RESUMEN
Sphingomyelin synthase is responsible for the production of sphingomyelin (SGM), the second most abundant phospholipid in mammalian plasma, from ceramide, a major sphingolipid. Knowledge of the effects of cigarette smoke on SGM production is limited. In the present study, we examined the effect of chronic cigarette smoke on sphingomyelin synthase (SGMS) activity and evaluated how the deficiency of Sgms2, one of the two isoforms of mammalian SGMS, impacts pulmonary function. Sgms2-knockout and wild-type control mice were exposed to cigarette smoke for 6 months, and pulmonary function testing was performed. SGMS2-dependent signaling was investigated in these mice and in human monocyte-derived macrophages of nonsmokers and human bronchial epithelial (HBE) cells isolated from healthy nonsmokers and subjects with chronic obstructive pulmonary disease (COPD). Chronic cigarette smoke reduces SGMS activity and Sgms2 gene expression in mouse lungs. Sgms2-deficient mice exhibited enhanced airway and tissue resistance after chronic cigarette smoke exposure, but had similar degrees of emphysema, compared with smoke-exposed wild-type mice. Sgms2-/- mice had greater AKT phosphorylation, peribronchial collagen deposition, and protease activity in their lungs after smoke inhalation. Similarly, we identified reduced SGMS2 expression and enhanced phosphorylation of AKT and protease production in HBE cells isolated from subjects with COPD. Selective inhibition of AKT activity or overexpression of SGMS2 reduced the production of several matrix metalloproteinases in HBE cells and monocyte-derived macrophages. Our study demonstrates that smoke-regulated Sgms2 gene expression influences key COPD features in mice, including airway resistance, AKT signaling, and protease production.
Asunto(s)
Resistencia de las Vías Respiratorias/fisiología , Nicotiana/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Humo/efectos adversos , Productos de Tabaco/efectos adversos , Transferasas (Grupos de Otros Fosfatos Sustitutos)/deficiencia , Animales , Bronquios/citología , Células Cultivadas , Ceramidas/metabolismo , Células Epiteliales , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Macrófagos/metabolismo , Metaloproteinasas de la Matriz/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-akt/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología , Esfingomielinas/biosíntesis , Transferasas (Grupos de Otros Fosfatos Sustitutos)/biosíntesis , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/fisiologíaRESUMEN
OBJECTIVE: Multi-frequency tympanometry and its components are extensively used to identify middle ear disorders. However, there are a limited number of studies that have attempted to determine its test-retest reliability. Thus, the present study attempted to determine the test-retest reliability of the different components of multi-frequency tympanometry. MATERIALS AND METHODS: The resonant frequency (RF), F45, and ΔG were determined three times in 40adults with normal hearing. The results obtained across the three trials were compared to determine the test-retest reliability. RESULTS: F45 and ΔG had excellent intra- and inter-session reliabilities. The reliability of the RF was also good, but it was relatively less compared to that of the other two measures. The study also showed that there was no effect of gender on the reliability measures. CONCLUSION: Thus, F45 and ΔG can be clinically used considering theirhigh reliability, and the RF should be interpreted with caution. However, further studies on a larger group of patientsincluding a clinical group are essential for determining the further applicability of these results.