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 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Inflammation Research
Published in: Inflammation Research 5/2015

01-05-2015 | Original Research Paper

Different profiles of notch signaling in cigarette smoke-induced pulmonary emphysema and bleomycin-induced pulmonary fibrosis

Authors: Shi Li, Xiaofei Hu, Zheng Wang, Meng Wu, Jinnong Zhang

Published in: Inflammation Research | Issue 5/2015

Login to get access

Abstract

Objective

Different profiles of Notch signaling mediate naive T cell differentiation which might be involved in pulmonary emphysema and fibrosis.

Methods

C57BL/6 mice were randomized into cigarette smoke (CS) exposure, bleomycin (BLM) exposure, and two separate groups of control for sham exposure to CS or BLM. The paratracheal lymph nodes of the animals were analyzed by real-time PCR and immunohistochemistry. Morphometry of the lung parenchyma, measurement of the cytokines, and cytometry of the bronchoalveolar lavage fluid (BALF) were also done accordingly.

Results

In comparison with controls, all Notch receptors and ligands were upregulated by chronic CS exposure, especially Notch3 and DLL1 (P < 0.01), and this was in line with emphysema-like morphology and Th1-biased inflammation. While Notch3 and DLL1 were downregulated by BLM exposure (P < 0.01), those was in line with fibrotic lung remodeling and Th2 polarization.

Conclusions

This founding implies that the CS exposure but not the BLM exposure is capable of initiating Notch signaling in lymphoid tissue of the lung, which is likely relevant to the pathogenesis of pulmonary emphysema. Unable to initiate the Th1 response or inhibit it may lead to Th2 polarization and aberrant repair.
Appendix
Available only for authorised users
Literature
1.
Crystal RG, Bitterman PB, Mossman B, Schwarz MI, Sheppard D, Almasy L, et al. Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med. 2002;166:236–46.CrossRefPubMed
2.
3.
Grumelli S, Corry DB, Song LZ, Song L, Green L, Huh J, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 2004;1:e8.CrossRefPubMedCentralPubMed
4.
Wang Z, Chen YW, Zhang JN, Hu XF, Peng MJ. Pentoxifylline attenuates cigarette smoke-induced overexpression of CXCR3 and IP-10 in mice. Chin Med J (Engl). 2012;125:1980–5.
5.
Eppert BL, Wortham BW, Flury JL, Borchers MT. Functional characterization of T cell populations in a mouse model of chronic obstructive pulmonary disease. J Immunol. 2013;190:1331–40.CrossRefPubMedCentralPubMed
6.
Zhang J, Zheng L, Bai M. Dynamic expression of tumor necrosis factor-alpha and vascular endothelial growth factor in rat model of pulmonary emphysema induced by smoke exposure. J Huazhong Univ Sci Technolog Med Sci. 2007;27:505–7.CrossRefPubMed
7.
Churg A, Zhou S, Preobrazhenska O, Tai H, Wang R, Wright JL. Expression of profibrotic mediators in small airways versus parenchyma after cigarette smoke exposure. Am J Respir Cell Mol Biol. 2009;40:268–76.CrossRefPubMed
8.
Tilley AE, Harvey BG, Heguy A, Hackett NR, Wang R, O’Connor TP, et al. Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:457–66.CrossRefPubMedCentralPubMed
9.
Wang Z, Zhang JN, Hu XF, Chen XL, Wang XR, Zhao TT, et al. Effects of pentoxifylline on Wnt/beta-catenin signaling in mice chronically exposed to cigarette smoke. Chin Med J (Engl). 2010;123:2688–94.
10.
Mitaka K, Miyazaki Y, Yasui M, Furuie M, Miyake S, Inase N, et al. Th2-biased immune responses are important in a murine model of chronic hypersensitivity pneumonitis. Int Arch Allergy Immunol. 2011;154:264–74.CrossRefPubMed
11.
12.
Lukacs NW, Hogaboam C, Chensue SW, Blease K, Kunkel SL. Type 1/type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest. 2001;120:5S–8S.CrossRefPubMed
13.
Shimizu Y, Kuwabara H, Ono A, Higuchi S, Hisada T, Dobashi K, et al. Intracellular Th1/Th2 balance of pulmonary CD4(+) T cells in patients with active interstitial pneumonia evaluated by serum KL-6. Immunopharmacol Immunotoxicol. 2006;28:295–304.CrossRefPubMed
14.
Konigshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3:e2142.CrossRefPubMedCentralPubMed
15.
Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest. 2009;119:772–87.PubMedCentralPubMed
16.
Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ, Chapman HA Jr, et al. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J Exp Med. 2000;192:1587–600.CrossRefPubMedCentralPubMed
17.
Sandler NG, Mentink-Kane MM, Cheever AW, Wynn TA. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol. 2003;171:3655–67.CrossRefPubMed
18.
Kimura T, Ishii Y, Yoh K, Morishima Y, Iizuka T, Kiwamoto T, et al. Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis. Am J Pathol. 2006;169:96–104.CrossRefPubMedCentralPubMed
19.
Adler SH, Chiffoleau E, Xu L, Dalton NM, Burg JM, Wells AD, et al. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J Immunol. 2003;171:2896–903.CrossRefPubMed
20.
Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell. 2004;117:515–26.CrossRefPubMed
21.
Radtke F, Fasnacht N, Macdonald HR. Notch signaling in the immune system. Immunity. 2010;32:14–27.CrossRefPubMed
22.
Xu K, Moghal N, Egan SE. Notch signaling in lung development and disease. Adv Exp Med Biol. 2012;727:89–98.CrossRefPubMed
23.
Amsen D, Antov A, Flavell RA. The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol. 2009;9:116–24.CrossRefPubMed
24.
Bailis W, Yashiro-Ohtani Y, Fang TC, Hatton RD, Weaver CT, Artis D, et al. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity. 2013;39:148–59.CrossRefPubMedCentralPubMed
25.
Liu T, Hu B, Choi YY, Chung M, Ullenbruch M, Yu H, et al. Notch1 signaling in FIZZ1 induction of myofibroblast differentiation. Am J Pathol. 2009;174:1745–55.CrossRefPubMedCentralPubMed
26.
Aoyagi-Ikeda K, Maeno T, Matsui H, Ueno M, Hara K, Aoki Y, et al. Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway. Am J Respir Cell Mol Biol. 2011;45:136–44.PubMed
27.
Schrier DJ, Kunkel RG, Phan SH. The role of strain variation in murine bleomycin-induced pulmonary fibrosis. Am Rev Respir Dis. 1983;127:63–6.PubMed
28.
Harrison JH Jr, Lazo JS. Plasma and pulmonary pharmacokinetics of bleomycin in murine strains that are sensitive and resistant to bleomycin-induced pulmonary fibrosis. J Pharmacol Exp Ther. 1988;247:1052–8.PubMed
29.
Yao H, Edirisinghe I, Rajendrasozhan S, Chiba Y, Mizuguchi J, Yoshimoto T. Cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1174–86.CrossRefPubMed
30.
Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;294:L152–60.CrossRefPubMed
31.
Thurlbeck WM. Measurement of pulmonary emphysema. Am Rev Respir Dis. 1967;95:752–64.PubMed
32.
Thurlbeck WM. The internal surface area of nonemphysematous lungs. Am Rev Respir Dis. 1967;95:765–73.PubMed
33.
34.
Thrall RS, Phan SH, McCormick JR, Ward PA. The development of bleomycin-induced pulmonary fibrosis in neutrophil-depleted and complement-depleted rats. Am J Pathol. 1981;105:76–81.PubMedCentralPubMed
35.
Clark JG, Kuhn C 3rd. Bleomycin-induced pulmonary fibrosis in hamsters: effect of neutrophil depletion on lung collagen synthesis. Am Rev Respir Dis. 1982;126:737–9.PubMed
36.
Osanai K, Takahashi K, Suwabe A, Takada K, Ikeda H, Sato S, et al. The effect of cigarette smoke on bleomycin-induced pulmonary fibrosis in hamsters. Am Rev Respir Dis. 1988;138:1276–81.CrossRefPubMed
37.
Cisneros-Lira J, Gaxiola M, Ramos C, Selman M, Pardo A. Cigarette smoke exposure potentiates bleomycin-induced lung fibrosis in guinea pigs. Am J Physiol Lung Cell Mol Physiol. 2003;285:L949–56.CrossRefPubMed
38.
Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2645–53.CrossRefPubMed
39.
Demoor T, Bracke KR, Vermaelen KY, Dupont L, Joos GF, Brusselle GG. CCR7 modulates pulmonary and lymph node inflammatory responses in cigarette smoke-exposed mice. J Immunol. 2009;183:8186–94.CrossRefPubMed
40.
Zhu J, Kaplan AM, Goud SN. Immunologic alterations in bleomycin-treated mice: role of pulmonary fibrosis in the modulation of immune responses. Am J Respir Crit Care Med. 1996;153:1924–30.CrossRefPubMed
41.
Trujillo G, Hartigan AJ, Hogaboam CM. T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice. Fibrogenesis Tissue Repair. 2010;3:18.CrossRefPubMedCentralPubMed
42.
van der Strate BW, Postma DS, Brandsma CA, Melgert BN, Luinge MA, Geerlings M, et al. Cigarette smoke-induced emphysema: a role for the B cell. Am J Respir Crit Care Med. 2006;173:751–8.CrossRefPubMed
43.
Maekawa Y, Tsukumo S, Chiba S, Hirai H, Hayashi Y, Okada H, et al. Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity. 2003;19:549–59.CrossRefPubMed
44.
45.
Sun J, Krawczyk CJ, Pearce EJ. Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. J Immunol. 2008;180:1655–61.CrossRefPubMed
46.
Metadata
Title
Different profiles of notch signaling in cigarette smoke-induced pulmonary emphysema and bleomycin-induced pulmonary fibrosis
Authors
Shi Li
Xiaofei Hu
Zheng Wang
Meng Wu
Jinnong Zhang
Publication date
01-05-2015
Publisher
Springer Basel
Published in
Inflammation Research / Issue 5/2015
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-015-0816-y

Other articles of this Issue 5/2015

Inflammation Research 5/2015 Go to the issue

Original Research Paper

RNA-sequencing studies identify genes differentially regulated during inflammation-driven lung tumorigenesis and targeted by chemopreventive agents

Review

Inflammation and prostate cancer: friends or foe?

Original Research Paper

Association of systemic inflammation with epicardial fat and coronary artery calcification

Review

The experimental model of nephrotic syndrome induced by Doxorubicin in rodents: an update

Original Research Paper

Resveratrol alleviates vascular inflammatory injury by inhibiting inflammasome activation in rats with hypercholesterolemia and vitamin D2 treatment

Original Research Paper

Systemic changes following carrageenan-induced paw inflammation in rats
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
Image Credits