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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2014

Open Access 01-12-2014 | Research

Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation

Authors: B Garrett Bodine, Brock G Bennion, Emma Leatham, Felix R Jimenez, Alex J Wright, Zac R Jergensen, Connor J Erickson, Cameron M Jones, Jeff P Johnson, Steven M Knapp, Paul R Reynolds

Published in: Respiratory Research | Issue 1/2014

Login to get access

Abstract

Background

Receptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors expressed abundantly by distal pulmonary epithelium. Our lab has discovered RAGE-mediated effects in the orchestration of lung inflammation induced by tobacco smoke and environmental pollutants; however, the specific contribution of RAGE to the progression of proximal airway inflammation is still inadequately characterized.

Methods and results

We generated a Tet-inducible transgenic mouse that conditionally overexpressed RAGE using the club cell (Clara) secretory protein (CCSP) promoter expressed by club (Clara) cells localized to the proximal airway. RAGE was induced for 40 days from weaning (20 days of age) until sacrifice date at 60 days. Immunohistochemistry, immunoblotting, and qPCR revealed significant RAGE up-regulation when compared to non-transgenic controls; however, H&E staining revealed no detectible morphological abnormalities and apoptosis was not enhanced during the 40 days of augmentation. Freshly procured bronchoalveolar lavage fluid (BALF) from CCSP-RAGE TG mice had significantly more total leukocytes and PMNs compared to age-matched control littermates. Furthermore, CCSP-RAGE TG mice expressed significantly more tumor necrosis factor alpha (TNF-α), interleukin 7 (IL-7), and interleukin 14 (IL-14) in whole lung homogenates compared to controls.

Conclusions

These data support the concept that RAGE up-regulation specifically in lung airways may function in the progression of proximal airway inflammation.
Appendix
Available only for authorised users
Literature
1.
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P: RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999, 97: 889-901. 10.1016/S0092-8674(00)80801-6.PubMedCrossRef
2.
Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C: Blockade of amphoterin/RAGE signalling suppresses tumor growth and metastases. Nature (London). 2000, 405: 354-360. 10.1038/35012626.CrossRef
3.
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Nagashima M, Morser J, Migheli A: RAGE and amyloid beta peptide neurotoxicity in Alzheimer's disease. Nature (London). 1996, 382: 685-691. 10.1038/382685a0.CrossRef
4.
Demling N, Ehrhardt C, Kasper M, Laue M, Knels L, Rieber EP: Promotion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tissue Res. 2006, 14: 475-488. 10.1007/s00441-005-0069-0.CrossRef
5.
Buckley ST and Ehrhardt C: The receptor for advanced glycation endproducts (RAGE) and the lung.J Biomed Biotechnol 2010, 2010:doi:10.1155/2010/917108,
6.
Jemal A, Ward E, Hao Y, Thun M: Trends in the leading causes of death in the United States, 1970-2002. JAMA. 2005, 294 (10): 1255-1259. 10.1001/jama.294.10.1255.PubMedCrossRef
7.
Reynolds PR, Kasteler S, Cosio MG, Sturrock A, Huecksteadt TP, Hoidal JR: RAGE: developmental expression and positive feedback regulation by Egr-1 during cigarette smoke exposure in pulmonary epithelial cells. AJP: Lung Cell Mol Physiol. 2008, 294 (6): L1094-L1101.
8.
Reynolds PR, Kasteler SD, Schmitt RE, Hoidal JR: RAGE signals through Ras during tobacco smoke-induced pulmonary inflammation. Am J Resp Cell Mol Biol. 2010, 45: 411-418. 10.1165/rcmb.2010-0231OC.CrossRef
9.
Robinson AB, Stogsdill JA, Lewis JP, Wood TA, Reynolds PR: RAGE and tobacco smoke: insights into modeling chronic obstructive pulmonary disease. Frontiers in Resp Physiol. 2012, 3: 301-
10.
Robinson AB, Dickson KD, Bennion BG, Reynolds PR: RAGE signaling by alveolar macrophages influences tobacco smoke-induced inflammation. AJP: Lung Cell Mol Physiol. 2012, 302 (11): L1192-L1199.
11.
Downward J: Cell cycle: routine role for Ras. Curr Biol. 1997, 7: R258-R260. 10.1016/S0960-9822(06)00116-3.PubMedCrossRef
12.
Winston JT, Coats SR, Wang YZ, Pledger WJ: Regulation of the cell cycle machinery by oncogenic ras. Oncogene. 1996, 12: 127-134.PubMed
13.
Wu L, Ma L, Nicholson LF, Black PN: Advanced glycation end products and its receptor (RAGE) are increased in patients with COPD. Respir Med. 2011, 105 (3): 329-336. 10.1016/j.rmed.2010.11.001.PubMedCrossRef
14.
Zhang S, Xu N, Nie J, Dong L, Li J, Tong J: Proteomic alteration in lung disease of rates exposed to cigarette smoke. Toxicol Lett. 2008, 178 (3): 191-196. 10.1016/j.toxlet.2008.03.014.PubMedCrossRef
15.
Zhang SP, Wu YW, Wu ZZ, Liu HY, Nie JH, Tong J: Up-regulation of RAGE and S100A6 in rats exposed to cigarette smoke. Environ Toxicol Pharmacol. 2009, 28 (2): 259-264. 10.1016/j.etap.2009.04.013.PubMedCrossRef
16.
Ullah MA, Loh Z, Gan WJ, Zhang V, Yang H, Li JH, Yamamoto Y, Schmidt AM, Armour CL, Hughes JM, Phipps S, Sukkar MB: Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation. J Allergy Clin Immunol. 2014, S0091-6749 (13): 02939-4.
17.
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007, National Institutes of Health, Bethesda, MD
18.
Peters JM, Avol E, Navidi W: A study of twelve Southern California communities with differing levels and types of air pollution: I. Prevalence of respiratory morbidity. Am J Respir Crit Care Med. 1999, 159: 760-767. 10.1164/ajrccm.159.3.9804143.PubMedCrossRef
19.
Van der Vaart H, Postma DS: Acute effects of cigarette smoking on inflammation in healthy intermittent smokers. Respir Res. 2005, 6: 22-10.1186/1465-9921-6-22.PubMedPubMedCentralCrossRef
20.
Boulet L-P, Lemiere C, Archambault F: Smoking and asthma: clinical and radiologic features, lung function, and airwary inflammation. Chest. 2006, 129: 661-668. 10.1378/chest.129.3.661.PubMedCrossRef
21.
Maier WC, Arrighi HM, Morray B: Indoor risk factors for asthma and wheezing among Seattle school children. Environ Health Perspect. 1997, 105: 208-214. 10.1289/ehp.97105208.PubMedPubMedCentralCrossRef
22.
Lam TH, Chung SF, Betson CL: Respiratory symptoms due to active and passive smoking in junior secondary school students in Hong Kong. Int J Epidemiol. 1998, 27: 41-48. 10.1093/ije/27.1.41.PubMedCrossRef
23.
Martinez FD, Wright AL, Taussig LM: Asthma and wheezing in the first six years of life. N Engl J Med. 1995, 332: 133-138. 10.1056/NEJM199501193320301.PubMedCrossRef
24.
Reynolds PR, Stogsdill JA, Stogsdill MA, Heimann NB: Up-regulation of RAGE by alveolar epithelium influences cytodifferentiation and causes severe lung hypoplasia. Am J Respir Cell Mol Biol. 2011, 45: 1195-1202. 10.1165/rcmb.2011-0170OC.PubMedCrossRef
25.
Tichelaar JW, Lu W, Whitsett JA: Conditional expression of fibroblast growth factor-7 in the developing and mature lung. J Biol Chem. 2000, 275 (16): 11858-11864. 10.1074/jbc.275.16.11858.PubMedCrossRef
26.
Stogsdill MP, Stogsdill JA, Bodine BG, Fredrickson AC, Sefcik TL, Wood TA, Kasteler SK, Reynolds PR: Conditional RAGE over expression in the adult murine lung causes airspace enlargement and induces inflammation. Am J Resp Cell Mol Biol. 2013, 49 (1): 128-134. 10.1165/rcmb.2013-0013OC.CrossRef
27.
Reynolds PR, Schmitt RE, Kasteler SD, Sturrock A, Sanders K, Bierhaus A, Nawroth PP, Paine R, Hoidal JR: Receptors for advanced glycation end-products targeting protect against hyperoxia-induced lung injury in mice. Am J Respir Cell Mol Biol. 2010, 42 (5): 545-551. 10.1165/rcmb.2008-0265OC.PubMedCrossRef
28.
Rao NV, Argyle B, Xu Z, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, Hoidal JR, Kennedy TP: Low anticoagulant heparin targets multiple sites in inflammation, suppresses heparin-induced thrombocytopenia and inhibits interaction of RAGE with its disparate ligands. Am J Physiol Cell Physiol. 2010, 299 (1): C97-C110. 10.1152/ajpcell.00009.2010.PubMedCrossRef
29.
Reynolds PR, Wasley KM, Allison CH: Diesel particulate matter induces RAGE expression in pulmonary epithelium and RAGE signaling influences NF-κB-mediated inflammation. Environ Health Perspect. 2010, 119 (3): 332-339. 10.1289/ehp.1002520.PubMedPubMedCentralCrossRef
30.
Reynolds PR, Mucenski ML, Le Cras TD, Nichols WC, Whitsett JA: Midkine is regulated by hypoxia and causes pulmonary vascular remodeling. J Biol Chem. 2004, 279 (35): 37124-37132. 10.1074/jbc.M405254200.PubMedCrossRef
31.
Stogsdill JA, Stogsdill MA, Porter JL, Hancock JM, Robinson AB, Reynolds PR: Embryonic overexpression of receptors for advanced glycation end-products by alveolar epithelium induces an imbalance between proliferation and apoptosis. Am J Respir Cell Mol Biol. 2012, 47: 60-66. 10.1165/rcmb.2011-0385OC.PubMedCrossRef
32.
Winden DR, Ferguson NT, Bukey BR, Geyer AJ, Wright AJ, Jergensen ZR, Robinson AB, Stogsdill JR, Reynolds PR: Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation. Respir Res. 2013, 14 (1): 108-10.1186/1465-9921-14-108.PubMedPubMedCentralCrossRef
33.
Perl AK, Kist R, Shan Z, Scherer G, Whitsett JA: Normal lung development and function after Sox9 inactivation in the respiratory epithelium. Genesis. 2005, 41: 23-32. 10.1002/gene.20093.PubMedCrossRef
34.
Lee CC, Lai YT, Chang HT, Liao JW, Shyu WC, Li CY, Wang CN: Inhibition of high-mobility group box 1 in lung reduced airway inflammation and remodeling in a mouse model of chronic asthma. Biochem Pharmacol. 2013, 86 (7): 940-949. 10.1016/j.bcp.2013.08.003.PubMedCrossRef
35.
Milutinovic PS, Alcorn JF, Englert JM, Crum LT, Oury TD: The receptor for advanced glycation end products is a central mediator of asthma pathogenesis. Am J Pathol. 2012, 181 (4): 1215-1225. 10.1016/j.ajpath.2012.06.031.PubMedPubMedCentralCrossRef
36.
Zhou Y, Jiang YQ, Wang WX, Zhou ZX, Wang YG, Yang L, Ji YL: HMGB1 and RAGE levels in induced sputum correlate with asthma severity and neutrophil percentage. Hum Immunol. 2012, 73 (11): 1171-1174. 10.1016/j.humimm.2012.08.016.PubMedCrossRef
37.
Clarke DL, Davis NH, Majithiya JB, Piper SC, Lewis A, Sleeman MA, Corkill DJ, May RD: Development of a mouse model mimicking key aspects of a viral asthma exacerbation. Clin Sci (Lond). 2014, 126 (8): 567-580. 10.1042/CS20130149.CrossRef
38.
Idriss HT, Naismith JH: TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech. 2000, 50 (3): 184-195. 10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H.PubMedCrossRef
39.
Alek-Ardakani S, Croft M: Tumor necrosis factor receptor/tumor necrosis factor family members in antiviral CD8 T-cell immunity. J Interferon Cytokine Res. 2010, 30 (4): 205-218. 10.1089/jir.2010.0026.CrossRef
40.
Zelová H, Hošek J: TNF-α signaling and inflammation: interactions between old acquaintances. Inflamm Res. 2013, 62 (7): 641-651. 10.1007/s00011-013-0633-0.PubMedCrossRef
41.
Namen AE, Schmierer AE, March CJ, Overell RW, Park LS, Urdal DL, Mochizuki DY: B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988, 167 (3): 988-1002. 10.1084/jem.167.3.988.PubMedCrossRef
42.
Appasamy PM: Interleukin-7: biology and potential clinical applications. Cancer Invest. 1993, 11 (4): 487-499. 10.3109/07357909309018880.PubMedCrossRef
43.
Thomas PS, Heywood G: Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax. 2002, 57 (9): 774-778. 10.1136/thorax.57.9.774.PubMedPubMedCentralCrossRef
44.
Fuentes-Mattei E, Rivera E, Gioda A, Sanchez-Rivera D, Roman-Velazquez FR, Jimenez-Velez BD: Use of human bronchial epithelial cells (BEAS-2B) to study immunological markers resulting from exposure to PM(2.5) organic extract from Puerto Rico. Toxicol Appl Pharmacol. 2010, 243 (3): 381-389. 10.1016/j.taap.2009.12.009.PubMedPubMedCentralCrossRef
45.
Matías V, San Feliciano L, Fernández JE, Lapeña S, Garrido E, Ardura J, Soga MJ, Aragón MP, Remesal A, Benito F, Andrés J, Centeno F, Marugán V, Bachiller R, Bermejo-Martin JF: Host and environmental factors influencing respiratory secretion of pro-wheezing biomarkers in preterm children. Pediatr Allergy Immunol. 2012, 23 (5): 441-447. 10.1111/j.1399-3038.2012.01269.x.PubMedCrossRef
46.
Zhao YL, Duanmu HJ, Li L, Song CX, Zhao B: Study of the expression profile of immunogenesis associated genes in tuberculosis by microarray. Zhonghua Jie He He Hu Xi Za Zhi. 2005, 28 (5): 301-304.PubMed
Metadata
Title
Conditionally induced RAGE expression by proximal airway epithelial cells in transgenic mice causes lung inflammation
Authors
B Garrett Bodine
Brock G Bennion
Emma Leatham
Felix R Jimenez
Alex J Wright
Zac R Jergensen
Connor J Erickson
Cameron M Jones
Jeff P Johnson
Steven M Knapp
Paul R Reynolds
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2014
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-014-0133-y

Other articles of this Issue 1/2014

Respiratory Research 1/2014 Go to the issue

Research

Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia

Research

Exhaled breath condensate in intubated neonates- a window into the lung’s glutathione status

Research

Frequent utilization of the emergency department for acute exacerbation of chronic obstructive pulmonary disease

Research

The short and long term effects of exercise training in non-cystic fibrosis bronchiectasis – a randomised controlled trial

Research

Impact of ozone exposure on the response to glucocorticoid in a mouse model of asthma: involvements of p38 MAPK and MKP-1

Research

FEV1 inversely correlates with metalloproteinases 1, 7, 9 and CRP in COPD by biomass smoke exposure
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

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

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

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

Watch now

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