RESUMO
COPD is an inflammatory lung disease, which is often exacerbated with microbial infections resulting in worsening of respiratory symptoms. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti-oxidant/anti-inflammatory activity. We have recently reported that GA protects against the elastase (ET) induced lung inflammation and emphysema and the present work was designed to investigate the beneficial effects of Gallic acid against ET + Lipopolysachharide (LPS) induced COPD exacerbation like condition in mice model. Our data showed that i.t. administration of LPS at 21 days after ET instillation resulted in significant infiltration of inflammatory cells particularly neutrophils (p < 0.0001) into the lungs along with elevated levels of pro-inflammatory cytokines like TNF-α, IL-1ß and IL-6 (p < 0.0001). Interestingly, daily administration of GA (200 mg/Kg b. wt.) starting 7 days before ET instillation, significantly blunted the ET + LPS induced inflammation as indicated by reduced number of inflammatory cells particularly neutrophils (p < 0.0001) in BALF along with suppression of myeloperoxidase activity (p = 0.0009) and production of pro-inflammatory cytokines (p < 0.0001). Further, GA also restored the redox imbalance in the lungs towards normal. Additionally, phosphorylation of p65-NF-κB was found to be reduced (p = 0.015), which was associated with downregulation in the gene expression of IL-1ß (p = 0.022) and TNF-α (p = 0.04). Conversely, GA treatment resulted in increased protein levels of Nrf2 (p = 0.021) with concomitant increase in transcription of its downstream target genes HO-1 (p = 0.033) and Prdx-1 (p = 0.006). Overall, our data show that GA effectively modulates COPD exacerbation manifestations in mice potentially by restoring redox imbalance in lungs.
Assuntos
Ácido Gálico/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Inflamação , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/metabolismo , Oxirredução , Estresse Oxidativo , Peroxidase/metabolismo , Polifenóis/metabolismoRESUMO
OBJECTIVE AND DESIGN: Gallic acid (GA) a naturally occurring phenolic compound, known to possess antioxidant/anti-inflammatory activities. The aim of the present work was to investigate the beneficial effects of GA against COPD-linked lung inflammation/emphysema by utilizing elastase (ET) and cigarette smoke (CS)-induced mice model. MATERIALS: Male BALB/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to ET/CS exposure. Broncho-alveolar lavage was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung homogenate was assessed for MPO activity/GSH/MDA/protein carbonyls. Further, Lung tissue was subjected to semi-quantitative RT-PCR, immunoblotting, and histological analysis. RESULTS: GA suppressed the ET-induced neutrophil infiltration, elevated MPO activity and production of pro-inflammatory cytokines (IL-6/TNF-α/IL-1ß) at 24 h. Reduced inflammation was accompanied with normalization of redox balance as reflected by ROS/GSH/MDA/protein carbonyl levels. Further, GA suppressed phosphorylation of p65NF-κB and IκBα along with down-regulation of IL-1ß/TNF-α/KC/MIP-2/GCSF genes. Furthermore, GA offered protection against ET-induced airspace enlargement and ameliorated MMP-2/MMP-9. Finally, GA suppressed the CS-induced influx of neutrophils and macrophages and blunted gene expression of TNF-α/MIP-2/KC. CONCLUSION: Overall, our data show that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice.
Assuntos
Anti-Inflamatórios/uso terapêutico , Enfisema/tratamento farmacológico , Ácido Gálico/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Enfisema/genética , Enfisema/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Elastase Pancreática , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumaça/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/genética , NicotianaRESUMO
We have previously shown that PARP-1 inhibition provides protection against lung inflammation in the context of asthma and acute lung injury. Olaparib is a potent new generation PARP inhibitor that has been approved for human testing. The present work was designed to evaluate its beneficial potential against LPS-induced acute lung injury and acute kidney injury upon intratracheal administration of the endotoxin in mice. Administration of olaparib at different doses, 30 min after LPS treatment showed that single intraperitoneal injection of the drug at 5 mg/kg b.wt. reduced the total number of inflammatory cells particularly neutrophils in the lungs. This was associated with reduced pulmonary edema as the total protein content in the bronchoalveolar fluid was found to be decreased substantially. Olaparib provided strong protection against LPS-mediated secondary kidney injury as reflected by restoration of serum levels of urea, creatinine, and uric acid toward normal. The drug restored the LPS-mediated redox imbalance toward normal in lung and kidney tissues as assessed by measuring malondialdehyde and GSH levels. Finally, RT-PCR data revealed that olaparib downregulates the LPS-induced expression of NF-κB-dependent genes namely TNF-α, IL-1ß, and VCAM-1 in the lungs without altering the expression of total p65NF-κB. Overall, the data suggest that olaparib has a strong potential to protect against LPS-induced lung injury and associated dysfunctioning of kidney in mice. Given the fact that olaparib is approved by FDA for human testing, our findings can pave the way for testing of the drug on humans inflicted with acute lung injury.