Inhibitors of ceramide de novo biosynthesis rescue damages induced by cigarette smoke in airways epithelia

Abstract

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.

Cellular and Molecular Signatures of Oxidative Stress in Bronchial Epithelial Cell Models Injured by Cigarette Smoke Extract

“…For these reasons, immortalized human bronchial epithelial (HBE) cells are widely used and established as experimental models to study lung diseases [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”

Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases

“…Very recently, Bodas et al showed that Cer/Sph ratio was elevated in COPD subjects as well as in mice exposed to cigarette smoke, worsening COPD-emphysema severity [98]. Excessive Cer content triggers damages of structural airway epithelial cells [99][100][101], which is involved in pulmonary tissue destruction [102] and contributes to maintain pulmonary inflammation [103].…”

Brain Cancer-Activated Microglia: A Potential Role for Sphingolipids

“…It has already been demonstrated in different diseases that Cer plays a pro-inflammatory role in, for instance, airway inflammation, pulmonary edema, inflammatory bowel disease, inflammation during labor, post myocardium ischemic and cystic fibrosis [159][160][161][162][163][164][165][166][167][168]. But, the role of SLs in microglia was depicted only a few years ago when Jung and colleagues [162] showed that Cer with acyl chain length C2 to C8 was able to block the inflammation induced by LPS.…”