Games E et al. (2016), Structurally Related Monoterpenes p-Cymene, Car...

ECB-ART-44978

Molecules 2016 Oct 20;2110:. doi: 10.3390/molecules21101390.

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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.

Games E , Guerreiro M , Santana FR , Pinheiro NM , de Oliveira EA , Lopes FD , Olivo CR , Tibério IF , Martins MA , Lago JH , Prado CM .

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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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Species referenced: Echinodermata
Genes referenced: LOC574780 mmp7

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	Figure 1. Structure of monoterpenes p-cymene, carvacrol and thymol.
	Figure 2. Effects of monoterpenes p-cymene, carvacrol and thymol on lung inflammation. Data are presented as mean ± standard error (SE) (n = 7 to 8 mice/group) of number of cells recovered in bronchoalveolar lavage fluid collected at the 28th day of the experimental protocol. SAL + VE: control group with vehicle treatment; PPE + VE: porcine pancreatic elastase instillation and vehicle treatment; PPE + TM: porcine pancreatic elastase instillation and thymol treatment; PPE + CV: porcine pancreatic elastase instillation and carvacrol treatment; PPE + pC: porcine pancreatic elastase instillation and p-cymene treatment. * p < 0.01 and # p < 0.05.
	Figure 3. Effects of monoterpenes thymol, carvacrol and p-cymene in BALF cytokine levels. Data are presented as mean ± standard error (SE) (n = 6 to 8 mice/group) of levels of: IL-6 (A); KC (B); IL-1β (C); and IL-17 (D) detected in BALF of mice on the 28th day of the experimental protocol. SAL + VE: control group with vehicle treatment; PPE + VE: porcine pancreatic elastase instillation and vehicle treatment; PPE + TM: porcine pancreatic elastase instillation and thymol treatment; PPE + CV: porcine pancreatic elastase instillation and carvacrol treatment; PPE + pC: porcine pancreatic elastase instillation and p-cymene treatment. * p < 0.01, ** p < 0.001 and # p < 0.05.
	Figure 4. Effects of monoterpenes thymol, carvacrol and p-cymene on alveolar septa. Data are presented as mean ± standard error (SE) (n = 5 mice/group) of: mean linear intercepts (Lm) (A); volume proportion of collagen fibers (B); and the number of positive cells to MMP-9 (C); and TIMP-1 (D) in lung of mice in the 28th day of the protocol. The photomicrographs represent the lung tissue of one animal from control (E,L,Q,V), PPE treated with vehicle (F,M,R,W) and PPE treated with thymol (G,N,S,X), carvacrol (H,O,T,Y) or p-cymene group (K,P,U,Z) stained with HE (first line), picro-sirius to detect collagen fibers (second line), by immunohistochemistry to MMP-9 and TIMP-1 (third and fourth line respectively). Arrows indicate lung emphysema, collagen deposition and positive cells. SAL + VE: control group with vehicle treatment; PPE + VE: porcine pancreatic elastase instillation and vehicle treatment; PPE + TM: porcine pancreatic elastase instillation and thymol treatment; PPE + CV: porcine pancreatic elastase instillation and carvacrol treatment; PPE + pC: porcine pancreatic elastase instillation and p-cymene treatment. * p < 0.01, ** p < 0.001 and # p < 0.05.
	Figure 5. Effects of monoterpenes thymol, carvacrol and p-cymene in the NF-κB expression in alveolar septa and oxidative stress pathway. Data are presented as mean ± standard error (SE) (n = 5 to 7 mice/group) of the number of positive cells to NF-κB (A) detected in alveolar septa, the volume proportion of 8-iso-PGF-2α expression (B) detected in alveolar septa and exhaled nitric oxide detected in the exhaled air (C) from mice in the day 28 of the protocol. Panels D to H represent tissue stained to detect NF-κB and panels I to M to detect isoprostane by immunohistochemistry. Arrows represent positive cells in lung tissue. SAL + VE: control group with vehicle treatment; PPE + VE: porcine pancreatic elastase instillation and vehicle treatment; PPE + TM: porcine pancreatic elastase instillation and thymol treatment; PPE + CV: porcine pancreatic elastase instillation and carvacrol treatment; PPE + pC: porcine pancreatic elastase instillation and p-cymene treatment. * p < 0.01, ** p < 0.001 and # p < 0.05.
	Figure 6. Monoterpenes probably mechanism is related to reduction in inflammation, oxidative stress and in NF-κB in lung of PPE-instilated animals. (A) The PPE instillation induces inflammation and increase marker of oxidative stress. Cytokines such as IL-6, KC, IL-1β and IL-17 are released and induce the perpetuation of inflammation. Together with oxidative stress, there is activation in NF-κB pathway, which in turn up-regulated transcription of proinflammatory cytokines and iNOS, that can induce an increase in exhaled nitric oxide. Augment in MMP-9 positive cells can amplify inflammation and contribute to the destruction of lung tissue culminating with collagen fibers deposition; (B) The administration of monoterpenes led to a reduction of the inflammatory process and consequent reduction in oxidative stress, which is related to the effects of monoterpenes in cytokines reduction (IL-6, KC, IL-1b and IL-17), NF-κB and isoprostane. These anti-inflammatory and antioxidant effects contributed to reduction in tissue destruction.

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