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Respiratory Research
Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Research

Early life exposure to nicotine modifies lung gene response after elastase-induced emphysema

Authors: Sanja Blaskovic, Yves Donati, Isabelle Ruchonnet-Metrailler, Yannick Avila, Dominik Schittny, Christian Matthias Schlepütz, Johannes Constantin Schittny, Constance Barazzone-Argiroffo

Published in: Respiratory Research | Issue 1/2022

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Abstract

Background

Chronic obstructive pulmonary disease (COPD) is among the top 5 causes of mortality in the world and can develop as a consequence of genetic and/or environmental factors. Current efforts are focused on identifying early life insults and how these contribute to COPD development. In line with this, our study focuses on the influence of early life nicotine exposure and its potential impact on (a) lung pulmonary functions, and (b) elastase-induced emphysema in adulthood.

Methods

To address this hypothesis, we developed a model of 2 hits, delivered at different time points: mouse pups were first exposed to nicotine/placebo in utero and during lactation, and then subsequently received elastase/placebo at the age of 11 weeks. The effect of nicotine pretreatment and elastase instillation was assessed by (a) measurement of pulmonary function at post-elastase day (ped) 21, and (b) transcriptomic profiling at ped3 and 21, and complementary protein determination. Statistical significance was determined by 3- and 2-way ANOVA for pulmonary functions, and RNAseq results were analyzed using the R project.

Results

We did not observe any impact of nicotine pre- and early post-natal exposure compared to control samples on lung pulmonary functions in adulthood, as measured by FLEXIVENT technology. After elastase instillation, substantial lung damage was detected by x-ray tomography and was accompanied by loss in body weight at ped3 as well as an increase in cell numbers, inflammatory markers in BAL and lung volume at ped21. Lung functions showed a decrease in elastance and an increase in deep inflation volume and pressure volume (pv) loop area in animals with emphysema at ped21. Nicotine had no effect on elastance and deep inflation volume, but did affect the pv loop area in animals with emphysema at ped21. Extensive transcriptomic changes were induced by elastase at ped3 both in the nicotine-pretreated and the control samples, with several pathways common to both groups, such as for cell cycle, DNA adhesion and DNA damage. Nicotine pretreatment affected the number of lymphocytes present in BAL after elastase instillation and some of the complement pathway related proteins, arguing for a slight modification of the immune response, as well as changes related to general body metabolism. The majority of elastase-induced transcriptomic changes detected at ped3 had disappeared at ped21. In addition, transcriptomic profiling singled out a common gene pool that was independently activated by nicotine and elastase.

Conclusions

Our study reports a broad spectrum of transient transcriptomic changes in mouse emphysema and identifies nicotine as influencing the emphysema-associated immune system response.
Appendix
Available only for authorised users
Footnotes
1
Significant pathway maps (top 10 or less) obtained by the GeneGo pathway maps analysis are shown in bold letters.
 
Literature
1.
The Lancet Respiratory M. Early-life origins of respiratory diseases: a key to prevention. Lancet Respir Med. 2020;8(10):935.
2.
Rusznak C, Mills PR, Devalia JL, Sapsford RJ, Davies RJ, Lozewicz S. Effect of cigarette smoke on the permeability and IL-1beta and sICAM-1 release from cultured human bronchial epithelial cells of never-smokers, smokers, and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2000;23(4):530–6.PubMedCrossRef
3.
Givi ME, Folkerts G, Wagenaar GT, Redegeld FA, Mortaz E. Cigarette smoke differentially modulates dendritic cell maturation and function in time. Respir Res. 2015;16:131.PubMedPubMedCentralCrossRef
4.
Robbins CS, Franco F, Mouded M, Cernadas M, Shapiro SD. Cigarette smoke exposure impairs dendritic cell maturation and T cell proliferation in thoracic lymph nodes of mice. J Immunol. 2008;180(10):6623–8.PubMedCrossRef
5.
Alrouji M, Manouchehrinia A, Gran B, Constantinescu CS. Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis. J Neuroimmunol. 2019;329:24–34.PubMedCrossRef
6.
Cui WY, Li MD. Nicotinic modulation of innate immune pathways via alpha7 nicotinic acetylcholine receptor. J Neuroimmune Pharmacol. 2010;5(4):479–88.PubMedCrossRef
7.
Blaskovic S, Donati Y, Zanetti F, Ruchonnet-Metrailler I, Lemeille S, Cremona TP, et al. Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development. Am J Physiol Lung Cell Mol Physiol. 2020;318(4):L606–18.PubMedCrossRef
8.
9.
Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet. 1986;1(8489):1077–81.PubMedCrossRef
10.
Duffy S, Weir M, Criner GJ. The complex challenge of chronic obstructive pulmonary disease. Lancet Respir Med. 2015;3(12):917–9.PubMedCrossRef
11.
Stocks J, Hislop A, Sonnappa S. Early lung development: lifelong effect on respiratory health and disease. Lancet Respir Med. 2013;1(9):728–42.PubMedCrossRef
12.
Trocme C, Deffert C, Cachat J, Donati Y, Tissot C, Papacatzis S, et al. Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways. J Pathol. 2015;235(1):65–78.PubMedCrossRef
13.
Mund SI, Stampanoni M, Schittny JC. Developmental alveolarization of the mouse lung. Dev Dyn. 2008;237(8):2108–16.PubMedCrossRef
14.
Roth-Kleiner M, Berger TM, Tarek MR, Burri PH, Schittny JC. Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network. Dev Dyn. 2005;233(4):1261–71.PubMedCrossRef
15.
Scherle W. A simple method for volumetry of organs in quantitative stereology. Mikroskopie. 1970;26(1):57–60.PubMed
16.
Doras C, Petak F, Bayat S, Baudat A, Von Garnier C, Eigenmann P, et al. Lung responses in murine models of experimental asthma: value of house dust mite over ovalbumin sensitization. Respir Physiol Neurobiol. 2018;247:43–51.PubMedCrossRef
17.
Hantos Z, Adamicza A, Govaerts E, Daroczy B. Mechanical impedances of lungs and chest wall in the cat. J Appl Physiol. 1992;73(2):427–33.PubMedCrossRef
18.
Thiesse J, Namati E, Sieren JC, Smith AR, Reinhardt JM, Hoffman EA, et al. Lung structure phenotype variation in inbred mouse strains revealed through in vivo micro-CT imaging. J Appl Physiol. 2010;109(6):1960–8.PubMedPubMedCentralCrossRef
19.
Barazzone C, Belin D, Piguet PF, Vassalli JD, Sappino AP. Plasminogen activator inhibitor-1 in acute hyperoxic mouse lung injury. J Clin Invest. 1996;98(12):2666–73.PubMedPubMedCentralCrossRef
20.
Barre SF, Haberthur D, Cremona TP, Stampanoni M, Schittny JC. The total number of acini remains constant throughout postnatal rat lung development. Am J Physiol Lung Cell Mol Physiol. 2016;311(6):L1082–9.PubMedCrossRef
21.
22.
Kaeslin M, Wehrle I, Grossniklaus-Burgin C, Wyler T, Guggisberg U, Schittny JC, et al. Stage-dependent strategies of host invasion in the egg-larval parasitoid Chelonus inanitus. J Insect Physiol. 2005;51(3):287–96.PubMedCrossRef
23.
Lovric G, Mokso R, Schleputz CM, Stampanoni M. A multi-purpose imaging endstation for high-resolution micrometer-scaled sub-second tomography. Phys Med. 2016;32(12):1771–8.PubMedCrossRef
24.
Buhrer M, Stampanoni M, Rochet X, Buchi F, Eller J, Marone F. High-numerical-aperture macroscope optics for time-resolved experiments. J Synchrotron Radiat. 2019;26(Pt 4):1161–72.PubMedPubMedCentralCrossRef
25.
Haberthur D, Hintermuller C, Marone F, Schittny JC, Stampanoni M. Radiation dose optimized lateral expansion of the field of view in synchrotron radiation X-ray tomographic microscopy. J Synchrotron Radiat. 2010;17(5):590–9.PubMedPubMedCentralCrossRef
26.
Stock SR. Recent advances in X-ray microtomography applied to materials. Int Mater Rev. 2013;53(3):129–81.CrossRef
27.
Borisova E, Lovric G, Miettinen A, Fardin L, Bayat S, Larsson A, et al. Micrometer-resolution X-ray tomographic full-volume reconstruction of an intact post-mortem juvenile rat lung. Histochem Cell Biol. 2020;115:215.
28.
Paganin D, Mayo SC, Gureyev TE, Miller PR, Wilkins SW. Simultaneous phase and amplitude extraction from a single defocused image of a homogeneous object. J Microsc. 2002;206(Pt 1):33–40.PubMedCrossRef
29.
30.
Marone F, Studer A, Billich H, Sala L, Stampanoni M. Towards on-the-fly data post-processing for real-time tomographic imaging at TOMCAT. Adv Struct Chem Imaging. 2017;3(1):1.PubMedPubMedCentralCrossRef
31.
Miettinen A, Oikonomidis IV, Bonnin A, Stampanoni M. NRStitcher: non-rigid stitching of terapixel-scale volumetric images. Bioinformatics. 2019;35(24):5290–7.PubMedCrossRef
32.
Wang WZ, Oeschger FM, Lee S, Molnar Z. High quality RNA from multiple brain regions simultaneously acquired by laser capture microdissection. BMC Mol Biol. 2009;10:69.PubMedPubMedCentralCrossRef
33.
Clement-Ziza M, Munnich A, Lyonnet S, Jaubert F, Besmond C. Stabilization of RNA during laser capture microdissection by performing experiments under argon atmosphere or using ethanol as a solvent in staining solutions. RNA. 2008;14(12):2698–704.PubMedPubMedCentralCrossRef
34.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21.PubMedCrossRef
35.
36.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.PubMedCrossRef
37.
RDC T. R: a language and environment for statistical computing. R Foundation for Statistical Computing. 2011.
38.
Demedts IK, Bracke KR, Van Pottelberge G, Testelmans D, Verleden GM, Vermassen FE, et al. Accumulation of dendritic cells and increased CCL20 levels in the airways of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(10):998–1005.PubMedCrossRef
39.
Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 2008;181(7):4666–75.PubMedCrossRef
40.
Shan M, Cheng HF, Song LZ, Roberts L, Green L, Hacken-Bitar J, et al. Lung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysema. Sci Transl Med. 2009;1(4):4–10.CrossRef
41.
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(6):457–66.PubMedCrossRef
42.
Burrows B, Knudson RJ, Lebowitz MD. The relationship of childhood respiratory illness to adult obstructive airway disease. Am Rev Respir Dis. 1977;115(5):751–60.PubMed
43.
Strieder DJ. Editorial: pediatric origins of chronic obstructive lung disease. Bull Physiopathol Respir (Nancy). 1974;10(3):273–9.
44.
Devos FC, Maaske A, Robichaud A, Pollaris L, Seys S, Lopez CA, et al. Forced expiration measurements in mouse models of obstructive and restrictive lung diseases. Respir Res. 2017;18(1):123.PubMedPubMedCentralCrossRef
45.
Limjunyawong N, Fallica J, Horton MR, Mitzner W. Measurement of the pressure-volume curve in mouse lungs. J Vis Exp. 2015;95:52376.
46.
Anciaes AM, Olivo CR, Prado CM, Kagohara KH, Pinto Tda S, Moriya HT, et al. Respiratory mechanics do not always mirror pulmonary histological changes in emphysema. Clinics (Sao Paulo). 2011;66(10):1797–803.
47.
Tazaki G, Kondo T, Tajiri S, Tsuji C, Shioya S, Tanigaki T. Functional residual capacity and airway resistance in rats of COPD model induced by systemic hyaluronidase. Tokai J Exp Clin Med. 2006;31(3):125–7.PubMed
48.
49.
Rangasamy T, Misra V, Zhen L, Tankersley CG, Tuder RM, Biswal S. Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. Am J Physiol Lung Cell Mol Physiol. 2009;296(6):L888-900.PubMedPubMedCentralCrossRef
50.
Imai K, Mercer BA, Schulman LL, Sonett JR, D’Armiento JM. Correlation of lung surface area to apoptosis and proliferation in human emphysema. Eur Respir J. 2005;25(2):250–8.PubMedCrossRef
51.
Sugano N, Shimada K, Ito K, Murai S. Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaB activation. Biochem Biophys Res Commun. 1998;252(1):25–8.PubMedCrossRef
52.
Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, et al. Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol. 2006;146(1):116–23.PubMedPubMedCentralCrossRef
53.
Gao YJ, Holloway AC, Zeng ZH, Lim GE, Petrik JJ, Foster WG, et al. Prenatal exposure to nicotine causes postnatal obesity and altered perivascular adipose tissue function. Obes Res. 2005;13(4):687–92.PubMedCrossRef
54.
Holloway AC, Lim GE, Petrik JJ, Foster WG, Morrison KM, Gerstein HC. Fetal and neonatal exposure to nicotine in Wistar rats results in increased beta cell apoptosis at birth and postnatal endocrine and metabolic changes associated with type 2 diabetes. Diabetologia. 2005;48(12):2661–6.PubMedCrossRef
55.
Somm E, Schwitzgebel VM, Vauthay DM, Camm EJ, Chen CY, Giacobino JP, et al. Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology. 2008;149(12):6289–99.PubMedCrossRef
56.
Broekhuizen R, Vernooy JH, Schols AM, Dentener MA, Wouters EF. Leptin as local inflammatory marker in COPD. Respir Med. 2005;99(1):70–4.PubMedCrossRef
57.
Kythreotis P, Kokkini A, Avgeropoulou S, Hadjioannou A, Anastasakou E, Rasidakis A, et al. Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2009;9:11.PubMedPubMedCentralCrossRef
58.
Capettini LS, Montecucco F, Mach F, Stergiopulos N, Santos RA, da Silva RF. Role of renin-angiotensin system in inflammation, immunity and aging. Curr Pharm Des. 2012;18(7):963–70.PubMedCrossRef
59.
Correa LH, Heyn GS, Magalhaes KG. The impact of the adipose organ plasticity on inflammation and cancer progression. Cells. 2019;8(7):662.PubMedCentralCrossRef
60.
Meysman M. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J. 2006;28(3):670.PubMedCrossRef
61.
Vanderslice P, Biediger RJ, Woodside DG, Berens KL, Holland GW, Dixon RA. Development of cell adhesion molecule antagonists as therapeutics for asthma and COPD. Pulm Pharmacol Ther. 2004;17(1):1–10.PubMedCrossRef
62.
Lamonaca P, Prinzi G, Kisialiou A, Cardaci V, Fini M, Russo P. Metabolic disorder in chronic obstructive pulmonary disease (COPD) patients: towards a personalized approach using marine drug derivatives. Mar Drugs. 2017;15(3):81.PubMedCentralCrossRef
63.
Metadata
Title
Early life exposure to nicotine modifies lung gene response after elastase-induced emphysema
Authors
Sanja Blaskovic
Yves Donati
Isabelle Ruchonnet-Metrailler
Yannick Avila
Dominik Schittny
Christian Matthias Schlepütz
Johannes Constantin Schittny
Constance Barazzone-Argiroffo
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-01956-4

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