Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Pulmonary Medicine
Published in: BMC Pulmonary Medicine 1/2015

Open Access 01-12-2015 | Research article

Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells

Authors: Hanna Müller, Christian Nagel, Christel Weiss, Jan Mollenhauer, Johannes Poeschl

Published in: BMC Pulmonary Medicine | Issue 1/2015

Login to get access

Abstract

Background

Deleted in malignant brain tumors 1 (DMBT1) is an innate defence protein expressed in the lungs of preterm infants and adults. Recent studies showed that DMBT1 is important in angiogenesis and can bind to different growth factors including VEGF. We aimed at examining relationships between VEGF and IL-6 levels to DMBT1 expression in the lungs of preterm and term infants and in lung epithelial cells in vitro.

Methods

We examined by ELISA VEGF levels in 120 tracheal aspirates of 57 preterm and term infants and tested for correlation with different perinatal factors as well as with DMBT1 levels. To examine the effect of DMBT1 on VEGF and IL-6 expression we compared type II lung epithelial A549 cells stably transfected with a DMBT1 expression plasmid (DMBT1+ cells) to A549 cells stably transfected with an empty expression plasmid (DMBT1- cells). The concentrations of VEGF and IL-6 were determined via ELISA in the supernatant of the unstimulated cells and after stimulation with LPS, TNFα and Phorbol-12-myristate-13-acetate (PMA).

Results

The VEGF levels in the tracheal aspirates of preterm and term infants were significantly correlated with DMBT1 levels (p = 0.0032), the postnatal age (p = 0.0073) and the presence of neonatal infection/sepsis (p = 0.0002). Unstimulated DMBT1+ A549 cells showed significantly higher VEGF expression (p = 0.0017) than DMBT1- cells. Significantly elevated VEGF levels were also confirmed for DMBT1+ cells after stimulation with TNFα (p = 0.0008), LPS (p = 0.0232) and PMA (p = 0.0025). The IL-6 levels were comparable in DMBT1+ versus DMBT1- cells without stimulation (p = 0.6028), but they were significantly reduced in DMBT1+ cells after stimulation with TNFα (p = 0.0003), LPS (p = 0.0088) and PMA (p = 0.0039).

Conclusions

The data indicate that DMBT1 promotes VEGF and suppresses IL-6 production in alveolar tissues, which could point to DMBT1 having a possible role in the transition from inflammation to regeneration and being a potentially useful clinical marker.
Literature
1.
Ligtenberg AJM, Veerman ECI, Nieuw Amerongen AV, Mollenhauer J. Salivary agglutinin/glycoprotein-340/DMBT1: a single molecule with variable composition and with different functions in infection, inflammation and cancer. Biol Chem. 2007;388:1275–89.CrossRefPubMed
2.
Madsen J, Mollenhauer J, Holmskov U. Review: Gp-340/DMBT1 in mucosal innate immunity. Innate Immun. 2010;16:160–7.CrossRefPubMed
3.
Martínez VG, Moestrup SK, Holmskov U, Mollenhauer J, Lozano F. The conserved scavenger receptor cysteine-rich superfamily in therapy and diagnosis. Pharmacol Rev. 2011;63:967–1000.CrossRefPubMed
4.
Mollenhauer J, Helmke B, Müller H, Kollender G, Lyer S, Diedrichs L, et al. Sequential changes of the DMBT1 expression and location in normal lung tissue and lung carcinomas. Gene Chromosome Canc. 2002;35:164–9.CrossRef
5.
Renner M, Bergmann G, Krebs I, End C, Lyer S, Hilberg F, et al. DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn’s disease. Gastroenterology. 2007;133:1499–509.CrossRefPubMed
6.
Rosenstiel P, Sina C, End C, Renner M, Lyer S, Till A, et al. Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion. J Immunol. 2007;178:8203–11.CrossRefPubMed
7.
Müller H, Hu J, Popp R, Schmidt MHH, Müller-Decker K, Mollenhauer J, et al. Deleted in malignant brain tumors 1 is present in the vascular extracellular matrix and promotes angiogenesis. Arterioscler Thromb Vasc Biol. 2012;32:442–8.CrossRefPubMed
8.
Janér J, Lassus P, Haglund C, Paavonen K, Alitalo K, Andersson S. Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants. Am J Respir Crit Care Med. 2006;174:326–30.CrossRefPubMed
9.
Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol. 2006;290:L209–21.CrossRefPubMed
10.
Maeda S, Suzuki S, Suzuki T, Endo T, Moriya T, Chida M, et al. Analysis of intrapulmonary vessels and epithelial-endothelial interactions in the human developing lung. Lab Invest. 2002;82:293–301.CrossRefPubMed
11.
Tuder RM, Petrache I, Elias JA, Voelkel NF, Henson P. Apoptosis and emphysema: the missing link. Am J Respir Cell Mol Biol. 2003;28:551–4.CrossRefPubMed
12.
Brown KR, England KM, Goss KL, Snyder JM, Acarregiu MJ. VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol. 2001;281:L1001–10.PubMed
13.
Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med. 2001;8:702–10.
14.
Fehrenbach H, Haase M, Kasper M, Koslowski R, Schuh D, Muller M. Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis. Virchow Arch. 1999;435:20–31.CrossRef
15.
Perkins GD, Roberts J, McAuley DF, Armstrong L, Millar A, Gao F, et al. Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury. Thorax. 2005;60:153–8.CrossRefPubMedPubMedCentral
16.
Akeson AL, Cameron JE, Le Cras TD, Whitsett JA, Greenberg JM. Vascular endothelial growth factor-A induces prenatal neovascularization and alters bronchial development in mice. Pediatr Res. 2005;57:82–8.CrossRefPubMed
17.
18.
Müller H, End C, Weiss C, Renner M, Bhandiwad A, Helmke BM, et al. Respiratory Deleted in Malignant Brain Tumours 1 (DMBT1) levels increase during lung maturation and infection. Clin Exp Immun. 2008;151:123–9.CrossRefPubMedPubMedCentral
19.
Müller H, End C, Renner M, Helmke BM, Gassler N, Weiss C, et al. Deleted in malignant brain tumors 1 (DMBT1) is present in hyaline membranes and modulates surface tension of surfactant. Respir Res. 2007;8:69.CrossRefPubMedPubMedCentral
20.
Giedion A, Haefliger H, Dangel P. Acute pulmonary X-ray changes in hyaline membrane disease treated with artificial ventilation and positive end-expiratory pressure (PEP). Pediatr Radiol. 1973;1:145–52.CrossRefPubMed
21.
Foster KA, Oster CG, Mayer MM, Avery ML, Audus KL. Characterization of the A549 cell lines as a type II pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998;243:359–66.CrossRefPubMed
22.
End C, Lyer S, Renner M, Stahl C, Ditzer J, Holloschi A, et al. Generation of a vector system facilitating cloning of DMBT1 variants and recombinant expression of functional full-length DMBT1. Protein Expr Purif. 2005;41:275–86.CrossRefPubMed
23.
Gurkan OU, He C, Zielinski R, Rabb H, King LS, Dodd-o JM, et al. Interleukin-6 mediates pulmonary vascular permeability in a two-hit model of ventilator-associated lung injury. Exp Lung Res. 2011;37:575–84.CrossRefPubMedPubMedCentral
24.
End C, Bikker F, Renner M, Bergmann G, Lyer S, Blaich S, et al. DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands. Eur J Immunol. 2009;39:833–42.CrossRefPubMed
25.
Mura M, Dos Santos CC, Stewart D, Liu M. Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol. 2004;97:1605–17.CrossRefPubMed
26.
Lassus P, Ristimäki A, Ylikorkala O, Viinikka L, Andersson S. Vascular endothelial growth factor in human preterm lung. Am J Respir Crit Care Med. 1999;159:1429–33.CrossRefPubMed
27.
Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;164:1971–80.CrossRefPubMed
28.
Ambalavanan N, Novak ZE. Peptide growth factors in tracheal aspirates of mechanically ventilated preterm neonates. Pediatr Res. 2003;53:240–4.CrossRefPubMed
29.
Koyama S, Sato E, Tsukadaira A, Haniuda M, Numanami H, Kurai M, et al. Vascular endothelial growth factor mRNA and protein expression in airway epithelial cell lines in vitro. Eur Respir J. 2002;20:1449–56.CrossRefPubMed
30.
Boussat S, Eddahibi S, Coste A, Fataccioli V, Gauge M, Housset B, et al. Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2000;279:L371–8.PubMed
31.
Shenberger JS, Zhang L, Powell RJ, Barchowsky A. Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes. Free Radic Biol Med. 2007;43:844–52.CrossRefPubMedPubMedCentral
32.
Buchanan FG, Chang W, Sheng H, Shao J, Morrow JD, DuBois RN. Up-regulation of the enzymes involved in prostacyclin synthesis via Ras induces vascular endothelial growth factor. Gastroenterology. 2004;127:1391–400.CrossRefPubMed
33.
Schuette R, LaPointe MC. Phorbol ester stimulates cyclooxygenase-2 expression and prostanoid production in cardiac myocytes. Am J Physiol Heart Circ Physiol. 2000;279:H719–25.PubMed
34.
Xu H, Czerwinski P, Hortmann M, Sohn H-Y, Förstermann U, Li H. Protein kinase C α promotes angiogenic activity of human endothelial cells via induction of vascular endothelial growth factor. Cardiovasc Res. 2008;78:349–55.CrossRefPubMed
35.
Luo H, Chen Z, Jin H, Zhuang M, Wang T, Su C, et al. Cyclooxygenase-2 up-regulates vascular endothelial growth factor via a protein kinase C pathway in non-small cell lung cancer. J Exp Clin Cancer Res. 2011;30:6.CrossRefPubMedPubMedCentral
36.
Thaikoottathil JV, Martin RJ, Zdunek J, Weinberger A, Rino JG, Chu HW. Cigarette smoke extract reduces VEGF in primary human airway epithelial cells. Eur Respir J. 2009;33:835–43.CrossRefPubMed
37.
Cayabyab RG, Kwong K, Jones C, Minoo P, Durand M. Lung inflammation and pulmonary function in infants with meconium aspiration syndrome. Pediatr Pulmonol. 2007;42:898–905.CrossRefPubMed
38.
39.
Aghai ZH, Kode A, Saslow JG, Nakhla T, Farhath S, Stahl GE, et al. Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res. 2007;62:483–8.CrossRefPubMed
40.
Donnarumma G, Paoletti I, Buommino E, Iovene MR, Tudisco L, Cozza V, et al. Anti-inflammatory effects of moxifloxacin and human β-defensin 2 association in human lung epithelial cell line (A549) stimulated with lipopolysaccharide. Peptides. 2007;28:2286–92.CrossRefPubMed
41.
Kang W, Nielsen O, Fenger C, Madsen J, Hansen S, Tornoe I, et al. The scavenger receptor, cysteine-rich domain-containing molecule gp-340 is differentially regulated in epithelial cell lines by phorbol ester. Clin Exp Immunol. 2002;130:449–58.CrossRefPubMedPubMedCentral
42.
Kang SS, Jeon JH, Woo SJ, Yang JS, Kim KW, Yun CH, et al. IFN-γ renders human intestinal epithelial cells responsive to lipopolysaccharide of Vibrio cholerae by down-regulation of DMBT1. Comp Immunol Microbiol Infect Dis. 2012;35:345–54.CrossRefPubMed
Metadata
Title
Deleted in malignant brain tumors 1 (DMBT1) elicits increased VEGF and decreased IL-6 production in type II lung epithelial cells
Authors
Hanna Müller
Christian Nagel
Christel Weiss
Jan Mollenhauer
Johannes Poeschl
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2015
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-015-0027-x

Other articles of this Issue 1/2015

BMC Pulmonary Medicine 1/2015 Go to the issue

Research article

Incidence of new-onset wheeze: a prospective study in a large middle-aged general population

Research article

Role of bronchoalveolar lavage in the diagnosis of acute exacerbations of idiopathic pulmonary fibrosis: a retrospective study

Case report

Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood

Research article

Inhalation therapy with the synthetic TIP-like peptide AP318 attenuates pulmonary inflammation in a porcine sepsis model

Study protocol

Study protocol: the effects of air pollution exposure and chronic respiratory disease on pneumonia risk in urban Malawian adults - the Acute Infection of the Respiratory Tract Study (The AIR Study)

Research article

Evaluation of a web-based asthma self-management system: a randomised controlled pilot trial

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits