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Respir Res
2015 Jun 30;16:79. doi: 10.1186/s12931-015-0233-3.
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A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-κB, oxidative stress and metalloproteinases.
Taguchi L
,
Pinheiro NM
,
Olivo CR
,
Choqueta-Toledo A
,
Grecco SS
,
Lopes FD
,
Caperuto LC
,
Martins MA
,
Tiberio IF
,
Câmara NO
,
Lago JH
,
Prado CM
.
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BACKGROUND: Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema.
METHODS: Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2α and p65-NF-κB in the fixed tissues as well as to evaluate cytokine levels and p65-NF-κB protein expression.
RESULTS: In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-α, IL-1β and M-CSF in the BALF as well as the levels of NF-κB and 8-iso-PGF-2α in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function.
CONCLUSION: These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.
Fig. 1. Lung mechanics and lung inflammation. The mean and standard error (SE) of respiratory system elastance (Ers) a and lung tissue elastance (Htis) b evaluated using a Flexivent ventilator under anesthesia 28 days after elastase or saline instillation. After the lung mechanics were evaluated, the animals were exsanguinated, and bronchoalveolar lavage fluid was collected. We quantified total cells c, macrophages d, lymphocytes e, neutrophils f and eosinophils g in the four groups. SAL+Ve: control group with vehicle treatment; ELA+Ve: elastase instillation and vehicle treatment; SAL + SK: control group treated with sakuranetin; ELA+SK: elastase- and sakuranetin-treated group. *p < 0.05 compared with the control (SAL+Ve and SAL+SK); **p < 0.05 compared with the ELA+Ve group
Fig. 3. Expression of MMP-9, MMP-12 and TIMP-1 in lung tissue. The mean and SE of the number of cells in the lung parenchyma that were positive for TIMP-1 a, MMP-9 b and MMP-12 c. Representative photomicrographs of lung parenchyma immunostained for TIMP-1 d-f, MMP-9 g-i and MMP-12 j-l. The number of positive cells for TIMP-1, MMP-9 and MMP-12 increased in animals that received elastase e, h and k compared with control animals d, g and j. Interestingly, sakuranetin increased the number of TIMP-1-positive cells and reduced the number of MMP-9- and MMP-12-positive cells in the elastase-treated groups f, i and l; see arrows). *p < 0.001 compared with the SAL+Ve and SAL+SK groups; **p < 0.05 compared with the ELA+Ve group
Fig. 4. Oxidative stress in lung tissue. 8-iso-PGF-2α-positive area (mean and SE) within the lung parenchyma a. Representative photomicrographs of the lung parenchyma immunostained for 8-iso-PGF-2α b-d. Vehicle-treated animals that received elastase showed an increase in the 8-iso-PGF-2α-positive area c compared with animals in the control group b. This response was attenuated in elastase-treated animals that received sakuranetin treatment d compared with the ELA+Ve animals c. Arrows represent the isoprostane-positive area. *p < 0.001 compared with the SAL+Ve group; **p < 0.001 compared with the ELA+Ve group
Fig. 5. NF-κB in lung tissue. NF-κB-positive area (mean and SE) in the lung parenchyma a. Representative photomicrographs of the lung parenchyma immunostained for NF-κB b-d. Vehicle-treated animals that received elastase showed an increase in the NF-κB-positive area c compared with animals in the control group b. This response was attenuated in elastase animals by sakuranetin treatment d; compared with the ELA+Ve group c. NF-kB protein content and a representative Western blot of NF-kB e-f. The Western blot corroborates the immunohistochemistry data. *p < 0.05 compared with the SAL+Ve group; **p < 0.05 compared with the ELA+Ve group
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