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      Structurally Related Monoterpenes p-Cymene, Carvacrol and Thymol Isolated from Essential Oil from Leaves of Lippia sidoides Cham. (Verbenaceae) Protect Mice against Elastase-Induced Emphysema

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          Abstract

          Background: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and inflammation. Natural products, such as monoterpenes, displayed anti-inflammatory and anti-oxidant activities and can be used as a source of new compounds to COPD treatment. Our aim was to evaluate, in an elastase-induced pulmonary emphysema in mice, the effects of and underlying mechanisms of three related natural monoterpenes ( p-cymene, carvacrol and thymol) isolated from essential oil from leaves Lippia sidoides Cham. (Verbenaceae). Methods: Mices received porcine pancreatic elastase (PPE) and were treated with p-cymene, carvacrol, thymol or vehicle 30 min later and again on 7th, 14th and 28th days. Lung inflammatory profile and histological sections were evaluated. Results: In the elastase-instilled animals, the tested monoterpenes reduced alveolar enlargement, macrophages and the levels of IL-1β, IL-6, IL-8 and IL-17 in bronchoalveolar lavage fluid (BALF), and collagen fibers, MMP-9 and p-65-NF-κB-positive cells in lung parenchyma ( p < 0.05). All treatments attenuated levels of 8-iso-PGF2α but only thymol was able to reduced exhaled nitric oxide ( p < 0.05). Conclusion: Monoterpenes p-cymene, carvacrol and thymol reduced lung emphysema and inflammation in mice. No significant differences among the three monoterpenes treatments were found, suggesting that the presence of hydroxyl group in the molecular structure of thymol and carvacrol do not play a central role in the anti-inflammatory effects.

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          Most cited references74

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          Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.

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            Animal models of chronic obstructive pulmonary disease.

            The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.
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              T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.

              There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22(+) and IL-23(+) immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A(+) and IL-22(+) immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22(+) cells correlated significantly with the number of both CD4(+) and CD8(+) cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                20 October 2016
                October 2016
                : 21
                : 10
                : 1390
                Affiliations
                [1 ]Department of Biological Science, Universidade Federal de São Paulo, Diadema 09913-030, Brazil; ellengames@ 123456gmail.com (E.G.); marinaguerreiro88@ 123456gmail.com (M.G.); fe.paula.roncon@ 123456gmail.com (F.R.S.); dupontemerson@ 123456hotmail.com (E.A.d.O.)
                [2 ]Department of Medicine, School of Medicine, Universidade de São Paulo, São Paulo 01246903, SP, Brazil; pinheiro.nathalia@ 123456gmail.com (N.M.P.); fernandadtqsl@ 123456gmail.com (F.D.T.Q.S.L.); clariceolivo@ 123456gmail.com (C.R.O.); iocalvo@ 123456uol.com.br (I.F.L.C.T.); mmartins@ 123456usp.br (M.A.M.)
                [3 ]Department of Exact Science and Earth, Universidade Federal de São Paulo, Diadema 09913-030, Brazil; joaohglago@ 123456gmail.com
                [4 ]Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre 09606-045, SP, Brazil
                [5 ]Department of Bioscience, Federal University of São Paulo, Campus Baixada Santista, Santos 11015-020, SP, Brazil
                Author notes
                [* ]Correspondence: carla.prado@ 123456unifesp.br ; Tel.: +55-13-3878-3732
                Article
                molecules-21-01390
                10.3390/molecules21101390
                6273112
                27775634
                60cf8778-9761-4f4d-b2de-500eec01f6db
                © 2016 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 August 2016
                : 12 October 2016
                Categories
                Article

                copd,elastase-induced emphysema,monoterpenes,p-cymene,carvacrol,thymol,lung inflammation

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