bronchial fibroblasts were incubated with different concentrations of the drugs (24 h) 6 activators, and [(3)H]-Thymidine was added (24 h) to measure their proliferation. IL-6 production in the supernatants of confluent monolayers cultured in the presence of the drugs or forskolin (24 h) was analyzed by enzyme-linked immunosorbent assay. Both drugs alone and in the presence of the activators enhanced fibroblast proliferation in a seemingly synergistic way for both fetal and bronchial fibroblasts. Dexamethasone was found to decrease IL-6 production, while salbutamol increased it. These observations if corroborated by in vivo data may possibly account for the deleterious effect of long-term therapy with β(2)-bronchodilators and inhaled glucocorticosteroids on the natural history of asthma.
    World Allergy Organization Journal 12/2011; 4(12):249-56. DOI:10.1097/WOX.0b013e31821d1186.
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    ABSTRACT: Pulmonary epithelioid hemangioendothelioma (PEH), previously known as "intravascular bronchoalveolar tumor," is a rare vascular malignancy with an unpredictable prognosis. Treatment can vary from observation in asymptomatic patients to surgery in patients with resectable disease or chemotherapy in patients with disseminated disease. This report describes the clinical, radiological and pathological features of three cases of PEH and a review of the current literature.
    The Israel Medical Association journal: IMAJ 11/2011; 13(11):676-9. · 0.90 Impact Factor
  • Paediatric respiratory reviews 06/2011; 12. DOI:10.1016/S1526-0542(11)70065-3 · 2.22 Impact Factor
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Martin Kohan · Andres F Muro · Reem Bader · Neville Berkman
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    ABSTRACT: Asthma is characterized by airway inflammation, airway remodeling, and airway hyperresponsiveness (AHR). Myofibroblast differentiation and subepithelial fibrosis are key features of airway remodeling. Extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, has been implicated in fibroblast differentiation during wound healing and tissue fibrosis. We sought to investigate the role of EDA-FN in airway remodeling using a murine model of chronic allergen-induced experimental asthma. EDA(-/-) and wild-type (WT) mice were sensitized and exposed to inhaled ovalbumin (OVA) or saline for 5 weeks. EDA-FN expression was evaluated by means of PCR and immunostaining. Peribronchial fibrosis, smooth muscle area, mucus-producing cell numbers, bronchoalveolar cell counts, and lung function were assessed in WT and EDA(-/-) mice. Fibroblast activation and differentiation were evaluated ex vivo by using OVA-treated WT and EDA(-/-) lung fibroblasts. Exposure to OVA increased EDA-FN expression in lung tissue and primary lung fibroblasts. OVA-treated EDA(-/-) mice showed reduced airway fibrosis and AHR and impaired expression of TGF-β1 and IL-13 without changes in airway inflammation or other aspects of remodeling. Lung fibroblasts from OVA-treated EDA(-/-) mice exhibited reduced proliferation, migration, α-smooth muscle actin expression, and collagen deposition and impaired TGF-β1 and IL-13 release compared with that seen in WT mice. EDA-FN is essential for the development of OVA-induced airway fibrosis and AHR. The effect of the EDA domain on airway fibrosis after OVA challenge is through activation and differentiation of fibroblasts. Fibroblast activation and airway fibrosis are necessary for the development of AHR.
    The Journal of allergy and clinical immunology 02/2011; 127(2):439-446.e1-5. DOI:10.1016/j.jaci.2010.10.021 · 11.25 Impact Factor
  • Martin Kohan · Andres F Muro · Eric S White · Neville Berkman
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    ABSTRACT: Fibroblast differentiation is an essential step during wound healing and fibrosis. Fibronectin (FN) is a major component of the extracellular matrix and occurs in two main forms: plasma and cellular FN. The latter includes the alternatively spliced domain A (EDA). Although EDA-containing cellular fibronectin (EDA-FN) is associated with fibroblast differentiation, how EDA-FN promotes differentiation is incompletely understood. In this study, we investigate the mechanism by which EDA-FN contributes to fibroblast differentiation with emphasis on the characterization of the EDA-FN receptor. We show that EDA-FN increases α-SMA expression (immunofluorescence), collagen deposition, cell contractility, and focal adhesion kinase (FAK) activation (immunoblotting); whereas plasma FN, a form lacking EDA, shows no effect. Primary lung fibroblasts constitutively express α(4)β(7) integrin receptor (FACS and RT-PCR). Blocking of α(4)β(7) reduces fibroblast adhesion to EDA-FN and inhibits α-SMA expression, collagen deposition, and FAK activation induced by EDA-FN. Using recombinant EDA-containing peptides, we demonstrate that the EDA segment is sufficient to induce fibroblast differentiation via binding to α(4)β(7). EDA-FN induces MAPK-Erk1/2 activation and inhibition of MEK1/2 attenuates EDA-FN-induced α-SMA expression. Our findings demonstrate that EDA-FN induces fibroblast differentiation by a mechanism that involves binding of EDA to α(4)β(7) integrin followed by activation of FAK and MAPK-associated signaling pathways.
    The FASEB Journal 11/2010; 24(11):4503-12. DOI:10.1096/fj.10-154435 · 5.48 Impact Factor
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    ABSTRACT: Although the etiology of sarcoidosis is unknown, genetic susceptibility has been demonstrated. Granuloma formation is a key feature in the pathophysiology of sarcoidosis and Crohn's Disease, raising the possibility that these diseases share common pathogenetic pathways. An association between sarcoidosis and the protein "CD14", a molecule that is part of the lipopolysaccharide (LPS) cell surface receptor complex, has been suggested. In the current study we evaluated the CD14 gene promoter 159 C-->T polymorphic site and soluble CD14 levels in a cohort of 74 sarcoidosis patients compared to 85 healthy controls. We further sought to identify correlations between clinical phenotype, specific genotypes and soluble CD14 levels. We found the TT genotype to be more prevalent in the sarcoidosis patient group than in controls (p=0.03). Serum levels of soluble CD14 were higher in the sarcoidosis patients (p=0.001). Within the patient cohort, CC homozygous patients presented at an older age with milder disease as assessed with the SAC score, longer time to diagnosis, and less impairment of pulmonary function tests. Our study suggests a role of CD14 in the pathogenesis of sarcoidosis, and a clinical phenotype-genotype association. Further mechanistic and epidemiologic studies are needed in order to establish the specific role of CD14 in the etiology, pathogenesis and clinical phenotype of sarcoidosis.
    Respiratory medicine 09/2010; 104(9):1336-43. DOI:10.1016/j.rmed.2010.03.029 · 2.92 Impact Factor
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    ABSTRACT: In December 2008, bronchoalveolar lavage fluid samples obtained from 3 patients were positive for Burkholderia cepacia complex on culture. Samples obtained from bronchoscopes and rinse-water samples obtained from the washer-disinfector were found to be positive for B. cepacia complex. The cause of this pseudo-outbreak was that the washer-disinfector was installed without the required antibacterial filter.
    Infection Control and Hospital Epidemiology 07/2010; 31(7):769-71. DOI:10.1086/653611 · 3.94 Impact Factor
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    ABSTRACT: Eotaxin-2/CCL24 and eotaxin-3/CCL26 play an important role in eosinophil chemotaxis and activation in asthma. We previously demonstrated that eotaxin/CCL11 is profibrogenic for human lung fibroblasts. The effect of eotaxin-2/ CCL24 and eotaxin-3/CCL26 on lung fibroblasts has not yet been investigated. To evaluate whether eotaxin-2/CCL24 and eotaxin-3/CCL26 modulate fibrotic properties of lung fibroblasts. Fibroblast proliferation was evaluated by means of 3-hydroxythymidine incorporation. Collagen production was assessed by means of 3-hydroxyproline incorporation and biochemical staining. Chemotaxis was determined using Boyden chambers. Expression of alpha-smooth muscle actin was evaluated by means of immunostaining. Transforming growth factor beta1 release was assessed using enzyme-linked immunosorbent assay. Parametric analysis of variance, followed by the Tukey-Kramer multiple comparisons test, was used to calculate statistical significance. Eotaxin-2/CCL24 but not eotaxin-3/CCL26 stimulated human lung fibroblast proliferation and collagen synthesis. In contrast, eotaxin-3/CCL26 but not eotaxin-2/CCL24 promoted fibroblast migration. Neither eotaxin-2/CCL24 nor eotaxin-3/ CCL26 induced the expression of alpha-smooth muscle actin or transforming growth factor beta1 from lung fibroblasts. Eotaxin-2/CCL24 and eotaxin-3/CCL26 have differential profibrogenic effects on human lung fibroblasts. These CC chemokines may, therefore, contribute to airway remodeling in asthma.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 01/2010; 104(1):66-72. DOI:10.1016/j.anai.2009.11.003 · 2.75 Impact Factor
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    ABSTRACT: Eosinophils are critically involved in allergic inflammation and tissue remodeling. Osteopontin (OPN) is a glycoprotein molecule which exhibits pro-fibrogenic and pro-angiogenic properties and has recently also been implicated in allergic diseases. In this study, we investigated the expression and function of OPN in human eosinophils. Osteopontin mRNA (RT-PCR) and protein (immunofluorescence) expression in peripheral blood eosinophils from atopic human subjects were evaluated. Soluble OPN release was determined in resting and activated eosinophils. The contribution of OPN to eosinophil-induced angiogenesis was determined using the chick embryo chorio- allantoic membrane (CAM) assay and OPN-induced eosinophil chemotaxis was determined (ChemoTx System microplate wells). Finally, OPN expression in bronchoalveolar lavage (BAL) fluids from mild asthmatic and normal control subjects was determined. Osteopontin is expressed in human eosinophils and is increased following GM-CSF and IL-5 activation. Eosinophil-derived OPN contributes to eosinophil-induced angiogenesis. Recombinant OPN promotes eosinophil chemotaxis in vitro and this effect is mediated by alpha(4)beta(1) integrin binding. Soluble OPN is increased in the bronchoalveolar lavage fluid from mild asthmatic subjects and correlates with eosinophil counts. We therefore conclude that OPN is likely to contribute to the process of angiogenesis observed in the airways in asthma.
    Allergy 10/2009; 65(2):168-74. DOI:10.1111/j.1398-9995.2009.02148.x · 6.00 Impact Factor
  • M Kohan · AF Muro · N Berkman
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
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    ABSTRACT: Eosinophil-derived major basic protein (MBP) plays an active role in allergic inflammation and tissue remodelling. However, its role in angiogenesis has not been established as yet. Therefore our objective was to investigate whether MBP exhibits any direct pro-angiogenic effects. Rat aortic endothelial cells and human umbilical vascular endothelial cells were cultured with different concentrations of MBP and their viability (Trypan blue exclusion test), proliferation (thymidine incorporation) and capillary-like structure formation (matrigel assay) were investigated in vitro. The angiogenic activity of MBP was then tested in vivo using the chick chorio allantoic membrane (CAM) assay. Subcytotoxic concentrations of MBP induce endothelial cell proliferation and enhance the pro-mitogenic effect of vascular endothelial growth factor (VEGF), but do not affect their VEGF release. MBP promotes capillarogenesis by endothelial cells seeded on matrigel and sprouting formation in the CAM assay. Furthermore, we have shown that the pro-angiogenic effect of MBP is not due to its cationic charge since stimulation of the CAMs with the synthetic polycation, poly-L-arginine does not induce any angiogenic effects. These data demonstrate that MBP has pro-angiogenic effects in vitro and in vivo, providing a novel mechanism whereby MBP can participate in tissue inflammation and remodelling in atopic diseases.
    Allergy 03/2009; 64(3):368-74. DOI:10.1111/j.1398-9995.2008.01822.x · 6.00 Impact Factor
  • Martin Kohan · Raphael Breuer · Neville Berkman
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    ABSTRACT: Airway remodeling is a central feature of asthma; however, the mechanisms underlying its development have not been fully elucidated. We have demonstrated that osteopontin, an inflammatory cytokine and an extracellular matrix glycoprotein with profibrotic properties, is up-regulated in a murine model of allergen-induced airway remodeling. In the present study, we determined whether osteopontin plays a functional role in airway remodeling. Osteopontin (OPN)-deficient (OPN(-/-)) and wild-type mice were sensitized and exposed to inhaled ovalbumin (OVA) or saline for 5 weeks. Collagen production, peribronchial smooth muscle area, mucus-producing cell number, and bronchoalveolar cell counts were assessed. The functional behavior and phenotype of lung fibroblasts from OVA-treated OPN(-/-) and from wild-type mice were studied using ex vivo cultures. OVA-treated OPN(-/-) mice exhibited reduced lung collagen content, smooth muscle area, mucus-producing cells, and inflammatory cell accumulation as compared with wild-type mice. Reduced matrix metalloproteinase-2 activity and expression of transforming growth factor-beta1 and vascular endothelial growth factor were observed in OVA-treated OPN(-/-) mice. Lung fibroblasts from OVA-treated OPN(-/-) mice showed reduced proliferation, migration, collagen deposition, and alpha-smooth muscle actin expression in comparison with OVA-treated wild-type lung fibroblasts. Thus, OPN is key for the development of allergen-induced airway remodeling in mice. In response to allergen, OPN induces the switching of lung fibroblasts to a pro-fibrogenic myofibroblast phenotype.
    American Journal of Respiratory Cell and Molecular Biology 02/2009; 41(3):290-6. DOI:10.1165/rcmb.2008-0307OC · 4.11 Impact Factor

Publication Stats

2k Citations
409.88 Total Impact Points

Institutions

  • 1993–2015
    • Hebrew University of Jerusalem
      • • Department of Pharmacology
      • • Human Genetics Center
      Yerushalayim, Jerusalem, Israel
  • 1991–2012
    • Hadassah Medical Center
      • Institute of Pulmonology
      Yerushalayim, Jerusalem District, Israel
  • 2004
    • Rambam Medical Center
      H̱efa, Haifa District, Israel
  • 1998
    • Carmel Medical Center
      H̱efa, Haifa District, Israel