| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 98 === There are more than 4,000 kind of compounds in cigarette smoke (CS) that may result in cancer and airway diseases. After inhalation of toxic materials in CS, it has been shown to induce increases in the production of various chemokines including interleukin-8 (IL-8) in lung epithelial cells (LECs). IL-8, a kind of proinflammatory, has been recognized as the key chemokine for recruitment of inflammatory cells to the alveolar spaces. Because their accessibility to CS, LECs play a critical role in the initiation and progression of the lung pulmonary inflammation. Whether CS can stimulate LECs leading to up-regulation of IL-8 remains unclear. Additionally, AMP-activated protein kinase (AMPK), a serine/threonine kinase possessing energy-sensing capability, is well known for its function in the activation of ATP-generating pathway. However, recent evidence suggests that AMPK may functionally modulate acute inflammatory responses in other cell types. For example, activation of AMPK increases the production of inflammatory cytokines via p38/NF-κB signaling pathway in human synovial fibroblast. In contrast, activation of AMPK attenuates lipopolysaccharide-induce neutrophil pro-inflammatory activity. Therefore, the objectives of this study were to investigate 1) exposure of mice to CS may activate AMPK phosporylation and, 2) whether exposure of cultured human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) may up-regulate IL-8 via CSE-induced activation of AMPK. We found that CS exposure increased total cell counts, differential cell counts, total protein and macrophage inflammatory protein-2 (MIP-2) expression in bronchial alveolar lavage fluid (BALF) and in lung tissue. Also, MIP-2 expression and activation of AMPK were increased in lung tissue. In cell model, CSE exposure increased protein expression of IL-8 in a dose- and time-dependant manner. Studies using specific pharmacological inhibitors and small interfering RNA (siRNA) revealed that the CSE-induced up-regulation of IL-8 was mediated trough activation of AMPK. These results suggest that CSE-induced up-regulation of IL-8 is mediated through AMPK activation.
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