naphthoquinones and Asthma

Air pollutants such as diesel exhaust particles (DEP) are thought to cause pulmonary diseases such as asthma as a result of oxidative stress. While DEP contain a large number of polycyclic aromatic hydrocarbons, we have focused on 9,10-phenanthrenequinone (9,10-PQ) and 1,2-naphthoquinone (1,2-NQ) because of their chemical properties based on their oxidative and chemical modification capabilities. We have found that 9,10-PQ interacts with electron donors such as NADPH (in the presence of enzymes) and dithiols, resulting in generation of excess reactive oxygen species (ROS) through redox cycling. We have also shown that 1,2-NQ is able to modify protein thiols, leading to protein adducts associated with activation of redox signal transduction pathways at lower concentrations and toxicity at higher concentrations. In this review, we briefly introduce our findings from the last two decades.

Topics: Air Pollutants; Antioxidant Response Elements; Asthma; NADP; Naphthoquinones; Oxidation-Reduction; Oxidative Stress; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Reactive Oxygen Species; Signal Transduction; Sulfhydryl Compounds; Vehicle Emissions

Topics: Adolescent; Age Factors; Albuterol; Androstadienes; Anticonvulsants; Asthma; Atovaquone; Attention Deficit Disorder with Hyperactivity; Beclomethasone; Carbamazepine; Child; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Drug Approval; Drug Combinations; Drug Delivery Systems; Drug Therapy; Epilepsies, Partial; Fluticasone-Salmeterol Drug Combination; HIV Protease Inhibitors; Humans; Insulin; Insulin Glargine; Insulin, Long-Acting; Lopinavir; Methylphenidate; Naphthoquinones; Nebulizers and Vaporizers; Oxcarbazepine; Pediatrics; Proguanil; Pyrimidinones; Ritonavir; United States

Shikonin is a naphthoquinone extracted from the root of Lithospermum erythrorhizon, and has been reported to suppress allergic airway inflammation in mice. However, the underlying mechanisms are unclear and need to be further elucidated. In this study, shikonin (0.5, 2 or 4mg/kg) was given intraperitoneally to ovalbumin (OVA)-challenged BALB/c mice. We found that the pathological airway remodeling of asthmatic mice was alleviated by shikonin, and the infiltrated inflammatory cells and collagen deposition in their lungs were reduced. Furthermore, the abnormal activation of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway and the elevation of matrix metalloproteinase 9 (MMP9) in the lung of asthmatic mice were suppressed by shikonin. The inactivation of NF-κB by shikonin was at least in part via inhibiting IκBα activation. In vitro, the treatment of shikonin inhibited the platelet-derived growth factor (PDGF)-induced proliferation of primary airway smooth muscle cells (ASMCs), and induced a G0/G1 arrest in these cells. In addition, ASMCs exposed to PDGF acquired an enhanced migratory ability, and the activities of MMP9 and matrix metalloproteinase 2 (MMP2) and expression of MMP9 of these cells were significantly up-regulated. These PDGF-induced alterations were also inhibited by shikonin. The inhibitory effects of shikonin on the proliferation and migration of ASMCs were comparable to pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB pathway. In conclusion, the present study sheds lights on how shikonin alleviates allergic airway remodeling.

Topics: Airway Remodeling; Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cell Movement; Cells, Cultured; Lung; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred BALB C; Myocytes, Smooth Muscle; Naphthoquinones; NF-kappa B; Platelet-Derived Growth Factor; Rats, Sprague-Dawley; Signal Transduction

Naphthoquinone (NQ), one of the extractable chemical compounds of diesel exhaust particles, enhances allergic asthma traits in mice. However, it remains unknown whether: (1) several types of NQs have the same potential to facilitate allergies; and (2) NQs synergistically disrupt the functional phenotypes of immune cells. The aim of the present study was to investigate the effects of two types (1,2- and 1,4-) of NQs on sensitized mononuclear cells using an ex vivo assay. Male BALB/c mice were repeatedly and intraperitoneally administered ovalbumin (OVA: 20 µg) plus alum with or without two different doses of each NQ. After the final administration, splenocytes (mononuclear cells) were isolated from these mice and cultured in the presence of OVA. Helper T-related cytokines in the culture supernatants and downstream molecules were then evaluated. Protein levels of interferon-γ were higher in the supernatants from 1,2-NQ and 1,4-NQ at low dose + OVA-exposed mononuclear cells following the OVA stimulation than in those from OVA-exposed mononuclear cells. Interleukin (IL)-13 levels were higher in the supernatants from low dose NQs + OVA-exposed mononuclear cells. IL-17 levels were significantly higher in the supernatants from low dose 1,2-NQ + OVA-exposed mononuclear cells. The quantity of phosphorylated STAT6 in the nuclei of these cells was significantly greater in the low dose NQ + OVA groups than in the OVA group. These findings suggest NQs differently enhance allergen sensitization in the context of the Th response against mononuclear cells such as lymphocytes.

Topics: Allergens; Animals; Asthma; Interferon-gamma; Interleukin-13; Interleukin-17; Leukocytes, Mononuclear; Male; Mice; Mice, Inbred BALB C; Naphthoquinones; Ovalbumin

Shikonin exhibits a wide range of anti-inflammatory actions. Here, we assessed its effects on maturation of murine bone marrow-derived dendritic cells (BM-DCs) and on allergic reactions in a murine model of asthma.. Cultured murine BM-DCs were used to investigate the effects of shikonin on expression of cell surface markers and their stimulation of T-cell proliferation and cytokine production. The therapeutic potential of shikonin was evaluated in a model of allergic airway disease.. Shikonin dose-dependently inhibited expression of major histocompatibility complex class II, CD80, CD86, CCR7 and OX40L on BM-DCs, induced by a mixture of ovalbumin (OVA; 100µg·mL(-1) ) and thymic stromal lymphopoietin (TSLP; 20ng·mL(-1) ). Shikonin-treated BM-DCs were poor stimulators of CD4(+) T lymphocyte and induced lower levels of interleukin (IL)-4, IL-5, IL-13 and tumour necrosis factor (TNF)-α release by responding T-cells. After intratracheal instillation of shikonin in OVA-immunized mice, OVA challenge induced lower IL-4, IL-5, IL-13, TNF-α and eotaxin release in bronchial alveolar lavage fluid, lower IL-4 and IL-5 production in lung cells and mediastinal lymph node cells and attenuated OVA-induced lung eosinophilia and airway hyperresponsiveness.. Shikonin effectively suppressed OVA + TSLP-induced BM-DC maturation in vitro and inhibited allergic inflammation and airway hyperresponsiveness in a murine model of asthma, showing good potential as a treatment for allergic asthma. Also, our model provides a novel platform for screening drugs for allergic diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Cytokines; Dendritic Cells; Drugs, Chinese Herbal; Female; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Naphthoquinones; Ovalbumin; Thymic Stromal Lymphopoietin; Tumor Necrosis Factor-alpha

Secreted phospholipases A(2) (sPLA(2)s) are released in plasma and other biologic fluids of patients with inflammatory, autoimmune, and allergic diseases.. We sought to evaluate sPLA(2) activity in the bronchoalveolar lavage fluid (BALF) of asthmatic patients and to examine the expression and release of sPLA(2)s from primary human lung mast cells (HLMCs).. sPLA(2) activity was measured in BALF and supernatants of either unstimulated or anti-IgE-activated HLMCs as hydrolysis of oleic acid from radiolabeled Escherichia coli membranes. Expression of sPLA(2)s was examined by using RT-PCR. The release of cysteinyl leukotriene (LT) C(4) was measured by means of enzyme immunoassay.. Phospholipase A(2) (PLA(2)) activity was higher in the BALF of asthmatic patients than in the control group. BALF PLA(2) activity was blocked by the sPLA(2) inhibitors dithiothreitol and Me-Indoxam but not by the cytosolic PLA(2) inhibitor AZ-1. HLMCs spontaneously released a PLA(2) activity that was increased on stimulation with anti-IgE. This PLA(2) activity was blocked by dithiothreitol and Me-Indoxam but not by AZ-1. HLMCs constitutively express mRNA for group IB, IIA, IID, IIE, IIF, III, V, X, XIIA, and XIIB sPLA(2)s. Anti-IgE did not modify the expression of sPLA(2)s. The cell-impermeable inhibitor Me-Indoxam significantly reduced (up to 40%) the production of LTC(4) from anti-IgE-stimulated HLMCs.. sPLA(2) activity is increased in the airways of asthmatic patients. HLMCs express multiple sPLA(2)s and release 1 or more of them when activated by anti-IgE. The sPLA(2)s released by mast cells contribute to LTC(4) production by acting in an autocrine fashion. Mast cells can be a source of sPLA(2)s in the airways of asthmatic patients.

Topics: Antibodies, Anti-Idiotypic; Asthma; Aziridines; Bronchoalveolar Lavage Fluid; Carbamates; Cells, Cultured; Dithiothreitol; Humans; Immunoglobulin E; Indolizines; Leukotriene C4; Lung; Mast Cells; Naphthoquinones; Phospholipases A2, Secretory

Topics: Adaptor Proteins, Signal Transducing; Animals; Asthma; Drug Delivery Systems; Mice; Naphthoquinones; Rats

Topics: Asthma; Child; Humans; Latex Hypersensitivity; Male; Naphthoquinones

Topics: Adult; Asthma; Female; Hair Dyes; Hair Preparations; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Naphthoquinones; Occupational Diseases; Peak Expiratory Flow Rate; Radioallergosorbent Test

Topics: Asthma; Humans; Mannich Bases; Naphthoquinones

Topics: Asthma; Epoxy Resins; Humans; Maleates; Naphthoquinones; Occupational Diseases; Phthalic Acids; Phthalic Anhydrides; Respiratory Hypersensitivity; Rhinitis; Rhinitis, Allergic, Seasonal; Toxicology