interleukin-8 and thermozymocidin

Exposure to cigarette smoke represents the most important risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation of the airways, imbalance of proteolytic activity resulting in the destruction of lung parenchyma, alveolar hypoxia, oxidative stress, and apoptosis. Sphingolipids are structural membrane components whose metabolism is altered during stress. Known as apoptosis and inflammation inducer, the sphingolipid ceramide was found to accumulate in COPD airways and its plasma concentration increased as well. The present study investigates the role of sphingolipids in the cigarette smoke-induced damage of human airway epithelial cells. Lung epithelial cells were pre-treated with sphingolipid synthesis inhibitors (myriocin or XM462) and then exposed to a mixture of nicotine, acrolein, formaldehyde, and acetaldehyde, the major toxic cigarette smoke components. The inflammatory and proteolytic responses were investigated by analysis of the mRNA expression (RT-PCR) of cytokines IL-1β and IL-8, and matrix metalloproteinase-9 and of the protein expression (ELISA) of IL-8. Ceramide intracellular amounts were measured by LC-MS technique. Ferric-reducing antioxidant power test and superoxide anion radical scavenging activity assay were used to assess the antioxidant power of the inhibitors of ceramide synthesis. We here show that ceramide synthesis is enhanced under treatment with a cigarette smoke mixture correlating with increased expression of inflammatory cytokines and matrix metalloproteinase 9. The use of inhibitors of ceramide synthesis protected from smoke induced damages such as inflammation, oxidative stress, and proteolytic imbalance in airways epithelia.

Topics: Bronchi; Cells, Cultured; Ceramides; Epithelial Cells; Fatty Acids, Monounsaturated; Humans; Interleukin-1beta; Interleukin-8; Matrix Metalloproteinase 9; Nicotiana; Smoke; Sulfides

Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects.. The therapeutic potential of myriocin, an inhibitor of the sphingolipid de novo synthesis rate limiting enzyme (Serine Palmitoyl Transferase, SPT),was investigated in CF cells and mice models.. We treated CF human respiratory epithelial cells with myriocin, This treatment resulted in reduced basal, as well as TNFα-stimulated, inflammation. In turn, TNFα induced an increase in SPT in these cells, linking de novo synthesis of ceramide to inflammation. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P. aeruginosa challenge, enabled a significant reduction of lung infection and reduced inflammation.. The presented data suggest that de novo ceramide synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection.. Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.

Topics: Animals; Anti-Inflammatory Agents; Antifungal Agents; Blotting, Western; Cell Proliferation; Ceramides; Chromatography, Liquid; Cystic Fibrosis; Drug Carriers; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Monounsaturated; Female; Humans; Interleukin-6; Interleukin-8; Male; Mice; Mice, Inbred CFTR; Nanoparticles; Pseudomonas aeruginosa; Pseudomonas Infections; Real-Time Polymerase Chain Reaction; Respiratory Mucosa; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids