Airway Resistance Caused by Sphingomyelin Synthase 2 Insufficiency in Response to Cigarette Smoke
| Autor: | Michael D. Kim, Melissa Rivas, Xian-Cheng Jiang, Raj Wadgaonkar, Christopher Railwah, Nathalie Baumlin, Ziyad Elgamal, Chongmin Huan, Robert F. Foronjy, Matthias Salathe, Begum Ahmed, Abdoulaye J. Dabo, Gayatri Gupta, Hannah Goldenberg, Justin Poon, Patrick J. Geraghty, Apurav A Panwala, Yeun-Po Chiang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine medicine.medical_specialty Ceramide Smoke inhalation Clinical Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Airway resistance Internal medicine Sphingomyelin synthase medicine Molecular Biology Protein kinase B COPD biology business.industry Cell Biology medicine.disease Sphingolipid 030104 developmental biology Endocrinology 030228 respiratory system chemistry biology.protein Sphingomyelin business |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 62:342-353 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|