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Research Article

Effect of Moringa oleifera Lam. Seed Extract on Toluene Diisocyanate-Induced Immune-Mediated Inflammatory Responses in Rats

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Pages 85-96 | Received 15 Nov 2006, Accepted 09 Feb 2007, Published online: 09 Oct 2008

REFERENCES

  • Abe Y., Ogino S., Irifune M., Imamura I., Liu Y. Q., Fukui H., Matsunaga T. Histamine content, synthesis and degradation in nasal mucosa and lung of guinea pigs treated with toluene diisocyanate (TDI). Clin. Exp. Allergy 1993; 23: 512–517
  • Arts I. C., Hollman P. C. Polyphenols and disease risk in epidemiologic studies. Am. J. Clin Nutr. 2005; 81: 317S–325S
  • Ban M., Morel G., Langonne I., Huguet N., Pepsin E., Binet S. TDI can induce repiratory allergy with TH2-dominated response in mice. Toxicology 2006; 218: 39–47
  • Ban M., Hettich D., Goutet M., Bonnet P. TDI inhalation in guinea-pigs involves migration of dendritic cells. Toxicol. Lett. 1997; 93: 185–194
  • Barnes P. J. Pathophysiology of asthma. Br. J. Clin. Pharmacol. 1996; 42: 3–10
  • Barnes P. J., Chung K. F., Page C. P. Inflammatory mediators of asthma. Pharmacol. Rev. 1998; 50: 515–596
  • Baur X., Mareck W., Ammon J., Czuppon A. B., Marczynski B., Raulf-Heimsoth M., Roemmelt H., Fruhman G. Respiratory and other hazards of isocyanates. Int. Arch. Occup. Environ. Health. 1994; 66: 141–152
  • Becklake M. R. Prevalence and determinants. Asthma in the workplace, 1st Edition, I. L. Bernstein, M. Chan-Yeung, J. L. Malo, D. I. Bernstein. Marcel Dekker, New York 1993; 29–59
  • Bernstein J. A. Occupational asthma. “My job is making me sick”. Postgrad Med. 1992; 92: 109–118
  • Bernstein L. Isocyanate-induced pulmonary diseases: A current perspective. J. Allergy Clin. Immunol. 1982; 70: 24–35
  • Bolognesi C., Baur X., Marczynski B., Norppa H., Sepai O., Sabbioni G. Carcinogenic risk of toluene diisocyanate and 4,4′-methylenediphenyl diisocyanate: Epidemiological and experimental evedence. CRC Crit. Rev. Toxicol. 2001; 131: 737–772
  • Bousquet J., Jeffery P. K., Busse W. W., Johnson M., Vignola A. M. Asthma: From bronchoconstriction to airways inflammation and remodeling. Am. J. Respir. Crit. Care. Med. 2000; 161: 1720–1745
  • Bradding P., Roberts J. A., Britten K. M., Montefort S., Djukanovic R., Mueller R., Heusser C. H., Howarth P. H., Holgate S. T. Interleukins-4, -5 and -6, and tumor necrosis factor-α in normal and asthmatic airways: Evidence for the human mast cell as a source of these cytokines. Am. J. Respir. Cell Mol. Biol. 1994; 10: 471–480
  • Britton J. R., Pavord I. D., Richards K. A., Knox A. J., Wisniewski A. F., Lewis S. A. Dietary antioxidant vitamin intake and lung function in the general population. Am. J. Respir. Crit. Care Med. 1995; 151: 1383–1387
  • Broide D. H., Firestein G. S. Endobronchial allergen challenge: Demonstration of cellular source of granulocyte macrophage colony-stimulating factor by in situ hybridization. J. Clin. Invest. 1991; 88: 1048–1053
  • Broide D. H., Lotz M., Cuomo A. J., Coburn D. A., Federman E. C., Wasserman S. I. Cytokines in symptomatic asthma airways. J. Allergy Clin. Immunol. 1992; 89: 958–967
  • Caceres A., Cebreva O., Morales O., Miollined P., Mendia P. Pharmacological properties of M. oleifera 1. Preliminary screening for antimicrobial activity. J. Ethnopharmacol. 1991; 33: 213–216
  • Caceres A., Saravia A., Rizzo S., Zabala L., De-Leon E., Nave F. Pharmacological properties of M. oleifera 2. Screening for antispasmodic, anti-inflammatory and diuretic activity. J. Ethnopharmacol. 1992; 36: 233–237
  • Chan-Yeung M., Malo J. L. Natural history of occupational asthma. Asthma in the Workplace, 1st Edition, I. L. Bernstein, M. Chan-Yeung, J. L. Malo, D. I. Bernstein. Marcel Dekker, New York 1993; 299–322
  • Chaudhri R. D. Herbal Drug Industry: A Practical Approach to Industrial Pharmacognosy, R. D. Chaudhri. Eastern Publisher, New Delhi 1996; 58–62
  • Chitravanshi V. C., Gupta P. P., Kulshrestha D. K., Kar K., Dhawan B. N. Anti-allergic activity of Solanum xanthocarpum. Ind. J. Pharmacol. 1990; 22: 23–24
  • Chopra's Indigenous Drugs of India, R. N. Chopra, I. C. Chopra, K. Handa, D. Kapur. U.N. Dhur & Sons, Calcutta 1938
  • Coker R. K., Laurent G. J. Pulmonary fibrosis: Cytokines in the balance. Eur. Respir. J. 1998; 11: 1218–1221
  • Culpitt S. V., Rogers D. F., Fenwick P. S., Shah P., De Matos C., Russell R. E. Inhibition by red wine extract, resverotrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003; 58: 942–946
  • Dahot M. U., Memon A. R. Nutritive significance of oil extracted from Moringa oleifera seeds. J. Pharm. Univ. Karachi 1985; 3: 75–80
  • Das B. R., Kurup P. A., Narasimha Rao P. L. Antibiotic principle from Moringa Pterosperma Part IX. Inhibition of transaminase by isocyanates. Ind. J. Med. Res. 1958; 46: 75–77
  • Dayrit F. M., Alcantara A. D., Villasenor I. M. The antibiotic compound and its deactivation in aqueous solution. Phil. J. Sci. 1990; 119: 23–26
  • Dearman R. J., Basketter D. A., Kimber I. Characterization of chemical allergens as a function of divergent cytokine secretion profiles induced in mice. Toxicol. Appl. Pharmacol. 1996; 138: 308–316
  • De Raeve H. R., Thunnissen F. B., Kaneko F. T., Guo F. H., Lewis M., Kavuru M. S., Secic M., Thomassen M. J., Erzurum S. C. Decreased Cu, Zn-SOD activity in asthmatic airway epithelium: Correction by inhaled corticosteroid in vivo. Am. J. Physiol. 1997; 272: L148–L154
  • Devasagayam T. P. Lipid peroxidation in rat uterus. Biochim. Biophys. Acta 1986; 876: 507–514
  • Dworski R. Oxidant stress in asthma. Thorax 2000; 55(S2)S51–S53
  • Elias J. A., Wu Y., Zheng T., Panettieri R. Cytokine and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines. Am. J. Physiol. 1997; 273: L648–L655
  • Faizi S., Siddiqui B. S., Saleem R., Siddiqui S., Aftab K., Gilani A. H. Fully acetylated carbamate and hypotensive thiocarbamate glycosides from Moringa oleifera. Phytochemistry (Oxford) 1995; 38: 957–963
  • Filipovic M., Snezana C. The role of eosinophils in asthma. Med. Biol. 2001; 8: 6–10
  • Frigas E., Loegering D. A., Gleich G. J. Cytotoxic properties of the eosinophil major basic protein on tracheal epithelium. Lab Invest. 1980; 42: 35–43
  • Gavett S. H., O'Hearn D. J., Li X., Huang S. K., Finkelman F. D., Wills K. M. Interleukin-12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and TH2 cytokine expression in mice. J. Exp. Med. 1995; 182: 1527–1536
  • Gharaee-Kermani M., Nozaki Y., Hatano K., Phan S. H. Lung interleukin-4 gene expression in a murine model of bleomycin-induced pulmonary fibrosis. Cytokine 2001; 15: 138–147
  • Gokhale A. B., Dikshit V. J., Damre A. S., Kulkarni K. R., Saraf M. N. Influence of ethanolic extract of Tephrosia purpurea Linn. on mast cells and erythrocytes membrane integrity. Ind. J. Exp. Biol. 2000; 38: 837–840
  • Gosset P., Tsicopoulos A., Wallaert B., Vannimenus C., Joseph M., Tonnel A. B., Capron A. Increased secretion by tumor necrosis factor-α and interleukin-6 by alveolar macrophages consecutive to the development of the late asthmatic reaction. J. Allergy Clin. Immunol. 1991; 88: 561–571
  • Graham D. M., Blaiss M. S. Complementary/alternative medicine in the treatment of asthma. Ann. Allergy Asthma Immunol. 2000; 85: 438–447
  • Guevara A. P., Vargas C., Sakurai H., Fujiwara Y., Hashimoto K., Maoka T., Kozuka M., Ito Y., Tokuda H., Nishino H. An antitumor promoter from Moringa oleifera Lam. Mutat. Res. 1999; 440: 181–188
  • Guyton K. Z., Liu Y., Gorospe M., Xu Q., Holbrook N. J. Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J. Biol. Chem. 1996; 271: 4138–4142
  • Hatch G. E. Asthma, inhaled oxidants, and dietary antioxidants. Am. J. Clin. Nutr. 1995; 61: 625S–630S
  • Hogberg J., Larson R. E., Kristoferon A., Orrenius S. NADPH-dependent reductase solubilised from microsomes of peroxidation and its activity. Biochem. Biophys. Res. Commun. 1974; 56: 836–842
  • Ishimitsu R., Nishimura H., Kawauchi H., Kawakita K., Yoshikai Y. Dichotomous effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang, on allergic asthma in mice. Int. Immunopharmacol. 2001; 1: 857–865
  • Janssen Y. M., Houten B., Borm P. J., Mossman B. T. Cell and tissue responses to oxidative damage. Lab. Invest. 1993; 69: 261–274
  • Jatakanon A., Uasuf C., Maziak W. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 1999; 160: 1532–1539
  • Kanazawa H., Kurihara N., Hirata K., Takeda T. The role of free radicals in airway obstruction in asthmatic patients. Chest 1991; 100: 1319–1322
  • Karadi R. V., Gadge N. B., Alagawadi K. R., Savadi R. V., Mannur V. S., Kotti B. C. Antiarthritic activity of extracts of Moringa oleifera Lam. roots. Indian Drugs 2006; 43: 543–547
  • Kinnula V. L., Crapo J. D., Raivio K. O. Biology of disease: Generation and disposal of reactive oxygen metabolites in the lung. Lab. Invest. 1995; 73: 3–19
  • Kips J. C., Tavernier J., Pauwels R. A. Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am. Rev. Respir. Dis. 1992; 145: 332–336
  • Kirtikar K. R., Basu B. D. Indian Medicinal Plants, 2nd Edition, D. Dun, B. Singh, M. P. Singh. Bishen Singh Mahendra Pal Singh, New Cannaught Place-Dehradun 1975; Vol. 1: 676–683
  • Kouadio K., Zheng K. C., Tuekpe M. K., Todoriki H., Ariizumi M. Airway inflammatory and immunological events in a rat model exposed to toluene diisocyanate. Food Chem. Toxicol. 2005; 43: 1281–1288
  • Laandrault N., Pouchert P., Ravel P., Gase F., Cros G., Teissedro P. L. Antioxidant activities phenolic level of French wines from different varieties and vintages. J. Agric. Food Chem. 2001; 49: 3341–3343
  • Lane D. J., Lane T. V. Alternative and complementary medicine for asthma. Thorax 1991; 46: 787–797
  • Li X. Y., Donaldson K., Rahman I., MacNee W. An investigation of the role of glutathione in increased epithelial permeability induced by cigarette smoke in vivo in vitro. Am. J. Respir. Crit. Care Med. 1994; 149: 1518–1525
  • Lin J. Y., Chen M. L., Chiang B. L., Lin B. F. Ganoderma tsugae supplementation alleviates bronchoalveolar inflammation in an airway sensitization and challenge mouse model. Int. Immunopharmacol. 2006; 6: 241–251
  • Louis R., Lau L. C., Bron A. O., Roldaan A. C., Radermecker M., Djukanovic R. The relationship between airway inflammation and asthma severity. Am. J. Respir. Crit. Care Med. 2000; 161: 9–16
  • Lowry O. H., Rosenbrought N. J., Farr A. L., Randall R. J. Protein measurement with the Folin-phenol reagent. J. Biol. Chem. 1951; 193: 265–275
  • Mahajan S. G., Mali R. G., Mehta A. A. Protective effect of ethanolic extract of seeds of Moringa oleifera Lam. against inflammation associated with development of arthritis in rats. J Immunotoxicol. 2007; 4: 39–47
  • Mahajan S. G., Mali R. G., Mehta A. A. Anti-anaphylactic and anti-inflammatory activity of hydroalcoholic extract of leaves of Moringa oleifera. Planta Indica 2006; 2: 9–13
  • Maestrelli P., Occari P., Turato G., Papiris S. A., Di Stefano A., Mapp C. E., Milani G. F., Fabbri L. M., Saetta M. Expression of IL-4 and IL-5 proteins in asthma induced by toluene diisocyanate (TDI). Clin. Exp. Allergy 1997; 27: 1292–1298
  • Memon G. M., Khatri L. M. Isolation and spectroscopic studies of mono-palmitic, di-oleic triglyceride from seeds of Moringa oleifera Lam. Pak. J. Sci. Ind. Res. 1987; 30: 393–395
  • Michael L., Horst K. Synthesis of active principles from the leaves of Moringa oleifera using S-pent-4-enyl thioglycosides. Carbohydr. Res. 1998; 312: 33–44
  • Misra H. P., Fridovich I. The role of superoxide anion in the auto-oxidation of epinephrine and a simple assay for superoxide dismutase. Int. Biol. Chem. 1972; 247: 3170–3175
  • Montuschi P., Collins J. V., Ciabattoni G., Lazzeri N., Corradi M., Kharitonov S. A. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 2000; 162: 1175–1177
  • Moron M. S., Defierre J. W., Mannervik B. Levels of glutathione, glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim. Biophys. Acta 1979; 582: 67–78
  • Motojima S., Frigas E., Loegering D. A., Gleich G. J. Toxicity of eosinophil cationic proteins for guinea-pig tracheal epithelium in vitro. Am. Rev. Respir. Dis. 1989; 139: 801–805
  • Indian Materia Medica, K. M. Nadkarni, A. K. Nadkarni. Popular Prakashan, Mumbai 1976; Vol. 1: 811–816
  • Nair A. M., Saraf M. N. Inhibition of antigen and compound 48/80 induced contractions of guinea pig trachea by the ethanolic extract of the leaves of Vitex negundo Linn. Ind. J. Pharmacol. 1995; 27: 230–233
  • Nayampalli S., Desai N. K., Ainapure S. S. Anti-allergic properties of Tinospora cordifolia in animal models. Ind. J. Pharmacol. 1986; 18: 250–252
  • Njoku O. U., Adikwu M. U. Investigation on some physicochemical antioxidant and toxicological properties of Moringa oleifera seed oil. Acta. Pharma. Zagr. 1997; 47: 287–290
  • Novak Z., Nemeth I., Gyurkovits K., Varga S. I., Matkovics B. Examination of the role of oxygen free radicals in bronchial asthma in childhood. Clin. Chim. Acta 1991; 201: 247–252
  • Ohkawara Y., Yamauchi K., Tanno Y., Tamura H., Outani H., Nagura H., Ohkuda K., Takishima T. Human lung mast cells and pulmonary macrophages produce tumor necrosis factor-α in sensitized lung tissue after IgE receptor triggering. Am. J. Respir. Cell Mol. Biol. 1992; 7: 385–392
  • Ohno I., Ohkawara Y., Yamauchi K., Tanno Y., Takishima T. Production of tumour necrosis factor with IgE receptor triggering from sensitized lung tissue. Am. J. Respir. Cell Mol. Biol. 1990; 3: 285–289
  • Ordonez C. L., Shaughnessy T. E., Matthay M. A., Fahy J. V. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am. J. Respir. Crit. Care. Med. 2000; 161: 1185–1190
  • Modern Methods of Plant Analysis, D. Paech, M. V. Tracey. Springer-Verlag, Berlin 1955; Vol. IV: 373–374
  • Paredi P., Kharitonov S. A., Barnes P. J. Analysis of expired air for oxidation products. Am. J. Respir. Crit. Care Med. 2002; 166: 31–37
  • Plitnick L. M., Loveless S. E., Ladics G. S., Holsapple M. P., Smialowicz R. J., Woolhiser M. R., Anderson P. K., Smith C., Selgrade M. J. Cytokine mRNA profiles for isocyanates with known and unknown potential to induce respiratory sensitization. Toxicology 2005; 207: 487–499
  • Rahman I., MacNee W. Role of oxidants/antioxidants in smoking induced lung diseases. Free Rad. Biol. Med. 1996; 21: 669–681
  • Rahman I., MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax 1998; 53: 601–612
  • Rahman I., MacNee W. Lung glutathione and oxidative stress: Implications in cigarette smoke-induced airway disease. Am. J. Physiol. 1999; 277: L1067–L1088
  • Rahman I., MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur. Respir. J. 2000; 16: 534–554
  • Rahman I., Biswas S. K., Kode A. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 2006; 533: 222–239
  • Rajan B. K. Apiculture and farm forestry in semi-acid tracts of Karnataka. My Forest. 1986; 22: 41–49
  • Robinson D. S., Hamid Q., Sun Y., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-1ike bronchoalveolar T-lymphocyte population in atopic asthma. New Engl. J. Med. 1992; 326: 298–304
  • Sanchez M. D., Lopez C. J., Rios V. High-performance liquid chromatography method to measure α- and γ -tocopherol in leaves and fresh beans from Moringa oleifera. J. Chromatogr. A 2006; 1105: 111–114
  • Sedwick J. B., Geiger K. M., Busse W. W. Superoxide generation by hypodens eosinophils from patients with asthma. Am. Rev. Respir. Dis. 1990; 142: 120–125
  • Seltzer J., Bigby B. G., Stulbarg M., Holtzman M. J., Nadel J. A., Ueki I. F., Leikauf G. D., Goetzl E. J., Boushey H. A. Ozone-induced change in bronchial reactivity to methacholine and airway inflammation in humans. J. Appl. Physiol. 1986; 60: 1321–1326
  • Sengupta A., Gupta M. P. Studies on seed fat composition of Moringacea family. Fette Seifen Anstrich. 1970; 72: 6–10
  • Sergio R. The role of lymphocytes in allergic diseases. J. Allergy Clin. Immunol. 2000; 105: 399–408
  • Shanmugasundaram K. R., Kumar S. S., Rajajee S. Excessive free radical generation in the blood of children suffer from asthma. Clin. Chim. Acta 2001; 305: 107–114
  • Singh R. K., Bhattacharya S. K., Acharya S. B. Studies on extracts of Elaeocarpus sphaericus fruits on in vitro rat mast cells. Phytomedicine 2000; 7: 205–207
  • Sinha A. K. Colorimetric assay of catalase. Anal. Biochem. 1972; 47: 389–394
  • Sur S., Crotty T. B., Kephart G. M. Sudden onset fatal asthma: A distinct clinical entity with few eosinophils and relatively more neutrophils in the airway submucosa?. Am. Rev. Respir. Dis. 1993; 148: 713–719
  • Tanaka K., Okamoto Y., Nagaya Y. A nasal allergy model developed in the guinea pig by intranasal application of 2,4-toluene diisocyanate. Int. Arch. Allergy Appl. Immunol. 1988; 85: 392–397
  • Tekin D., Ayse S. B., Mungan D., Misirligil Z., Yavuzer S. The antioxidant defense in asthma. J. Asthma 2000; 37: 59–63
  • Tripathi R. M., Das P. K. Studies on anti-asthmatic and anti-anaphylactic activity of Albizzia lebbeck. Ind. J. Pharmacol. 1977; 9: 189–194
  • Varier V. P. Indian Medicinal Plants Compendium of 500 Species, P. K. Warrier, V. P. Nambiar, C. Ramankutty. Orient Longman Ltd. 1997; Vol. 4: 58–62
  • Varshavskii B. I., Trubnikov G. V., Galaktipmpva L. P., Koreniak N. A., Koledeznaia I. L., Oberemok A. N. Oxidant-antioxidant status of patients with bronchial asthma during inhalation and system glucocorticoid therapy. Ter. Arh. 2003; 75: 21–24
  • Villasenor I. M. Bioactive metabolites from Moringa oleifera Lam. Kimika 1994; 110: 47–52
  • Villasenor I. M., Dayrit F., Lim-Sylianco C. Y. Studies on M. oleifera seeds, Part II. Thermal degradation of roasted seeds. Phil. J. Sci. 1990; 119: 33–39
  • Villasenor I. M., Lim-Sylianco C. Y., Dayrit F. Mutagens from roasted seeds of Moringa oleifera. Mutat. Res. 1989; 224: 209–212
  • Wardlaw A. J., Dunnette S., Gleich G. J., Collins J. V., Kay A. B. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma: Relationship to bronchial hyperreactivity. Am. Rev. Respir. Dis. 1988; 137: 62–69
  • Wenzel S. E., Szefler S. J., Leung D. Y. Bronchoscopic evaluation of severe asthma. Am. J. Respir Crit. Care Med. 1997; 156: 737–743
  • Wisnewski A. V., Redlich C. A. Recent developments in diisocyanate asthma. Curr. Opin. Allergy Clin. Immunol. 2001; 1: 169–175
  • Wood L. G., Gibson P. G., Garg M. L. Biomarkers of lipid peroxidation, airway inflammation, and asthma. Eur. Respir. J. 2003; 21: 177–186
  • Ying S., Humbert M., Barkans J., Corrigan C. J., Pfister R., Menz G., Larche M., Robinson D. S., Durham S. R., Kay A. B. Expression of IL-4 and IL-5 mRNA and protein product by CD41 and CD81 T-cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J. Immunol. 1997; 158: 3539–3544
  • Zheng K. C., Ariizumi M., Todoriki H., Nong D. X. Cytokine profiles in airways of rats exposed to toluene diisocyanate. J. Occup. Health 2001a; 43: 39–45
  • Zheng K. C., Nong D. X., Morioka T., Todoriki H., Arizumi M. Elevated IL-4 and IL-6 in rats sensitized with toluene diisocyanate. Ind. Health 2001b; 39: 334–339
  • Zhimmet I., Tashkin D. P. Alternative medicines for allergy and asthma. J. Allergy Clin. Immunol. 2000; 106: 603–614
  • Zhu Z., Tang W., Ray A., Wu Y., Einarsson O., Landry M. L., Gwaltney J., Elias J. A. Rhinovirus stimulation of IL-6 in vivo in vitro: Evidence for NFκ B-dependent transcriptional activation. J. Clin. Invest. 1996; 97: 421–430

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