The effect of alpha linolenic acid on tracheal responsiveness, lung inflammation and immune markers in sensitized rats

Document Type : Original Article


1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Iran

3 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): The effects of alpha linolenic acid (ALA) on tracheal responsiveness (TR), total protein (TP), phospholipase A2 (PLA2), immunoglobulin E (IgE), interleukin 4 (IL-4), interferon gamma (INF-γ) level and INF-γ/IL4 ratio in bronchoalveolar lavage fluid (BALF) of sensitized rats were examined.
Materials and Methods: TR to methacholine and ovalbumin (OA), BALF levels of TP, PLA2 and IgE as well as IL-4, INF-γ and INF-γ/IL4 ratio were measured in control group (non-sensitized, group C), sensitized rats to OA (group S), S groups treated with two concentrations of ALA and dexamethasone group.
Results: TR to methacholine and OA, BALF levels of TP, PLA2, IgE and IL-4 were significantly increased but BALF level of INF-γ and INF-γ/IL4 ratio decreased in group S compared to group C (PConclusion: Results showed an immune modulatory effect of the ALA that increased INF-γ, INF-γ/IL4 ratio (as an index of Th1/Th2) and decreased IL-4 in sensitized rats. ALA also showed preventive effect on inflammatory markers and tracheal responsiveness in sensitized animals comparable to the effect of dexamethasone.


Main Subjects

1.Barbato A, Turato G, Baraldo S, Bazzan E, Calabrese F, Tura M, et al. Airway inflammation in childhood asthma. Am J Respir Crit Care Med 2003; 168:798–803.
2.Boulet LP. Physiopathology of airway hyperresponsiveness. Curr Allergy Asthma Rep 2003; 3:166–171.
3.Brannan JD, Lougheed MD. Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment. Front Physiol 2012; 3:1-11.
4.Vadas P, Pruzanski W. Role of secretory phospholipase A2 in the pathology of disease. Lab Invest 1986; 55:391-404.
5.Kashima N, Nakajima H, Katsura T, Sugihara S, Fukaura A, Takahashi T. Study of serum phosholipase A2 activity in bronchial asthmatic patients. Arerugi 1993; 42:723-727.
6.Qureshi S, Memon SA, Laghari AJ, Ghanghro AB. Metabolic total protein investigation in local industry workers exposed to acid anhydrids. Sindh Univ Res J 2009; 41:63-66.
7.Kelly C, Ward C, Stenton CS, Bird G, Hendrick DJ, Walters EH. Numbers and activity of cells obtained at bronchoalveolar lavage in asthma, and their relationship to airway responsiveness. Thorax 1998; 43:684–692.
8.Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 2004; 22:789–815.
9.Randolph DA, Stephens R, Carruthers CJLD. Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation. J Clin Invest 1999; 104:1021–1029.
10.Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007; 56: 641–648.
11.Busse WW, Coffman RL, Gelfand EW, Kay AB, Rosenwasser LJ. Mechanisms of persistent airway inflammation in asthma: a role for T cells and T-cell products. Am J Respir Crit Care Med 1995; 152:388–393.
12.Ren J, Chung SH. Anti-inflammatory effect of α-linolenic acid and its mode of action through the inhibition of nitric oxide production and inducible nitric oxide synthase gene expression via NF-κB and mitogen-activated protein kinase pathways. J Agric Food Chem 2007; 55:5073–5080.
13.Anand R, Kaithwas G. Anti-inflammatory potential of alpha-linolenic acid mediated through selective COX inhibition: computational and experimental data. Inflammation 2014; 37: 1297-1306.
14.Erdinest N, Shmueli O, Grossman Y, Ovadia H, Solomon A. Anti-inflammatory effects of alpha linolenic acid on human corneal epithelial cells. Invest Ophthalmol Vis Sci 2012; 53: 4396-4406.
15.Wendell SG, Baffi C, Holguin F. Fatty acids, inflammation and asthma. J Allergy Clin Immunol 2014; 133:1255–1264.
16.Kaithwas G, Mukherjee A, Chaurasia AK, Majumdar DK. Anti-inflammatory, analgesic and antipyretic activities of Linum usitatissimum L. (flaxseed/linseed) fixed oil. Indian J Exp Biol 2011; 49:932-938.
17.Francès H, Coudereau JP, Sandouk P, Clément M, Monier C, Bourre JM. Influence of a dietary alpha-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine. Eur J Pharmacol 1996; 18; 298:217-225.
18.Huang CB, Ebersole JL. A novel bioactivity of omega-3 polyunsaturated fatty acids and their ester derivatives. Mol Oral Microbiol 2010; 25:75-80.
19.Lee JY, Kim YS, Shin DH. Antimicrobial synergistic effect of linolenic acid and monoglyceride against Bacillus cereus and Staphylococcus aureus. J Agric Food Chem 2002; 50:2193-2199.
20.Dhar P, Chattopadhyay K, Bhattacharyya D, Roychoudhury A, Biswas A, Ghosh S. Antioxidative effect of conjugated linolenic acid in diabetic and non-diabetic blood: an in vitro study. J Oleo Sci 2006; 56:19-24.
21.Simopoulos AP. Omega-3 fatty acids and antioxidants in edible wild plants. Biol Res 2004; 37:263-277.
22.Blondeau N, Lipsky RH, Bourourou M, Duncan MW, Gorelick PB, Marini AM. Alpha-linolenic acid: an omega-3 fatty acid with neuroprotective properties—ready for use in the stroke clinic? Biomed Res Int 2015; 2015:1-8.
23.Pan H, Hu XZ, Jacobowitz DM, Chen C, McDonough J, Van Shura K, et al. Alpha-linolenic acid is a potent neuroprotective agent against soman-induced neuropathology. Neurotoxicology 2012; 33:1219-1229.
24.Pan H, Piermartiri TC, Chen J, McDonough J, Oppel C, Driwech W, et al. Repeated systemic administration of the nutraceutical alpha-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure. Neurotoxicology 2015; 51:38-50.
25.Jeromson S, Gallagher IJ, Galloway SDR, Hamilton DL. Omega-3 fatty acids and skeletal muscle health. Mar Drugs 2015; 13:6977–7004.
26.Cornish SM, Chilibeck PD. Alpha-linolenic acid supplementation and resistance training in older adults. Appl Physiol Nutr Metab 2009; 34:49-59.
27.Mizota T, Fujita-Kambara C, Matsuya N, Hamasaki S, Fukudome T, Goto H, et al. Effect of dietary fatty acid composition on Th1/Th2 polarization in lymphocytes. JPEN J Parenter Enteral Nutr 2009; 33:390-396.
28.Kankaanpää P, Sütas Y, Salminen S, Lichtenstein A, Isolauri E. Dietary fatty acids and allergy. Ann Med 1999; 31:282-287.
29.Salmon M, Walsh D, Huang T, Barnes P, Leonard T, Hay D, et al. Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats. Br J Pharmacol 1999; 127:1151-1158.
30.Kaveh M, Akram E, Nemati A, Boskabady MH. The extract of Portulaca oleracea and its constituent, alpha linolenic acid affects serum oxidantlevels and inflammatory cells in sensitized rats.  Iran J Allergy Asthma Immunol 2017; 16:256-270.
31.Kianmeher M, Ghorani V, Boskabady MH. Animal model of asthma, various methods and measured parameters: a methodological review. Iran J Allergy Asthma Immunol 2017; 15:445-65.
32.Shakeri F, Soukhtanloo M, Boskabady MH. The effect of hydro-ethanolic extract of Curcuma longa rhizome and curcumin on total and differential WBC and serum oxidant, antioxidant biomarkers in rat model of asthma. Iran J Basic Med Sci 2017; 20:155-165.
33.Boskabady MH, Bayrami G. The effect of safranal on tracheal responsiveness and white blood cells count in lung lavage of sensitized guinea-pigs. Pharmacol Rep 2014; 66: 56–61.
34.Shakeri F, Boskabady MH. Anti-inflammatory, antioxidant and immunomodulatory effects of curcumin in ovalbumin-sensitized rat. BioFactors, 217; 43:567-576.
35.Keyhanmanesh R, Boskabady MH, Khamneh S, Ebrahimi MA. The effect of thymoquinone, the main constituent of Nigella sativa on tracheal responsiveness and WBC count in lung lavage of sensitized guinea-pigs. Planta Med 2010; 76:218–222
36.Boskabady MH, Ziaei T. Effect of ascorbic acid on airway responsiveness in ovalbumin sensitized guinea pigs. Respirology 2003; 8:473-478.
37.Boskabady MH, Mehrjardi SS, Rezaee A, Rafatpanah H, jalali S. The impactof Zataria multiflora Boiss extracton in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance. J Ethnopharmacpol 2013; 150:1024-1031.
38.Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, Van Der Meer JW, et al. The effect of dietary supplementation with n—3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320:265-271.
39.Sun P, Wang J, Yang G, Khas-Erdene, Liu Q. Effects of different doses of free alpha-linolenic acid infused to the duodenum on the immune function of lactating dairy cows. Arch Anim Nutr 2010; 64:504-513.
40.Askari VR, Rezaei A, Boskabady MH, Sadeghnia H, Abnus K, Iranshahi M. The influence of hydro-ethanolic extract of Portulaca oleracea on Th1/Th2 balance in isolated human lymphocytes. J Ethnopharmacol 2016; 16:31626-31629.
41.Mickleborough TD, Rundell KW. Dietary polyunsaturated fatty acids in asthma-and exercise-induced bronchoconstriction. Eur J Clin Nutr 2005; 59:1335-1346.
42.Kelley DS, Branch LB, Love JE, Taylor PC, Rivera YM, Iacono JM. Dietary alpha-linolenic acid and immunocompetence in humans. Am J Clin Nutr 1991; 53:40-46.
43.Jeffery NM, Newsholme EA, Calder PC. Level of polyunsaturated fatty acids and the n-6 to n-3 polyunsaturated fatty acid ratio in the rat diet alter serum lipid levels and lymphocyte functions. Prostaglandins Leukot Essent Fatty Acids 1997; 57:149-160.
44.Stark AH, Crawford MA, Reifen R. Update on alpha‐linolenic acid. Nutr Rev 2008; 66:326-332.
45.Calder PC. Omega-3 polyunsaturated fatty acids, inflammation and immunity. World Rev Nutr Diet. 2001; 88:109-116.
46.Tang XY, Yu HP, Deng HJ, Chen X, Fan HZ, Gong YX, et al. Pathogenic mechanism of CD8(+) CD28(-) T cell and the effect of dexamethasone in asthmatic mouse. Zhonghua Yi Xue Za Zhi 2011; 91:1861-1865.
47.Boskabady MH, Boroushaki M, Aslani MR. Relaxant effect of Portulaca oleraceae on guinea pig tracheal chains and its possible mechanism (s) of action. Med Hypotheses Res 2004; 1:139-147.
48.Parry O, Okwuasaba F, Ejike C. Effect of an aqueous extract of Portulaca oleracea leaves on smooth muscle and rat blood pressure. J Ethnopharmacol 1988; 22:33-44.
49.Boroushaki MT, Boskabady MH, Maleka F. Antitussive effect of Portulaca oleracea L. in guinea pigs. Iran J Pharmac Res 2010; 3:187-190.
50.Malek F, Boskabady MH, Borushaki MT, Tohidi M. Bronchodilatory effect of Portulaca oleracea in airways of asthmatic patients. J Ethnopharmacol 2004; 93:57-62.
51.Boskabady MH, Hashemzehi M, Khazdair MR, Askari VR. Hydro-ethanolic extract of Portulaca oleracea affects beta-adrenoceptors of guinea pig tracheal smooth muscle. Iran J Pharm Res 2016; 15:867–874.
52.Hashemzehi M, Khazdair MR, Kiyanmehr M, Askari VR, Boskabady MH. Portulaca oleracea affects muscarinic receptors of guinea pig tracheal smooth muscle. Ind J Pharmac Scei 2016; 78:388-394.