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Respiratory Research
Published in: Respiratory Research 1/2010

Open Access 01-12-2010 | Research

Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype

Authors: Tonio Pera, Reinoud Gosens, Andries H Lesterhuis, Riham Sami, Marco van der Toorn, Johan Zaagsma, Herman Meurs

Published in: Respiratory Research | Issue 1/2010

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Abstract

Background

A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM.

Methods

To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility.

Results

Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction.

Conclusions

Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.
Literature
1.
Hogg JC, Timens W: The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009, 4:435–459.CrossRefPubMed
2.
Bosken CH, Wiggs BR, Pare PD, Hogg JC: Small airway dimensions in smokers with obstruction to airflow. Am Rev Respir Dis 1990, 142:563–570.CrossRefPubMed
3.
Saetta M, Di SA, Turato G, Facchini FM, Corbino L, Mapp CE, Maestrelli P, Ciaccia A, Fabbri LM: CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 157:822–826.CrossRefPubMed
4.
Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC: Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993, 148:1220–1225.CrossRefPubMed
5.
Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Pare PD: The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004, 350:2645–2653.CrossRefPubMed
6.
Tashkin DP, Altose MD, Bleecker ER, Connett JE, Kanner RE, Lee WW, Wise R: The lung health study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung Health Study Research Group. Am Rev Respir Dis 1992, 145:301–310.CrossRefPubMed
7.
Postma DS, Kerstjens HA: Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 158:S187-S192.CrossRefPubMed
8.
Hasday JD, Bascom R, Costa JJ, Fitzgerald T, Dubin W: Bacterial endotoxin is an active component of cigarette smoke. Chest 1999, 115:829–835.CrossRefPubMed
9.
Rylander R: Endotoxin in the environment--exposure and effects. J Endotoxin Res 2002, 8:241–252.PubMed
10.
Larsson L, Szponar B, Pehrson C: Tobacco smoking increases dramatically air concentrations of endotoxin. Indoor Air 2004, 14:421–424.CrossRefPubMed
11.
Larsson L, Szponar B, Ridha B, Pehrson C, Dutkiewicz J, Krysinska-Traczyk E, Sitkowska J: Identification of bacterial and fungal components in tobacco and tobacco smoke. Tob Induc Dis 2008, 4:4.CrossRefPubMedPubMedCentral
12.
Sarir H, Henricks PA, van Houwelingen AH, Nijkamp FP, Folkerts G: Cells, mediators and Toll-like receptors in COPD. Eur J Pharmacol 2008, 585:346–353.CrossRefPubMed
13.
George CL, Jin H, Wohlford-Lenane CL, O'Neill ME, Phipps JC, O'Shaughnessy P, Kline JN, Thorne PS, Schwartz DA: Endotoxin responsiveness and subchronic grain dust-induced airway disease. Am J Physiol Lung Cell Mol Physiol 2001, 280:L203-L213.PubMed
14.
Vogelzang PF, Gulden JW, Folgering H, Kolk JJ, Heederik D, Preller L, Tielen MJ, van Schayck CP: Endotoxin exposure as a major determinant of lung function decline in pig farmers. Am J Respir Crit Care Med 1998, 157:15–18.CrossRefPubMed
15.
Wright JL, Postma DS, Kerstjens HA, Timens W, Whittaker P, Churg A: Airway remodeling in the smoke exposed guinea pig model. Inhal Toxicol 2007, 19:915–923.CrossRefPubMed
16.
Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL: Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 2007, 62:706–713.CrossRefPubMedPubMedCentral
17.
Toward TJ, Broadley KJ: Goblet cell hyperplasia, airway function, and leukocyte infiltration after chronic lipopolysaccharide exposure in conscious Guinea pigs: effects of rolipram and dexamethasone. J Pharmacol Exp Ther 2002, 302:814–821.CrossRefPubMed
18.
Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF: Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. Am J Respir Cell Mol Biol 2002, 26:152–159.CrossRefPubMed
19.
Brass DM, Savov JD, Gavett SH, Haykal-Coates N, Schwartz DA: Subchronic endotoxin inhalation causes persistent airway disease. Am J Physiol Lung Cell Mol Physiol 2003, 285:L755-L761.CrossRefPubMed
20.
Jeffery PK: Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001, 164:S28-S38.CrossRefPubMed
21.
Wang RD, Tai H, Xie C, Wang X, Wright JL, Churg A: Cigarette smoke produces airway wall remodeling in rat tracheal explants. Am J Respir Crit Care Med 2003, 168:1232–1236.CrossRefPubMed
22.
Wang RD, Wright JL, Churg A: Transforming growth factor-beta1 drives airway remodeling in cigarette smoke-exposed tracheal explants. Am J Respir Cell Mol Biol 2005, 33:387–393.CrossRefPubMed
23.
Churg A, Tai H, Coulthard T, Wang R, Wright JL: Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med 2006, 174:1327–1334.CrossRefPubMed
24.
Churg A, Cosio M, Wright JL: Mechanisms of cigarette smoke-induced COPD: insights from animal models. Am J Physiol Lung Cell Mol Physiol 2008, 294:L612-L631.CrossRefPubMed
25.
Mio T, Romberger DJ, Thompson AB, Robbins RA, Heires A, Rennard SI: Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med 1997, 155:1770–1776.CrossRefPubMed
26.
Numanami H, Koyama S, Nelson DK, Hoyt JC, Freels JL, Habib MP, Amano J, Haniuda M, Sato E, Robbins RA: Serine protease inhibitors modulate smoke-induced chemokine release from human lung fibroblasts. Am J Respir Cell Mol Biol 2003, 29:613–619.CrossRefPubMed
27.
Oltmanns U, Chung KF, Walters M, John M, Mitchell JA: Cigarette smoke induces IL-8, but inhibits eotaxin and RANTES release from airway smooth muscle. Respir Res 2005, 6:74.CrossRefPubMedPubMedCentral
28.
Oltmanns U, Walters M, Sukkar M, Xie S, Issa R, Mitchell J, Johnson M, Chung KF: Fluticasone, but not salmeterol, reduces cigarette smoke-induced production of interleukin-8 in human airway smooth muscle. Pulm Pharmacol Ther 2008, 21:292–297.CrossRefPubMed
29.
Pace E, Ferraro M, Siena L, Melis M, Montalbano AM, Johnson M, Bonsignore MR, Bonsignore G, Gjomarkaj M: Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells. Immunology 2008, 124:401–411.CrossRefPubMedPubMedCentral
30.
Koyama S, Sato E, Nomura H, Kubo K, Miura M, Yamashita T, Nagai S, Izumi T: The potential of various lipopolysaccharides to release IL-8 and G-CSF. Am J Physiol Lung Cell Mol Physiol 2000, 278:L658-L666.PubMed
31.
Shan X, Hu A, Veler H, Fatma S, Grunstein JS, Chuang S, Grunstein MM: Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling. Am J Physiol Lung Cell Mol Physiol 2006, 291:L324-L333.CrossRefPubMed
32.
Sukkar MB, Xie S, Khorasani NM, Kon OM, Stanbridge R, Issa R, Chung KF: Toll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle. J Allergy Clin Immunol 2006, 118:641–648.CrossRefPubMed
33.
Gosens R, Meurs H, Bromhaar MM, McKay S, Nelemans SA, Zaagsma J: Functional characterization of serum- and growth factor-induced phenotypic changes in intact bovine tracheal smooth muscle. Br J Pharmacol 2002, 137:459–466.CrossRefPubMedPubMedCentral
34.
Dekkers BG, Schaafsma D, Nelemans SA, Zaagsma J, Meurs H: Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function. Am J Physiol Lung Cell Mol Physiol 2007, 292:L1405-L1413.CrossRefPubMed
35.
Gosens R, Schaafsma D, Meurs H, Zaagsma J, Nelemans SA: Role of Rho-kinase in maintaining airway smooth muscle contractile phenotype. Eur J Pharmacol 2004, 483:71–78.CrossRefPubMed
36.
Schaafsma D, McNeill KD, Stelmack GL, Gosens R, Baarsma HA, Dekkers BG, Frohwerk E, Penninks JM, Sharma P, Ens KM, Nelemans SA, Zaagsma J, Halayko AJ, Meurs H: Insulin increases the expression of contractile phenotypic markers in airway smooth muscle. Am J Physiol Cell Physiol 2007, 293:C429-C439.CrossRefPubMed
37.
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248–254.CrossRefPubMed
38.
Hirst SJ, Twort CH, Lee TH: Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol 2000, 23:335–344.CrossRefPubMed
39.
Coutts A, Chen G, Stephens N, Hirst S, Douglas D, Eichholtz T, Khalil N: Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen. Am J Physiol Lung Cell Mol Physiol 2001, 280:L999–1008.PubMed
40.
Panettieri RA, Tan EM, Ciocca V, Luttmann MA, Leonard TB, Hay DW: Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 1998, 19:453–461.CrossRefPubMed
41.
Lin J, Xu Y, Zhang Z, Ni W, Chen S: Effect of cigarette smoke extract on the role of protein kinase C in the proliferation of passively sensitized human airway smooth muscle cells. J Huazhong Univ Sci Technolog Med Sci 2005, 25:269–273.CrossRefPubMed
42.
Hu W, Xie J, Zhao J, Xu Y, Yang S, Ni W: Involvement of Bcl-2 Family in Apoptosis and Signal Pathways Induced by Cigarette Smoke Extract in the Human Airway Smooth Muscle Cells. DNA Cell Biol 2008,28(1):13–22.CrossRef
43.
Ishii T, Matsuse T, Igarashi H, Masuda M, Teramoto S, Ouchi Y: Tobacco smoke reduces viability in human lung fibroblasts: protective effect of glutathione S-transferase P1. Am J Physiol Lung Cell Mol Physiol 2001, 280:L1189-L1195.PubMed
44.
Slebos DJ, Ryter SW, van der TM, Liu F, Guo F, Baty CJ, Karlsson JM, Watkins SC, Kim HP, Wang X, Lee JS, Postma DS, Kauffman HF, Choi AM: Mitochondrial localization and function of heme oxygenase-1 in cigarette smoke-induced cell death. Am J Respir Cell Mol Biol 2007, 36:409–417.CrossRefPubMed
45.
van der TM, Slebos DJ, de Bruin HG, Leuvenink HG, Bakker SJ, Gans RO, Koeter GH, van Oosterhout AJ, Kauffman HF: Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis. Am J Physiol Lung Cell Mol Physiol 2007, 292:L1211-L1218.CrossRef
46.
Akira S, Takeda K, Kaisho T: Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001, 2:675–680.CrossRefPubMed
47.
Michel O, Nagy AM, Schroeven M, Duchateau J, Neve J, Fondu P, Sergysels R: Dose-response relationship to inhaled endotoxin in normal subjects. Am J Respir Crit Care Med 1997, 156:1157–1164.CrossRefPubMed
48.
Zwan JC, Orie NG, Kauffman HF, Wiers PW, de VK: Bronchial obstructive reactions after inhalation with endotoxin and precipitinogens of Haemophilus influenzae in patients with chronic non-specific lung disease. Clin Allergy 1982, 12:547–559.CrossRefPubMed
49.
Wang XR, Zhang HX, Sun BX, Dai HL, Hang JQ, Eisen EA, Wegman DH, Olenchock SA, Christiani DC: A 20-year follow-up study on chronic respiratory effects of exposure to cotton dust. Eur Respir J 2005, 26:881–886.CrossRefPubMed
50.
Michel O, Kips J, Duchateau J, Vertongen F, Robert L, Collet H, Pauwels R, Sergysels R: Severity of asthma is related to endotoxin in house dust. Am J Respir Crit Care Med 1996, 154:1641–1646.CrossRefPubMed
51.
Hackett TL, Holloway R, Holgate ST, Warner JA: Dynamics of pro-inflammatory and anti-inflammatory cytokine release during acute inflammation in chronic obstructive pulmonary disease: an ex vivo study. Respir Res 2008, 9:47.CrossRefPubMedPubMedCentral
52.
Patel IS, Seemungal TA, Wilks M, Lloyd-Owen SJ, Donaldson GC, Wedzicha JA: Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax 2002, 57:759–764.CrossRefPubMedPubMedCentral
53.
Wilkinson TM, Hurst JR, Perera WR, Wilks M, Donaldson GC, Wedzicha JA: Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD. Chest 2006, 129:317–324.CrossRefPubMed
54.
Toward TJ, Broadley KJ: Airway reactivity, inflammatory cell influx and nitric oxide in guinea-pig airways after lipopolysaccharide inhalation. Br J Pharmacol 2000, 131:271–281.CrossRefPubMedPubMedCentral
55.
Karimi K, Sarir H, Mortaz E, Smit JJ, Hosseini H, De Kimpe SJ, Nijkamp FP, Folkerts G: Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Respir Res 2006, 7:66.CrossRefPubMedPubMedCentral
56.
Halayko AJ, Tran T, Gosens R: Phenotype and functional plasticity of airway smooth muscle: role of caveolae and caveolins. Proc Am Thorac Soc 2008, 5:80–88.CrossRefPubMed
57.
Halayko AJ, Salari H, MA X, Stephens NL: Markers of airway smooth muscle cell phenotype. Am J Physiol 1996, 270:L1040-L1051.PubMed
58.
Halayko AJ, Solway J: Molecular mechanisms of phenotypic plasticity in smooth muscle cells. J Appl Physiol 2001, 90:358–368.PubMed
59.
Gosens R, Nelemans SA, Grootte Bromhaar MM, McKay S, Zaagsma J, Meurs H: Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. Am J Respir Cell Mol Biol 2003, 28:257–262.CrossRefPubMed
60.
Ammit AJ, Panettieri RA Jr: Invited review: the circle of life: cell cycle regulation in airway smooth muscle. J Appl Physiol 2001, 91:1431–1437.PubMed
61.
Ramakrishnan M, Musa NL, Li J, Liu PT, Pestell RG, Hershenson MB: Catalytic activation of extracellular signal-regulated kinases induces cyclin D1 expression in primary tracheal myocytes. Am J Respir Cell Mol Biol 1998, 18:736–740.CrossRefPubMed
62.
Orsini MJ, Krymskaya VP, Eszterhas AJ, Benovic JL, Panettieri RA Jr, Penn RB: MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation. Am J Physiol 1999, 277:L479-L488.PubMed
63.
Lee JH, Johnson PR, Roth M, Hunt NH, Black JL: ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2001, 280:L1019-L1029.PubMed
64.
Karpova AY, Abe MK, Li J, Liu PT, Rhee JM, Kuo WL, Hershenson MB: MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal myocytes. Am J Physiol 1997, 272:L558-L565.PubMed
65.
Fernandes DJ, Ravenhall CE, Harris T, Tran T, Vlahos R, Stewart AG: Contribution of the p38 MAPK signalling pathway to proliferation in human cultured airway smooth muscle cells is mitogen-specific. Br J Pharmacol 2004, 142:1182–1190.CrossRefPubMedPubMedCentral
66.
Zhai W, Eynott PR, Oltmanns U, Leung SY, Chung KF: Mitogen-activated protein kinase signalling pathways in IL-1 beta-dependent rat airway smooth muscle proliferation. Br J Pharmacol 2004, 143:1042–1049.CrossRefPubMedPubMedCentral
67.
68.
Vlahos R, Lee KS, Guida E, Fernandes DJ, Wilson JW, Stewart AG: Differential inhibition of thrombin- and EGF-stimulated human cultured airway smooth muscle proliferation by glucocorticoids. Pulm Pharmacol Ther 2003, 16:171–180.CrossRefPubMed
69.
Cheng SE, Luo SF, Jou MJ, Lin CC, Kou YR, Lee IT, Hsieh HL, Yang CM: Cigarette smoke extract induces cytosolic phospholipase A2 expression via NADPH oxidase, MAPKs, AP-1, and NF-kappaB in human tracheal smooth muscle cells. Free Radic Biol Med 2009, 46:948–960.CrossRefPubMed
70.
Sturrock A, Huecksteadt TP, Norman K, Sanders K, Murphy TM, Chitano P, Wilson K, Hoidal JR, Kennedy TP: Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2007, 292:L1543-L1555.CrossRefPubMed
71.
Lin WN, Luo SF, Lee CW, Wang CC, Wang JS, Yang CM: Involvement of MAPKs and NF-kappaB in LPS-induced VCAM-1 expression in human tracheal smooth muscle cells. Cell Signal 2007, 19:1258–1267.CrossRefPubMed
Metadata
Title
Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype
Authors
Tonio Pera
Reinoud Gosens
Andries H Lesterhuis
Riham Sami
Marco van der Toorn
Johan Zaagsma
Herman Meurs
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2010
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-11-48

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