Download PDF
Arzneimittelforschung 2011; 61(12): 685-692
DOI: 10.1055/s-0031-1300588
Antiallergic Drugs · Antiasthmatics · Antitussives · Bronchodilators · Bronchosecretogogues · Mucolytics
Editio Cantor Verlag Aulendorf (Germany)

Effect of Myrtol standardized on mucus hypersecretion and clearance of Pseudomonas aeruginosa in a rat model of chronic obstructive pulmonary disease

Lihua Cao
1   Institute of Respiratory Disease, First Affiliated Hospital, China Medical University, Shenyang, China
5   Department of Respiratory Medicine, Second Affiliated Hospital, Dalian Medical University, Dalian, China
,
Yu Chen
2   Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Shenyang, China
,
Yue Zhao
3   Department of Chromatin Cytobiology, China Medical University, Shenyang, China
,
Hongyan Zhang
4   Department of Cell Biology, China Medical University, Shenyang, China
,
Shengli Wang
3   Department of Chromatin Cytobiology, China Medical University, Shenyang, China
,
Zhenshan Wang
5   Department of Respiratory Medicine, Second Affiliated Hospital, Dalian Medical University, Dalian, China
,
Jian Kang
1   Institute of Respiratory Disease, First Affiliated Hospital, China Medical University, Shenyang, China
› Author Affiliations
Further Information

Publication History

Publication Date:
09 February 2012 (online)

    Permissions and Reprints

Abstract

This study aimed to investigate the effect of Myrtol standardized (GeloMyrtol® forte) in the treatment of chronic obstructive pulmonary disease (COPD) in an animal model. A total of 93 experimental rats were randomly divided into 6 groups: control (n = 6), exposure to cigarette smoke (CS, n = 6), CS plus Myrtol standardized treatment (CS + M, n = 6), Pseudomonas aeruginosa (PA) infection (PA, n = 25), CS + PA (n = 25), and CS + PA + M (n = 25). For all 62 CS rats, they were exposed to cigarette smoke for a period of 12 weeks. During this time period the 31 CS + M rats (CS + M; CS + PA + M) received 300 mg/kg/day Myrtol standardized intragastrically always 30 min prior to smoke exposure. For CS + PA and CS + PA + M rats, intratracheal PA inoculation was performed after the 12 weeks of smoke exposure. All intratracheal PA inoculations were followed by a post-infection examination at 6, 12, 24, 48 and 72 h in each 5 rats. All study animals were euthanized and their lungs were excised; the left lung was homogenized for determination of bacterial load and measurements of TNF-α and IL-6, the right lungs were preserved for histo- and immunohistochemical examinations (e. g. MUC5AC). The lungs from CS rats were pathologically similar to those of COPD patients with the characteristics of goblet cell metaplasia and MUC5AC hypersecretion. CS animals had a significantly greater number of MUC5AC positive cells in the bronchial epithelial cells, and significantly increased expression levels of TNF-α and IL-6 after PA infection. However, the administration of Myrtol standardized significantly (p = 0.002) attenuated MUC5AC hypersecretion, measured as integrity optical density (IOD), in CS+M rats (45.98 ± 6.25) as compared to CS alone (65.55 ± 11.18) rats. The same applies at different time points between CS + PA rats (65.15 ± 11.94, 75.88 ± 7.42, 81.2 ± 6.49, 75.14 ± 6.85 and 67.32 ± 10.61, respectively) and CS + PA + M rats (47.08 ± 4.78, 54.22 ± 6.59, 65.4 ± 6.12, 59.98 ± 4.96 and 48.43 ± 7.29, respectively). Similar effects were found in the production of IL-6 and TNF-α in the CS + PA + M lungs. Similarly the bacterial load of 10,980 ± 4,253 CFU in CS + PA + M was significantly lower compared to 42,400 ± 3,296 CFU in CS + PA lungs after 72 h PA infection. In conclusion, this experimental study demonstrates a significant therapeutic effect of Myrtol standardized in treating common pathological conditions, such as airway mucus hypersecretion and defect of mucociliary functions in COPD.

Key words

Bacterial clearance - Chronic obstructive pulmonary disease - Mucus production - Myrtol standardized - Pseudomonas aeruginosa infection
 

  • References

  • 1 Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol. 2007; 35: 116-29
    CrossrefPubMedGoogle Scholar
  • 2 Rabe KF, Beghé B, Luppi F, Fabbri LM. Update in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007; 175: 1222-32
    CrossrefPubMedGoogle Scholar
  • 3 Celli BR, MacNee W, Agusti A, Anzueto A, Berg B, Buist AS et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir. J 2004; 23: 932-46
    CrossrefPubMedGoogle Scholar
  • 4 Calverley PMA. Reducing the frequency and severity of exacerbations of chronic obstructive pulmonary disease. Proc Am Thor-ac Soc. 2004; 1: 121-4
    CrossrefPubMedGoogle Scholar
  • 5 Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomized placebo-controlled study. Lancet. 2008; 371: 2013-8
    CrossrefPubMedGoogle Scholar
  • 6 Meister R, Wittig T, Beuscher N, de Mey C. Efficacy and tolerability of Myrtol standardized in long-term treatment of chronic bronchitis: a double-blind, placebo-controlled study. Arzneimittelforschung. 1999; 49 (4) 351-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Behrbohm H, Kaschke O, Sydow K. Effect of the phytogenic secretolytic drug Gelomyrtol forte on mucociliary clearance of the maxillary sinus. Laryngo Rhino Otol. 1995; 74 (12) 733-7
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Wittig T Myrtol standardized – A Clinical Documentation. Ergebnisse Verlag; 2005 1st ed.; 22-26
    PubMed
  • 9 Juergens UR, Engelen T, Racké K, Stöber M, Gillissen A, Vetter H. Inhibitory activity of 1,8-cineol (eucalyptol) on cytokine production in cultured human lymphocytes and monocytes. Pulm Pharmacol Ther. 2004; 17 (5) 281-7
    CrossrefPubMedGoogle Scholar
  • 10 Beuscher N, Kietzmann M, Bien E, Champeroux P. Interference of Myrtol standardized with inflammatory and allergic mediators. Arzneimittelforschung. 1998; 48 (1) 985-9
    PubMedGoogle Scholar
  • 11 Anbarasi K, Vani G, Balakrishna K, Devi CS. Creatine kinase isoenzyme patterns upon chronic exposure to cigarette smoke: protective effect of Bacoside A. Vascul Pharmacol. 2005; 42 (2) 57-61
    CrossrefPubMedGoogle Scholar
  • 12 Swords WE, Buscher BA, Ver Steeg Ii K, Preston A, Nichols WA, Weiser JN et al. Non-typeable Haemophilus influenzae adhere to and invade human bronchial epithelial cells via an interaction of lipooligosaccharide with the PAF receptor. Mol Microbiol. 2000; 37 (l) 13-27
    CrossrefPubMedGoogle Scholar
  • 13 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 (l) 152-9
    PubMedGoogle Scholar
  • 14 Francisco JS, Moraes HP, Dias EP. Evaluation of the Image-Pro Plus 4.5 software for automatic counting of labeled nuclei by PCNA immunohistochemistry. Braz Oral Res. 2004; 18 (2) 100-4
    CrossrefPubMedGoogle Scholar
  • 15 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) method. Methods. 2001; 25: 402-8
    CrossrefPubMedGoogle Scholar
  • 16 Houtmeyers E, Gosselink R, Gayan-Ramirez G, Decramer M. Regulation of mucociliary clearance in health and disease. Eur Respir J. 1999; 13: 1177-88
    CrossrefPubMedGoogle Scholar
  • 17 Szilasi M, Dolinay T, Nemes Z, Strausz J. Pathology of chronic obstructive pulmonary disease. Pathol Oncol Res. 2006; 12: 52-60
    CrossrefPubMedGoogle Scholar
  • 18 Verra F, Escudier E, Lebargy F, Bernaudin JF, De Crémoux H, Bignon J. Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers. Am J Respir Crit Care Med. 1995; 151 (3) 630-4
    PubMedGoogle Scholar
  • 19 Zuhdi Alimam M, Piazza FM, Selby DM, Letwin N, Huang L, Rose MC. Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol. 2000; 22 (3) 253-60
    PubMedGoogle Scholar
  • 20 Kodavanti UP, Jackson MC, Ledbetter AD, Starcher BC, Evansky PA, Harewood A et al. The combination of elastase and sulfur dioxide exposure causes COPD-like lesions in the rat. Chest. 2000; 117 (5 Suppl 1) 299S-302S
    CrossrefPubMedGoogle Scholar
  • 21 Ha U, Lim JH, Jono H, Koga T, Srivastava A, Malley R et al. A novel role for Ikappa B kinase (IKK) alpha and IKK beta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. J Immunol. 2007; 178 (3) 1736-47
    PubMedGoogle Scholar
  • 22 Ozlü T, Cay M, Akbulut A, Yekeler H, Naziroglu M, Aksakal M. The facilitating effect of cigarette smoke on the colonization of instilled bacteria into the tracheal lumen in rats and the improving influence of supplementary vitamin E on this process. Respirology. 1999; 4 (3) 245-8
    CrossrefPubMedGoogle Scholar
  • 23 Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002; 2 (5) 372-7
    CrossrefPubMedGoogle Scholar
  • 24 Wedzicha JA. Airway infection accelerates decline of lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001; 164 (10) 1757-8
    PubMedGoogle Scholar
  • 25 Niederman MS. Introduction: COPD-the role of infection. Chest. 1997; 112: 301S-302S
    CrossrefPubMedGoogle Scholar
  • 26 Drannik AG, Pouladi MA, Robbins CS, Goncharova SI, Kianpour S, Stämpfli MR. Impact of cigarette smoke on clearance and inflammation after Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2004; 170 (11) 1164-71
    CrossrefPubMedGoogle Scholar
  • 27 Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003; 168 (8) 918-51
    CrossrefPubMedGoogle Scholar
  • 28 Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 2002; 347 (7) 465-71
    CrossrefPubMedGoogle Scholar
  • 29 Groenewegen KH, Wouters EF. Bacterial infections in patients requiring admission for an acute exacerbation of COPD: a 1-year prospective study. Respir Med. 2003; 97 (7) 770-7
    CrossrefPubMedGoogle Scholar
  • 30 Ramphal R, Arora SK. Recognition of mucin components by Pseudomonas aeruginosa. Glycoconjugate J. 2001; 18 (9) 709-13
    CrossrefPubMedGoogle Scholar
  • 31 Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006; 86 (l) 245-78
    CrossrefPubMedGoogle Scholar
  • 32 Busse PJ, Zhang TF, Srivastava K, Lin BP, Schofield B, Sealfon SC, Li XM. Chronic exposure to TNF-alpha increases airway mucus gene expression in vivo. J Allergy Clin Immunol. 2005; 116 (6) 1256-63
    PubMed
  • 33 Baginski TK, Dabbagh K, Satjawatcharaphong C, Swinney DC. Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli. Am J Respir Cell Mol Biol. 2006; 35 (2) 165-74
    CrossrefPubMedGoogle Scholar