lignans and Lung-Diseases

Cystic fibrosis (CF) leads to advanced lung disease despite aggressive care. Persistent inflammation and oxidative stress contribute to exacerbations and disease progression. Flaxseed (FS), a dietary botanical supplement with high fiber, lignan phenolics, and omega-3 fatty acids has anti-inflammatory and antioxidant properties in murine models of acute and chronic lung injury. This pilot study was designed to determine whether CF patients could tolerate FS, evaluate circulating FS metabolites, and study biomarkers of lung damage, as a prelude to studying clinical outcomes.. 10 CF patients and 5 healthy volunteers consumed 40 g of FS daily for 4 weeks with safety and tolerability being assessed. Urine was evaluated for systemic oxidative stress and plasma for FS metabolites (enterolignans) and cytokine levels. Buccal swabs were analyzed for gene expression of Nrf2-regulated antioxidant enzymes including Heme Oxygenase-1 (HO-1) and NAD(P)H Quinone Oxidoreductase 1 (NQO1).. All subjects completed the study without serious adverse events. Plasma levels of enterolignans were detectable in both healthy controls and CF volunteers. CF patients were stratified based on plasma enterolignan levels after 2 weeks of FS administration into high- (174 to 535 nM ED and 232 to 1841 nM EL) and low- (0 to 32 nM ED and 0 to 40 nM EL) plasma lignan cohorts. The low enterolignan level cohort experienced a statistically significant drop in urinary inflammatory IsoP and plasma TNFα levels, while demonstrating higher average NQO1 mRNA levels in buccal epithelium compared to high-lignan patients.. This pilot study demonstrated that FS is tolerated by CF patients. FS metabolites could be detected in the plasma. Future studies will assess appropriate dosing and target populations for FS, while exploring clinical outcomes.. ClinicalTrials.gov identifier: NCT02014181 .

Topics: Adolescent; Adult; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Cystic Fibrosis; Dietary Supplements; Fatty Acids, Omega-3; Female; Flax; Heme Oxygenase-1; Humans; Inflammation; Lignans; Lung; Lung Diseases; Male; Mice; Middle Aged; Oxidative Stress; Phenols; Phytotherapy; Pilot Projects; Plant Extracts; Seeds

Sesamin is a major component in lignans of sesame seeds, has been described to possess a lot of biological activity. The main objective of our study was to investigate the inhibitory effect and novel molecular mechanisms of sesamin on carrageenan-induced lung inflammation in rats. Here we showed that sesamin can obviously reduce polymorphonuclear neutrophils infiltration and exudate volume. Further studies exhibited sesamin can inhibit cytokines release, polymorphonuclear neutrophils markers production and the degree of lung tissues injury. Western blot analysis revealed that sesamin can inhibit the TRAF6 expression and NF-κB pathway activation in lung tissue. We found that sesamin can increase the expression of A20 and TAX1BP1 in lung tissues, and the interaction between the two molecules. In conclusion, all these results demonstrated that sesamin can attenuate carrageenan-induced lung inflammation, the mechanisms that may be related to upregulation of the novel target A20 and TAX1BP1 which can negative regulation for NF-κB pathway. Importantly, this is the first evidence showing that TAX1BP1 can be as a novel regulatory target to attenuate the lung inflammation.

Topics: Animals; Antioxidants; Apoptosis Regulatory Proteins; Biomarkers; Carrageenan; Dioxoles; Gene Expression Regulation; Inflammation; Lignans; Lung Diseases; Neoplasm Proteins; Neutrophils; NF-kappa B; Pleural Effusion; Rats; Tumor Necrosis Factor alpha-Induced Protein 3; Up-Regulation

Airway fibrosis, which is a crucial pathological condition occurring in various types of pulmonary disorders, is characterized by accumulation and activation of fibroblast cells, deposition of extracellular matrix (ECM) proteins, and increase of airway basement membrane. Transforming growth factor beta 1 (TGF-β1) is the principal profibrogenic cytokine that is responsible for fibrotic responses. In the present study, we aimed to investigate the antifibrotic effects of the natural polyphenolic compound, sesamin, on TGF-β1-induced fibroblast proliferation and activation, epithelial-mesenchymal transition (EMT), and ovalbumin (OVA)-induced airway fibrosis in vivo. We found that sesamin attenuated TGF-β1-induced proliferation of cultured lung fibroblasts. Sesamin inhibited TGF-β1-stimulated expression of alpha smooth muscle actin (α-SMA), suggesting that sesamin plays an inhibitory role in fibroblast activation. Sesamin blocked upregulation of the mesenchymal markers (fibronectin and vimentin) and downregulation of the epithelial marker (E-cadherin), indicating an inhibitory effect on TGF-β1-induced EMT in A549 cells. TGF-β1-induced Smad3 phosphorylation was also significantly reduced by sesamin in both cultured fibroblast and A549 cells. In the airway fibrosis induced by OVA in mice, sesamin inhibited the accumulation of α-SMA-positive cells and expression of collagen I in the airway. Histological studies revealed that sesamin protected against subepithelial fibrosis by reducing myofibroblast activation and collagen accumulation in the ECM. OVA-induced thickening of basement membrane was significantly alleviated in animals receiving sesamin treatments. These results suggest a therapeutic potential of sesamin as an antifibrotic agent.

Topics: Actins; Animals; Basement Membrane; Cell Line; Cell Proliferation; Collagen Type I; Dioxoles; Down-Regulation; Epithelial-Mesenchymal Transition; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Humans; Lignans; Lung Diseases; Mice; Mice, Inbred C57BL; Respiratory Mucosa; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta1

Classical Chinese pharmacopeias describe numerous excellent herbal formulations, and each prescription is an outstanding pool of effective compounds for drug discovery. Clarifying the bioactivity of the combined mechanisms of the ingredients in complex traditional Chinese medicine formulas is challenging. A classical formula known as Qingfei Xiaoyan Wan, used clinically as a treatment for prevalent chronic lung disease, was investigated in this work. A mutually enhanced bioactivity-guided ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) characterization system was proposed, coupled with a dual-luciferase reporter assay for β2AR-agonist cofactor screening. Arctiin, arctigenin, descurainoside and descurainolide B, four lignin compounds that showed synergistic bronchodilation effects with ephedrine, were revealed. The synergistic mechanism of arctigenin with the β2ARagonist involved with the reduction of free Ca2+ was clarified by a dual-luciferase reporter assay for intracellular calcium and the Ca2+ indicator fluo-4/AM to monitor changes in the fluorescence. The relaxant and contractile responses of airway smooth muscle are regulated by crosstalk between the intracellular cAMP and calcium signaling pathways. Our data indicated the non-selective βAR agonist ephedrine as the principal bronchodilator of the formula, whereas the lignin ingredients served as adjuvant ingredients. A greater understanding of the mechanisms governing the control of these pathways, based on conventional wisdom, could lead to the identification of novel therapeutic targets or new agents for the treatment of asthma and COPD.

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Asthma; Bronchodilator Agents; Calcium; Cell Line; Chromatography, High Pressure Liquid; Chronic Disease; Disease Models, Animal; Drug Synergism; Drugs, Chinese Herbal; Ephedrine; Flavonoids; Furans; Glucosides; Guinea Pigs; Humans; Lactones; Lignans; Lung Diseases; Medicine, Chinese Traditional; Myocytes, Smooth Muscle; Trachea

Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics has potent anti-inflammatory, anti-fibrotic and antioxidant properties. The usefulness of flaxseed as an alternative and complimentary treatment option has been known since ancient times. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed might modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury.. We evaluated gene expression in lungs of flaxseed-fed (10%FS) mice under unchallenged, control conditions. We reasoned that array technology would provide a powerful tool for studying the mechanisms behind this response and aid the evaluation of dietary flaxseed intervention with a focus on toxicologically relevant molecular gene targets. Gene expression levels in lung tissues were analyzed using a large-scale array whereby 28,800 genes were evaluated.. 3,713 genes (12.8%) were significantly (p < 0.05) differentially expressed, of which 2,088 had a >1.5-fold change. Genes affected by FS include those in protective pathways such as Phase I and Phase II.. The array studies have provided information on how FS modulates gene expression in lung and how they might be related to protective mechanisms. In addition, our study has confirmed that flaxseed is a nutritional supplement with potentially useful therapeutic applications in complementary and alternative (CAM) medicine especially in relation to treatment of lung disease.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Flax; Gene Expression Profiling; Lignans; Lung; Lung Diseases; Mice; Phenols; Phytotherapy; Plant Preparations; Seeds; Signal Transduction; Transcriptome

Occupational exposure to cedar and pine woods and pine resin (colophony) can cause asthma and chronic lung disease. Prior studies suggest that plicatic and abietic acids are responsible for the asthmatic reactions that occur in cedar-wood and colophony workers; however, the etiologic mechanism(s) of the chronic lung disease is unknown. To determine if plicatic acid from cedar wood and abietic acid from pine resin could directly damage lung cells, we exposed monolayers of rat type II and human A549 alveolar epithelial cells, intact rat lungs, and rat tracheal explants to solutions of plicatic and abietic acids. As indices of injury, we measured lysis of alveolar epithelial cells with a 51Cr technique, quantitative desquamation of epithelial cells from tracheal explants, and histologic alterations in tracheal explants and intact lungs. Plicatic and abietic acids both caused dose- and time-dependent lysis of alveolar epithelial cells. Instillation of plicatic and abietic acids into rat lungs produced bronchial epithelial sloughing. Abietic acid also caused destruction of the alveolar epithelium. The addition of either acid to rat tracheal explants caused epithelial desquamation that was dose- and time-dependent. Our results suggest that plicatic acid, a unique constituent of cedar wood, and abietic acid, the major constituent in pine resin, can produce lytic damage to alveolar, tracheal, and bronchial epithelial cells. We hypothesize that repeated occupational exposure to these substances might promote the chronic lung damage observed in some cedar- and pine-wood workers and in electronic workers exposed to colophony.

Topics: Abietanes; Bronchi; Diterpenes; Epithelial Cells; Humans; Kinetics; Lignans; Lung Diseases; Naphthols; Occupational Diseases; Phenanthrenes; Pulmonary Alveoli; Trachea