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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

General Research Article

Biochanin A Ameliorates Ovalbumin-induced Airway Inflammation through Peroxisome Proliferator-Activated Receptor-Gamma in a Mouse Model

Author(s): Madhavi Derangula, Kalpana Panati and Venkata R. Narala*

Volume 21, Issue 1, 2021

Published on: 03 May, 2020

Page: [145 - 155] Pages: 11

DOI: 10.2174/1871530320666200503051609

Price: $65

Abstract

Objective: Asthma is an inflammatory airway disease affecting most of the population in the world. The current medication for asthma relieves airway inflammation but it has serious adverse effects. Biochanin A (BCA), a phytoestrogen, is an active component present in red clover, alfalfa, soy having anti-oxidant and anti-inflammatory properties. BCA was identified as a natural activator of peroxisome proliferator-activated receptor-gamma (PPARγ).

Methods: The study aims to evaluate the effects of BCA in ovalbumin (OVA)-induced murine model of asthma and to study the role of PPARγ.

Results: We found that BCA administration reduced the severity of murine allergic asthma as evidenced histologically, and measurement of allergen-specific IgE levels in serum as well as in BAL fluid. BCA also reversed the elevated levels of inflammatory cytokines, cell infiltration, protein leakage into the airways and expression of hemoxygenase-1 in OVA-induced lungs. Further, we confirmed that BCA mediated inhibitory effects are mediated through PPARγ as assessed by treatment with PPARγ antagonist GW9662.

Conclusion: Our results suggest that BCA is efficacious in a preclinical model of asthma and may have the potential for the treatment of asthma in humans.

Keywords: Allergic airway disease, biochanin A, IgE, inflammation, isoflavones, PPARγ.

Graphical Abstract
[1]
Mims, J.W. Asthma: definitions and pathophysiology, International forum of allergy & rhinology In: Wiley Online Library; S2-S6., 2015; pp.
[2]
Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol., 1999, 17(1), 255-281.
[http://dx.doi.org/10.1146/annurev.immunol.17.1.255] [PMID: 10358759]
[3]
Bousquet, J.; Chanez, P.; Lacoste, J.Y.; Barnéon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P. Eosinophilic inflammation in asthma. N. Engl. J. Med., 1990, 323(15), 1033-1039.
[http://dx.doi.org/10.1056/NEJM199010113231505] [PMID: 2215562]
[4]
Sears, M.R.; Lötvall, J. Past, present and future--β2-adrenoceptor agonists in asthma management. Respir. Med., 2005, 99(2), 152-170.
[http://dx.doi.org/10.1016/j.rmed.2004.07.003] [PMID: 15715182]
[5]
Shukla, D.; Chakraborty, S.; Singh, S.; Mishra, B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin. Pharmacother., 2009, 10(14), 2343-2356.
[http://dx.doi.org/10.1517/14656560903200667] [PMID: 19678793]
[6]
Drazen, J.M.; Israel, E.; O’Byrne, P.M. Treatment of asthma with drugs modifying the leukotriene pathway. N. Engl. J. Med., 1999, 340(3), 197-206.
[http://dx.doi.org/10.1056/NEJM199901213400306] [PMID: 9895400]
[7]
Rowe, B. H.; Spooner, C.; Ducharme, F.; Bretzlaff, J.; Bota, G. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst. Rev., 2001, (1)
[http://dx.doi.org/10.1002/14651858.CD002178]
[8]
Bianco, S. Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation; Google Patents, 2000.
[9]
Hanania, N.A.; Chapman, K.R.; Kesten, S. Adverse effects of inhaled corticosteroids. Am. J. Med., 1995, 98(2), 196-208.
[http://dx.doi.org/10.1016/S0002-9343(99)80404-5] [PMID: 7847437]
[10]
Dahl, R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir. Med., 2006, 100(8), 1307-1317.
[http://dx.doi.org/10.1016/j.rmed.2005.11.020] [PMID: 16412623]
[11]
Gibbons, S. An overview of plant extracts as potential therapeutics. Expert Opin. Ther. Pat., 2003, 13(4), 489-497.
[http://dx.doi.org/10.1517/13543776.13.4.489]
[12]
Pope, G.S.; Elcoate, P.; Simpson, S. Isolation of an oestrogenic isoflavone (biochanin A) from red clover. Chem. Indistry and Industry, 1953, 41.
[13]
Ingham, J.L. Isolation and identification of Cicer isoflavonoids. Biochem. Syst. Ecol., 1981, 9(2-3), 125-128.
[http://dx.doi.org/10.1016/0305-1978(81)90030-2]
[14]
Zhao, S.; Zhang, L.; Gao, P.; Shao, Z. Isolation and characterisation of the isoflavones from sprouted chickpea seeds. Food Chem., 2009, 114(3), 869-873.
[http://dx.doi.org/10.1016/j.foodchem.2008.10.026]
[15]
Sartorelli, P.; Carvalho, C.S.; Reimão, J.Q.; Ferreira, M.J.P.; Tempone, A.G. Antiparasitic activity of biochanin A, an isolated isoflavone from fruits of Cassia fistula (Leguminosae). Parasitol. Res., 2009, 104(2), 311-314.
[http://dx.doi.org/10.1007/s00436-008-1193-z] [PMID: 18810492]
[16]
Raheja, S.; Girdhar, A.; Lather, V.; Pandita, D.; Biochanin, A. A phytoestrogen with therapeutic potential. Trends Food Sci. Technol., 2018, 79, 55-66.
[http://dx.doi.org/10.1016/j.tifs.2018.07.001]
[17]
Jalaludeen, A.M.; Lee, W.Y.; Kim, J.H.; Jeong, H.Y.; Ki, K.S.; Kwon, E.G.; Song, H. Therapeutic efficacy of biochanin A against arsenic-induced renal and cardiac damage in rats. Environ. Toxicol. Pharmacol., 2015, 39(3), 1221-1231.
[http://dx.doi.org/10.1016/j.etap.2015.04.020] [PMID: 25997126]
[18]
Lee, Y.S.; Seo, J-S.; Chung, H.T.; Jang, J.J. Inhibitory effects of biochanin A on mouse lung tumor induced by benzo(a)pyrene. J. Korean Med. Sci., 1991, 6(4), 325-328.
[http://dx.doi.org/10.3346/jkms.1991.6.4.325] [PMID: 1844641]
[19]
Ko, W-C.; Lin, L-H.; Shen, H-Y.; Lai, C-Y.; Chen, C-M.; Shih, C-H.; Biochanin, A. A phytoestrogenic isoflavone with selective inhibition of phosphodiesterase 4, suppresses ovalbumin-induced airway hyperresponsiveness. Evid. Based Complement. Alternat. Med., 2011, 2011
[http://dx.doi.org/10.1155/2011/635058]]
[20]
Sundaresan, A.; Radhiga, T.; Deivasigamani, B. Biological activity of Biochanin A: a review. Asian J. Pharm. Pharmacol., 2018, 4(1), 1-5.
[http://dx.doi.org/10.31024/ajpp.2018.4.1.1]
[21]
Yu, C.; Zhang, P.; Lou, L.; Wang, Y. Perspectives regarding the role of Biochanin A in humans. Front. Pharmacol., 2019, 10(793), 793.
[http://dx.doi.org/10.3389/fphar.2019.00793] [PMID: 31354500]
[22]
Mueller, M.; Lukas, B.; Novak, J.; Simoncini, T.; Genazzani, A.R.; Jungbauer, A. Oregano: a source for peroxisome proliferator-activated receptor γ antagonists. J. Agric. Food Chem., 2008, 56(24), 11621-11630.
[http://dx.doi.org/10.1021/jf802298w] [PMID: 19053389]
[23]
Clark, R.B.; Bishop-Bailey, D.; Estrada-Hernandez, T.; Hla, T.; Puddington, L.; Padula, S.J. The nuclear receptor PPAR γ and immunoregulation: PPAR γ mediates inhibition of helper T cell responses. J. Immunol., 2000, 164(3), 1364-1371.
[http://dx.doi.org/10.4049/jimmunol.164.3.1364] [PMID: 10640751]
[24]
Asada, K.; Sasaki, S.; Suda, T.; Chida, K.; Nakamura, H. Antiinflammatory roles of peroxisome proliferator-activated receptor γ in human alveolar macrophages. Am. J. Respir. Crit. Care Med., 2004, 169(2), 195-200.
[http://dx.doi.org/10.1164/rccm.200207-740OC] [PMID: 14563653]
[25]
Fahmi, H.; Di Battista, J.A.; Pelletier, J.P.; Mineau, F.; Ranger, P.; Martel-Pelletier, J. Peroxisome proliferator--activated receptor γ activators inhibit interleukin-1β-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum., 2001, 44(3), 595-607.
[http://dx.doi.org/10.1002/1529-0131(200103)44:3<595:AID-ANR108>3.0.CO;2-8] [PMID: 11263774]
[26]
Hetzel, M.; Walcher, D.; Grüb, M.; Bach, H.; Hombach, V.; Marx, N. Inhibition of MMP-9 expression by PPARgamma activators in human bronchial epithelial cells. Thorax, 2003, 58(9), 778-783.
[http://dx.doi.org/10.1136/thorax.58.9.778] [PMID: 12947137]
[27]
Mendez, M.; LaPointe, M.C. PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. Hypertension, 2003, 42(2), 844-850.
[http://dx.doi.org/10.1161/01.HYP.0000085332.69777.D1]]
[28]
Ward, J.E.; Fernandes, D.J.; Taylor, C.C.; Bonacci, J.V.; Quan, L.; Stewart, A.G. The PPARgamma ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation. Pulm. Pharmacol. Ther., 2006, 19(1), 39-46.
[http://dx.doi.org/10.1016/j.pupt.2005.02.005] [PMID: 16286236]
[29]
Narala, V.R.; Ranga, R.; Smith, M.R.; Berlin, A.A.; Standiford, T.J.; Lukacs, N.W.; Reddy, R.C. Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma. Respir. Res., 2007, 8(1), 90.
[http://dx.doi.org/10.1186/1465-9921-8-90] [PMID: 18053220]
[30]
Honda, K.; Marquillies, P.; Capron, M.; Dombrowicz, D. Peroxisome proliferator-activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J. Allergy Clin. Immunol., 2004, 113(5), 882-888.
[http://dx.doi.org/10.1016/j.jaci.2004.02.036] [PMID: 15131570]
[31]
Horváth, I.; Donnelly, L.E.; Kiss, A.; Paredi, P.; Kharitonov, S.A.; Barnes, P.J. Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress. Thorax, 1998, 53(8), 668-672.
[http://dx.doi.org/10.1136/thx.53.8.668] [PMID: 9828853]
[32]
Kitada, O.; Kodama, T.; Kuribayashi, K.; Ihaku, D.; Fujita, M.; Matsuyama, T.; Sugita, M. Heme oxygenase-1 (HO-1) protein induction in a mouse model of asthma. Clin. Exp. Allergy, 2001, 31(9), 1470-1477.
[http://dx.doi.org/10.1046/j.1365-2222.2001.01179.x] [PMID: 11591199]
[33]
Vogt, B.A.; Alam, J.; Croatt, A.J.; Vercellotti, G.M.; Nath, K.A. Acquired resistance to acute oxidative stress. Possible role of heme oxygenase and ferritin. Lab. Invest., 1995, 72(4), 474-483.
[PMID: 7723286]
[34]
Stocker, R. Induction of haem oxygenase as a defence against oxidative stress. Free Radic. Res. Commun., 1990, 9(2), 101-112.
[http://dx.doi.org/10.3109/10715769009148577] [PMID: 2189794]
[35]
Shaik, F.B.; Panati, K.; Narasimha, V.R.; Narala, V.R. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T(H)2 cytokines. Biochem. Biophys. Res. Commun., 2015, 463(4), 600-605.
[http://dx.doi.org/10.1016/j.bbrc.2015.05.104] [PMID: 26067554]
[36]
Narala, V.R.; Fukumoto, J.; Hernández-Cuervo, H.; Patil, S.S.; Krishnamurthy, S.; Breitzig, M.; Galam, L.; Soundararajan, R.; Lockey, R.F.; Kolliputi, N. Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice. Am. J. Physiol. Lung Cell. Mol. Physiol., 2018, 314(5), L860-L870.
[http://dx.doi.org/10.1152/ajplung.00365.2017] [PMID: 29388469]
[37]
Panati, K.; Subramani, P.A.; Reddy, M.M.; Derangula, M.; Arva Tatireddigari, V.R.R.; Kolliputi, N.; Narala, V.R. The nitrated fatty acid, 10-nitrooleate inhibits the neutrophil chemotaxis via peroxisome proliferator-activated receptor gamma in CLP-induced sepsis in mice. Int. Immunopharmacol., 2019, 72, 159-165.
[http://dx.doi.org/10.1016/j.intimp.2019.04.001] [PMID: 30981081]
[38]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 1951, 193(1), 265-275.
[PMID: 14907713]
[39]
Cao, R.; Dong, X-W.; Jiang, J-X.; Yan, X-F.; He, J-S.; Deng, Y-M.; Li, F-F.; Bao, M-J.; Xie, Y-C.; Chen, X-P.; Xie, Q-M.M. (3) muscarinic receptor antagonist bencycloquidium bromide attenuates allergic airway inflammation, hyperresponsiveness and remodeling in mice. Eur. J. Pharmacol., 2011, 655(1-3), 83-90.
[http://dx.doi.org/10.1016/j.ejphar.2011.01.024] [PMID: 21277298]
[40]
Wang, L.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Blunder, M.; Liu, X.; Malainer, C.; Blazevic, T.; Schwaiger, S.; Rollinger, J.M.; Heiss, E.H.; Schuster, D.; Kopp, B.; Bauer, R.; Stuppner, H.; Dirsch, V.M.; Atanasov, A.G. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem. Pharmacol., 2014, 92(1), 73-89.
[http://dx.doi.org/10.1016/j.bcp.2014.07.018] [PMID: 25083916]
[41]
Wu, L.C.; Zarrin, A.A. The production and regulation of IgE by the immune system. Nat. Rev. Immunol., 2014, 14(4), 247-259.
[http://dx.doi.org/10.1038/nri3632] [PMID: 24625841]
[42]
Platts-Mills, T. A. The role of immunoglobulin E in allergy and asthma. American journal of respiratory and critical care medicine, 2001, 164(supplement_1), S1-S5.
[http://dx.doi.org/10.1164/ajrccm.164.supplement_1.2103024]
[43]
Reddy, A.T.; Lakshmi, S.P.; Dornadula, S.; Pinni, S.; Rampa, D.R.; Reddy, R.C. The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease. J. Immunol., 2013, 191(5), 2053-2063.
[http://dx.doi.org/10.4049/jimmunol.1300730]]
[44]
Patel, H.J.; Belvisi, M.G.; Bishop-Bailey, D.; Yacoub, M.H.; Mitchell, J.A. Activation of peroxisome proliferator-activated receptors in human airway smooth muscle cells has a superior anti-inflammatory profile to corticosteroids: relevance for chronic obstructive pulmonary disease therapy. J. Immunol., 2003, 170(5), 2663-2669.
[http://dx.doi.org/10.4049/jimmunol.170.5.2663] [PMID: 12594295]
[45]
Zhang, Y.; Chen, W.A. Biochanin A inhibits lipopolysaccharide-induced inflammatory cytokines and mediators production in BV2 microglia. Neurochem. Res., 2015, 40(1), 165-171.
[http://dx.doi.org/10.1007/s11064-014-1480-2] [PMID: 25432463]
[46]
Villacorta, L.; Schopfer, F.J.; Zhang, J.; Freeman, B.A.; Chen, Y.E. PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin. Sci., 2009, 116(3), 205-218.
[http://dx.doi.org/10.1042/CS20080195]]
[47]
Benayoun, L.; Letuve, S.; Druilhe, A.; Boczkowski, J.; Dombret, M.C.; Mechighel, P.; Megret, J.; Leseche, G.; Aubier, M.; Pretolani, M. Regulation of peroxisome proliferator-activated receptor γ expression in human asthmatic airways: relationship with proliferation, apoptosis, and airway remodeling. Am. J. Respir. Crit. Care Med., 2001, 164(8 Pt 1), 1487-1494.
[http://dx.doi.org/10.1164/ajrccm.164.8.2101070] [PMID: 11704601]
[48]
Mueller, C.; Weaver, V.; Vanden Heuvel, J.P.; August, A.; Cantorna, M.T. Peroxisome proliferator-activated receptor γ ligands attenuate immunological symptoms of experimental allergic asthma. Arch. Biochem. Biophys., 2003, 418(2), 186-196.
[http://dx.doi.org/10.1016/j.abb.2003.08.006] [PMID: 14522590]
[49]
Thangavel, N.; Al Bratty, M.; Akhtar Javed, S.; Ahsan, W.; Alhazmi, H.A. Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs. Int. J. Med. Chem., 2017, 2017, 1069718-1069718.
[http://dx.doi.org/10.1155/2017/1069718] [PMID: 28656106]
[50]
Woerly, G.; Honda, K.; Loyens, M.; Papin, J-P.; Auwerx, J.; Staels, B.; Capron, M.; Dombrowicz, D. Peroxisome proliferator-activated receptors α and γ down-regulate allergic inflammation and eosinophil activation. J. Exp. Med., 2003, 198(3), 411-421.
[http://dx.doi.org/10.1084/jem.20021384] [PMID: 12900517]
[51]
Kitada, O. Expression of heme oxygenase-1 and its effects in allergic airway inflammation and hyperresponsiveness. Arerugi=[Allergy], 2002, 51(11), 1095-1102.
[52]
Kharitonov, S.A.; Yates, D.; Robbins, R.A.; Logan-Sinclair, R.; Shinebourne, E.A.; Barnes, P.J. Increased nitric oxide in exhaled air of asthmatic patients. Lancet, 1994, 343(8890), 133-135.
[http://dx.doi.org/10.1016/S0140-6736(94)90931-8] [PMID: 7904001]
[53]
Barnes, P.J. Reactive oxygen species and airway inflammation. Free Radic. Biol. Med., 1990, 9(3), 235-243.
[http://dx.doi.org/10.1016/0891-5849(90)90034-G] [PMID: 2272532]
[54]
Cantoni, L.; Rossi, C.; Rizzardini, M.; Gadina, M.; Ghezzi, P. Interleukin-1 and tumour necrosis factor induce hepatic haem oxygenase. Feedback regulation by glucocorticoids. Biochem. J., 1991, 279(Pt 3), 891-894.
[http://dx.doi.org/10.1042/bj2790891] [PMID: 1835380]
[55]
Abdureyim, S.; Amat, N.; Umar, A.; Upur, H.; Berke, B.; Moore, N. Anti-inflammatory, immunomodulatory, and heme oxygenase-1 inhibitory activities of Ravan Napas, a formulation of Uighur traditional medicine, in a rat model of allergic asthma. Evidence-Based Complementary and Alternative Medicine, 2011, 2011
[http://dx.doi.org/10.1155/2011/725926]
[56]
Kuribayashi, K.; Iida, S.; Nakajima, Y.; Funaguchi, N.; Tabata, C.; Fukuoka, K.; Fujimori, Y.; Ihaku, D.; Nakano, T. Suppression of heme oxygenase-1 activity reduces airway hyperresponsiveness and inflammation in a mouse model of asthma. J. Asthma, 2015, 52(7), 662-668.
[http://dx.doi.org/10.3109/02770903.2015.1008138] [PMID: 26133060]
[57]
Garcia-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M.A.; Martinez, J.A. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm. Res., 2009, 58(9), 537-552.
[http://dx.doi.org/10.1007/s00011-009-0037-3]]
[58]
Lakshmi, S.P.; Reddy, A.T.; Banno, A.; Reddy, R.C. Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor gamma Regulates Inflammation and Mucin Expression in Allergic Airway Disease. J. Immunol., 2018, 201(6), 1775-1783.
[http://dx.doi.org/10.4049/jimmunol.1800649]]
[59]
Kobayashi, M.; Thomassen, M.J.; Rambasek, T.; Bonfield, T.L.; Raychaudhuri, B.; Malur, A.; Winkler, A.R.; Barna, B.P.; Goldman, S.J.; Kavuru, M.S. An inverse relationship between peroxisome proliferator-activated receptor γ and allergic airway inflammation in an allergen challenge model. Ann. Allergy Asthma Immunol., 2005, 95(5), 468-473.
[http://dx.doi.org/10.1016/S1081-1206(10)61173-8] [PMID: 16312170]
[60]
Barnes, P.J. Transcription factors in airway diseases. Lab. Invest., 2006, 86(9), 867-872.
[http://dx.doi.org/10.1038/labinvest.3700456] [PMID: 16865089]
[61]
Pascual, G.; Fong, A.L.; Ogawa, S.; Gamliel, A.; Li, A.C.; Perissi, V.; Rose, D.W.; Willson, T.M.; Rosenfeld, M.G.; Glass, C.K. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature, 2005, 437(7059), 759-763.
[http://dx.doi.org/10.1038/nature03988] [PMID: 16127449]
[62]
Kim, S.R.; Lee, K.S.; Park, H.S.; Park, S.J.; Min, K.H.; Jin, S.M.; Lee, Y.C. Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma. Mol. Pharmacol., 2005, 68(6), 1568-1575.
[http://dx.doi.org/10.1124/mol.105.017160] [PMID: 16150927]
[63]
Hu, X.; Qin, H.; Li, Y.; Li, J.; Fu, L.; Li, M.; Jiang, C.; Yun, J.; Liu, Z.; Feng, Y.; Yao, Y.; Yin, B. Biochanin A protect against lipopolysaccharide-induced acute lung injury in mice by regulating TLR4/NF-κB and PPAR-γ pathway. Microb. Pathog., 2020.138103846
[http://dx.doi.org/10.1016/j.micpath.2019.103846] [PMID: 31698051]
[64]
Baeuerle, P.A.; Henkel, T. Function and activation of NF-kappa B in the immune system. Annu. Rev. Immunol., 1994, 12, 141-179.
[http://dx.doi.org/10.1146/annurev.iy.12.040194.001041] [PMID: 8011280]
[65]
Qiu, L.; Lin, B.; Lin, Z.; Lin, Y.; Lin, M.; Yang, X. Biochanin A ameliorates the cytokine secretion profile of lipopolysaccharide-stimulated macrophages by a PPARγ-dependent pathway. Mol. Med. Rep., 2012, 5(1), 217-222.
[http://dx.doi.org/10.3892/mmr.2011.599] [PMID: 21946955]
[66]
Jatakanon, A.; Uasuf, C.; Maziak, W.; Lim, S.; Chung, K.F.; Barnes, P.J. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med., 1999, 160(5 Pt 1), 1532-1539.
[http://dx.doi.org/10.1164/ajrccm.160.5.9806170] [PMID: 10556116]
[67]
ten Brinke, A.; Zwinderman, A.H.; Sterk, P.J.; Rabe, K.F.; Bel, E.H. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am. J. Respir. Crit. Care Med., 2004, 170(6), 601-605.
[http://dx.doi.org/10.1164/rccm.200404-440OC] [PMID: 15215154]

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