期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 194, 期 3, 页码 333-344出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201509-1878OC
关键词
influenza; lung injury; syndecan-1; proteoglycan; c-Met
资金
- National Institutes of Health (NIH) [HL120947, HL103868, HL089455]
- American Heart Association
- Cystic Fibrosis Foundation
- Cystic Fibrosis Research Translation Center [NIH P30 DK089507]
Rationale: Syndecan-1 is a cell surface heparan sulfate proteoglycan primarily expressed in the lung epithelium. Because the influenza virus is tropic to the airway epithelium, we investigated the role of syndecan-1 in influenza infection. Objectives: To determine the mechanism by which syndecan-1 regulates the lung mucosal response to influenza infection. Methods: Wild-type (WT) and Sdc1(-/-) mice were infected with a H1N1 virus (PR8) as an experimental model of influenza infection. Human and murine airway epithelial cell cultures were also infected with PR8 to study the mechanism by which syndecan-1 regulates the inflammatory response. Measurement and Main Results: We found worsened outcomes and lung injury in Sdc1(-/-) mice compared with WT mice after influenza infection. Our data demonstrated that syndecan-1 suppresses bronchial epithelial apoptosis during influenza infection to limit widespread lung inflammation. Furthermore, we determined that syndecan-1 attenuated apoptosis by crosstalking with c-Met to potentiate its cytoprotective signals in airway epithelial cells during influenza infection. Conclusions: Our work shows that cell-associated syndecan-1 has an important role in regulating lung injury. Our findings demonstrate a novel mechanism in which cell membrane-associated syndecan-1 regulates the innate immune response to influenza infection by facilitating cytoprotective signals through c-Met signaling to limit bronchial epithelial apoptosis, thereby attenuating lung injury and inflammation.
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