Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

Shyamala Ganesan, Andrea N Faris, Adam T Comstock, Sangbrita S Chattoraj, Asamanja Chattoraj, John R Burgess, Jeffrey L Curtis, Fernando J Martinez, Suzanna Zick, Marc B Hershenson, Uma S Sajjan, Shyamala Ganesan, Andrea N Faris, Adam T Comstock, Sangbrita S Chattoraj, Asamanja Chattoraj, John R Burgess, Jeffrey L Curtis, Fernando J Martinez, Suzanna Zick, Marc B Hershenson, Uma S Sajjan

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema.

Methods: Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages.

Results: Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt-1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype.

Conclusions: Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12.

Figures

Figure 1
Figure 1
Quercetin partially improves lung function in elastase-LPS exposed mice. Mice were anesthetized and pressure-volume relationships, compliance and elastance were measured using flexivent system. Chord length was determined by morphometry. Seven days after the last exposure to elastase/LPS, untreated mice showed a leftward and upward shift in the pressure-volume (PV)-loop (A) compared to PBS-exposed vehicle treated mice, indicative of a loss of elastic recoil. Seventeen days after the last exposure to elastase/LPS, this curve shifted further, indicating progression in the loss of elastic recoil. Quercetin treatment for 10 days prevented progression in loss of elastic recoil in elastase/LPS-exposed mice but had no effect on PBS-exposed mice (B). Each of these mice was examined 17 days after the last elastase/LPS treatment. Elastase/LPS-exposed mice treated with quercetin also showed increased elastance (C), decreased compliance (D) and decreased alveolar chord length (E) compared to vehicle treated mice. Representative PV curves from 5 to 6 mice from each group are shown in A and B. Data in C, D and E represent mean and SD calculated from 6 animals per group (*different from PBS group, p≤0.05 one-way ANOVA; † different from vehicle treated mice, p≤0.05 Mann-Whitney test).
Figure 2
Figure 2
Quercetin treatment reduces TBARS and increases Hmox-1 expression in elastase/LPS exposed mice. Mice exposed to PBS or elastase/LPS were orally gavaged with 0.2 mg of quercetin or vehicle daily for 10 days and sacrificed on the last day of quercetin treatment. A to D. Elastase/LPS exposed mice show increased levels of TBARS, increased iNOS mRNA levels, decreased Hmox-1 mRNA and increased ratio of iNOS/Hmox-1 compared to PBS exposed mice treated with either vehicle or quercetin. Quercetin treatment reduces TBARS, increases Hmox-1 mRNA and decreases ratio of iNOS/Hmox-1 in elastase/LPS-exposed mice. Data represent mean and SEM (n = 10-14, *different from PBS/vehicle and PBS/quercetin group, p≤0.05; † different from vehicle treated elastase/LPS-exposed mice, p≤0.05 one-way ANOVA).
Figure 3
Figure 3
Quercetin treatment decreases chemokine and cytokine levels in elastase/LPS exposed mice. Mice exposed to elastase/LPS were orally gavaged with vehicle or quercetin as described. A to F. Elastase/LPS exposed mice show increased levels of KC, MIP2, MCP-1, IL-1β, IL-12p40 and MIP-1β compared to control naïve mice. Quercetin treatment reduces all the examined cytokines and chemokines. Data represent mean and SEM (n = 10, *different from PBS/vehicle group, p≤0.05; † different from vehicle-treated elastase/LPS exposed mice, p≤0.05 one-way ANOVA).
Figure 4
Figure 4
Quercetin treatment reduces lung inflammation and reverses goblet cell metaplasia. Lung sections from elastase/LPS exposed mice were stained with H & E or immunostained with an antibody to Muc5AC. A and B. Mice treated with vehicle show mild-to-moderate wide-spread lung inflammation, emphysema and goblet cell metaplasia. C and D. Mice treated with quercetin show less emphysema with very mild inflammation and a complete reduction in MUC5AC producing goblet cells. Asterisks in A and C represent emphysema. Arrows in B indicate MUC5AC- producing goblet cells. Images are representative of 6 mice per group. E. Examination of BAL fluid reveals increased numbers of total cells, macrophages and neutrophils in elastase/LPS treated mice, which were almost completely reversed by quercetin treatment. F. qPCR analysis of total lung RNA shows increased Muc5AC transcript levels in elastase/LPS-exposed mice, and this was reduced in quercetin treated mice. Data represent mean and SEM (n = 10, *different from PBS/vehicle group, p≤0.05; † different from vehicle treated elastase/LPS exposed mice, p≤0.05 one-way ANOVA).
Figure 5
Figure 5
Quercetin treatment decreases levels of MMP9 and MMP12 and increases expression of SIRT1 in elastase/LPS-exposed mice. mRNA expression of Mmp9, Mmp12, and Sirt1 was measured by qPCR. MMP activity was determined by gelatin zymography. Sirt1 protein level was measured in the lung homogenates by Western blot analysis. A and B. Quercetin treated elastase/LPS exposed mice show significantly reduced Mmp9 and Mmp12 mRNA levels compared to mice treated with vehicle. C Quercetin treatment completely reduces MMP9 and MMP12 activities in elastase/LPS exposed mice. D and E. Quercetin increases Sirt1 mRNA and protein levels in elastase/LPS exposed mice. F. Ratio of Sirt1 protein/β-actin normalized to control mice calculated from 6 mice per group. Data represent mean and SEM (n = 10, *different from PBS/vehicle group, p≤0.05; † different from vehicle-treated, elastase/LPS-exposed mice, p≤0.05 one-way ANOVA). Images in C and E are representative of 4 to 6 animals per group.
Figure 6
Figure 6
Inhibition of Sirt1 activity in quercetin-treated mice attenuates querecetin-induced changes in MMP expression and emphysema progression. Elastase/LPS-exposed mice were treated with vehicle or quercetin along with sirtinol or PBS. A and B. Mice treated with quercetin and sirtinol did not show reduced MMP9 or MMP12 mRNA expression. Results represent range of data with median (n = 4-6, *different from all other groups, p≤0.05; ANOVA on ranks). C-E. Sirtinol also inhibited quercetin's effects on elastic recoil (C), compliance (D) and elastance (E). Data represent mean and SEM (n = 4-6, *different from all other groups, p≤0.05; one-way ANOVA). C. Representative of 4-6 animals per group.
Figure 7
Figure 7
Quercetin decreases MMP9 and MMP12 and increases Sirt1 in LPS-treated alveolar macrophages. Mouse alveolar macrophages were treated with LPS (1 ng/ml) for 3 days and treated with DMSO (vehicle) or 25 µM quercetin for 16 h. A and B. LPS treatment induced mRNA expression of MMP9 and MMP12 which are partially reversed by quercetin. C and E. Quercetin increases Sirt1 mRNA and protein expression. D. MMP9 activity in LPS-exposed was abrogated by quercetin treatment. E. A representative Western blot showing Sirt1 and β-actin expression. F. Ratio of Sirt1 protein/β-actin normalized to untreated cells calculated from 3 independent experiments. G and H. Quercetin decreased LPS-induced histone H4 acetylation at the NF-κB binding sites in the promoter regions of both Mmp9 and Mmp12. Zymogram and immunoblot images are representative of three independent experiments. Data represent mean and SEM calculated from 3 independent experiments performed in duplicates or triplicates (*different from macrophages exposed to media in the absence of quercetin, p≤0.05; †different from LPS-exposed macrophages which are not treated with quercetin, p≤0.05 one-way ANOVA).

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