Titanium dioxide particle – induced goblet cell hyperplasia : association with mast cells and IL-13

Respiratory Research

Kwang Chul Kim¹  Hiroko Kyono³  Soo-Ho Kim²  Hun Soo Chang²  Pyeong-Oh Yoon²  Taiyoun Rhim²  Sang-Jun Park²  Choon-Sik Park²  Chun-Mi Kang²  Mi-Hyun Ahn² 

[1] Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA;Genome Research Center for Allergy and Respiratory disease, Soonchunhyang University Hospital, Bucheon, Korea;National Institute of Industrial Health, Kawasaki, Japan

关键词: cyclophosphamide;    dexamethasone;    mast cell;    IL-13;    particle;    Muc5ac;    goblet cells;   

Others  :  1227313
DOI  :  10.1186/1465-9921-6-34

 received in 2004-08-19, accepted in 2005-04-13,  发布年份 2005

【 摘 要 】

Background

Inhalation of particles aggravates respiratory symptoms including mucus hypersecretion in patients with chronic airway disease and induces goblet cell hyperplasia (GCH) in experimental animal models. However, the underlying mechanisms remain poorly understood.

Methods

To understand this, the numbers of goblet cells, Muc5ac (+) expressing epithelial cells and IL-13 expressing mast cells were measured in the trachea of sham or TiO₂ particles – treated rats using periodic acid-Schiff, toluidine blue and immunohistochemical staining. RT-PCR for Muc-1, 2 and 5ac gene transcripts was done using RNA extracted from the trachea. Differential cell count and IL-13 levels were measured in bronchoalveolar lavage (BAL) fluid. In pretreatment groups, cyclophosphamide (CPA) or dexamethasone (DEX) was given before instillation of TiO₂. TiO₂ treatment markedly increased Muc5ac mRNA expression, and Muc5ac (+) or PAS (+) epithelial cells 48 h following treatment.

Results

The concentration of IL-13 in BAL fluids was higher in TiO₂ treated – rats when compared to those in sham rats (p < 0.05). Pretreatment with cyclophosphamide (CPA) decreased the number of neutrophils and eosinophils in BAL fluid of TiO₂ treated – rats (p < 0.05), but affected neither the percentage of PAS (+) cells, nor IL-13 levels in the BAL fluids (p > 0.05). In contrast, pretreatment with dexamethasone (DEX) diminished the percentage of PAS (+) cells and the levels of IL-13 (p < 0.05). TiO₂ treatment increased the IL-13 (+) mast cells (p < 0.05) in the trachea, which was suppressed by DEX (p < 0.05), but not by CPA pretreatment (p > 0.05). In addition there were significant correlations of IL-13 (+) rate of mast cells in the trachea with IL-13 concentration in BAL fluid (p < 0.01) and with the percentage of Muc5ac (+) cells in the sham and TiO₂ treated rats (p < 0.05).

Conclusion

In conclusion, TiO₂ instillation induces GCH and Muc5ac expression, and this process may be associated with increased production of IL-13 by mast cells.

【 授权许可】

   
2005 Ahn et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Openshaw PJ, Turner-Warwick M: Observations on sputum production in patients with variable airflow obstruction; Implications for the diagnosis of asthma and chronic bronchitis. Respir Med 1989, 83:25-31.
• [2]Thurlbeck WM, Malaka D, Murphy K: Goblet cells in the peripheral airways in chronic bronchitis. Am Rev Respir Dis 1975, 112:65-9.
• [3]Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T: Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest 1992, 101:916-21.
• [4]Pope CA, Kanner RE: Acute effects of PM10 pollution on pulmonary function of smokers with mild to moderate chronic obstructive pulmonary disease. Am Rev Respir Dis 1993, 147:1336-40.
• [5]Schwartz J, Slater D, Larson TV, Pierson WE, Koenig JQ: Particulate air pollution and hospital emergency room visits for asthma in Seattle. Am Rev Respir Dis 1993, 147:826-31.
• [6]Pagan I, Costa DL, McGee JK, Richards JH, Dye JA: Metals mimic airway epithelial injury induced by in vitro exposure to Utah Valley ambient particulate matter extracts. J Toxicol Environ Health A 2003, 66:1087-112.
• [7]Seaton A, MacNee W, Donaldson K, Godden D: Particulate air pollution and acute health effects. Lancet 1995, 345:176-8.
• [8]Li XY, Gilmour PS, Donaldson K, MacNee W: Free radical activity and pro-inflammatory effects of particulate air pollution (PM10) in vivo and in vitro. Thorax 1996, 51:1216-1222.
• [9]Becker S, Soukup JM, Gilmour MI, Devlin RB: Stimulation of human and rat alveolar macrophages by urban air particulates: effects on oxidant radical generation and cytokine production. Toxicol Appl Pharmacol 1996, 141:637-48.
• [10]Fujii T, Hayashi S, Hogg JC, Vincent R, Van Eeden SF: Particulate matter induces cytokine expression in human bronchial epithelial cells. Am J Respir Cell Mol Biol 2001, 25:265-71.
• [11]Hamilton RF Jr, Holian A, Morandi MT: A comparison of asbestos and urban particulate matter in the in vitro modification of human alveolar macrophage antigen-presenting cell function. Exp Lung Res 2004, 30:147-62.
• [12]Li N, Hao M, Phalen RF, Hinds WC, Nel AE: Particulate air pollutants and asthma, A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clinical Immunology 2003, 109:250-265.
• [13]Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Whang Y, Elias JA: Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999, 103:779-788.
• [14]Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB: Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998, 282:2261-3.
• [15]Templeton DM: Titanium. In handbook on metals in clinical and analytic chemistry. Edited by Seiler HG, Siegel A, Siegel H. New York: Marcel Dekker; 1994:627-30.
• [16]Garabrant DH, Fine LJ, Oliver C, Bernstein L, Peters JM: Abnormalities of pulmonary function and pleural disease among titanium metal production workers. Scand J Work Environ Health 1987, 13:47-51.
• [17]Schapira RM, Ghio AJ, Effros RM, Morrisey J, Almagro UA, Dawson CA, Hacker AD: Hydroxyl radical production and lung injury in the rat following silica or titanium dioxide instillation in vivo. Am J Respir Cell Mol Biol 1995, 12:220-6.
• [18]Warheit DB, Hansen JF, Yuen IS, Kelly DP, Snajdr SI, Hartsky MA: Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation. Toxicol Appl Pharmacol 1997, 145:10-22.
• [19]Nagai H, Yamaguchi S, Tanaka H, Inagaki N: Effect of some immunosuppressors on allergic bronchial inflammation and airway hyperresponsiveness in mice. Int Arch Allergy Immunol 1995, 108:189-95.
• [20]Fushimi T, Okayama H, Shimura S, Saitoh H, Shirato K: Dexamethasone suppresses gene expression and production of IL-13 by human mast cell line and lung mast cells. J Allergy Clin Immunol 1998, 102:134-42.
• [21]Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987, 162:156-9.
• [22]Harkema JR, Hotchkiss JA: In vivo effects of endotoxin on intraepithelial mucosubstances in rat pulmonary airways. Quantitative histochemistry. Am J Pathol 1992, 141:307-17.
• [23]Cardozo C, Padilla ML, Choi HS, Lesser M: Goblet cell hyperplasia in large intrapulmonary airways after intratracheal injection of cathepsin B into hamsters. Am Rev Respir Dis 1992, 145:675-679.
• [24]Kibe A, Inoue H, Fukurama S, Machida K, Matsumoto K, Koto H, Ikegami T, Aizawa H, Hara N: Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyprresponsiveness, and goblet cell hyperplasia in mouse airways. Am J Respir Crit Care Med 2003, 167:50-56.
• [25]Dabbagh K, Takeyama K, Lee HM, Ueki IF, Lausier JA, Nadel JA: IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol 1999, 162:6233-7.
• [26]Ordonez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, Zhang Y, Novikov A, Dolganov G, Fahy JV: Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med 2001, 163:517-523.
• [27]Lucey EC, Stone PJ, Breuer R, Christensen TG, Calore JD, Catanese A, Franzblau C, Snider GL: Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes. Am Rev Respir Dis 1985, 132:362-6.
• [28]Townsend MJ, Fallon PG, Matthews DJ, Smith P, Jolin HE, McKenzie ANJ: IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 2000, 13:573-583.
• [29]Shim JJ, Dabbagh K, Ueki IF, Dao-Pick T, Burgel PR, Takeyama K, Tam DC, Nadel JA: IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol 2001, 280:L134-40.
• [30]Singer M, Lefort J, Vargaftig BB: Granulocyte depletion and dexamethasone differentially modulate airways hyperreactivity, inflammation, mucus accumulation, and secretion induced by rmIL-13 or antigen. Am J Respir Cell Mol Biol 2002, 26:74-84.
• [31]Lee HM, Takeyama K, Dabbagh K, Lausier JA, Ueki IF, Nadel JA: Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways. Am J Physiol Lung Cell Mol Physiol 2000, 278:L185-92.
• [32]Mathur M, Herrmann K, Li X, Qin Y, Weinstock J, Elliott D, Monahan J, Padrid P: TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma. Am J Respir Crit Care Med 1999, 159:580-7.
• [33]Cohn L, Homer RJ, MacLeod H, Mohrs M, Brombacher F, Bottomly K: Th2-induced airway mucus production is dependent on IL-4Ralpha, but not on eosinophils. J Immunol 1999, 162:6178-83.
• [34]Whittaker L, Niu N, Temann UA, Stoddard A, Flavell RA, Ray A, Homer RJ, Cohn L: Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 cells and interleukin-9. Am J Respir Cell Mol Biol 2002, 27:593-602.
• [35]Eum SY, Maghni K, Hamid Q, Eidelman DH, Campbell H, Isogai S, Martin JG: Inhibition of allergic airways inflammation and airway hyperresponsiveness in mice by dexamethasone : Role of eosinophils, IL-5, eotaxin, and IL-13. J Allergy Clin Immunol 2003, 111:1049-61.
• [36]Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT: Interleukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002, 282:L226-36.
• [37]Zhou Y, Dong Q, Louahed J, Dragwa C, Savio D, Huang M, Weiss C, Tomer Y, McLane MP, Nicolaides NC, Levitt RC: Characterization of a calcium-activated chloride channel as a shared target of Th2 cytokine pathways and its potential involvement in asthma. Am J Respir Cell Mol Biol 2001, 25:486-91.
• [38]Wills-Karp M, Chiaramonte M: Interleukin-13 in asthma. Curr Opin Pulm Med 2003, 9:21-7.
• [39]Burd PR, Thompson WC, Max EE, Mills FC: Activated mast cells produce interleukin 13. J Exp Med 1995, 181:1373-80.
• [40]Hancock A, Lynne Armstrong , Rafael Gama , Ann Millar : Production of Interleukin 13 by alveolar macrophages from normal and fibrotic lung. Am J Respir Cell Mol Biol 1998, 18:60-65.