1.Pulmonary alveolar macrophage cytotoxicity investigation of irregular shape mineral dusts.
Faqin DONG ; Jianjun DENG ; Xiaoyong PU ; Huang JOHN
Journal of Biomedical Engineering 2006;23(4):848-851
In order to study the damage mechanism of mineral dusts on the pulmonary alveolar macrophages (AM), the changes of their death ratio, malandialdthyde (MDA) content and activities of lactate dehydrogenase (LDH) and superoxide dismutase (SOD) were measured. And the technique of cell culture in vitro was used to investigate the cytotoxicity of six mineral dusts (twelve crystal habits) from twelve mineral deposits. The results showed that wollstonite and clinoptilolite had no AM cytotoxicity while other fibrous and grainy mineral dusts could damage pulmonary AM in various degrees. The cytotoxicity of fibrous mineral dusts was greater than that of the grainy ones, and the cytotoxicity of dusts was positively correlated with the active OH- content in dusts, but not necessarily so with its SiO2 content. The high pH values produced by dust was unfavorable for the cells survival and the dusts with a low bio-resistance were safe for cells. The content of variable valence elements in dusts could influence their cytotoxicity and the surface charge of dusts was not a stable factor on their toxicity. It indicates that the shape of mineral dusts is one of the factors affecting cytotoxicity, and that the cytotoxicity of mineral dusts mainly depends on their properties.
Animals
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Cell Death
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drug effects
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Cells, Cultured
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Dust
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Macrophages, Alveolar
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cytology
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drug effects
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enzymology
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Male
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Minerals
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chemistry
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toxicity
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Rabbits
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Toxicity Tests
2.Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract.
Sang Eun KIM ; Tran Thi THUY ; Ji Hyun LEE ; Jai Youl RO ; Young An BAE ; Yoon KONG ; Jee Yin AHN ; Dong Soon LEE ; Yeon Mock OH ; Sang Do LEE ; Yun Song LEE
Experimental & Molecular Medicine 2009;41(4):277-287
Matrix metalloproteinase-9 (MMP-9) may play an important role in emphysematous change in chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality and morbidity worldwide. We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, attenuates emphysematous change and MMP-9 induction in the lungs of rats exposed to cigarette smoke. However, it remained uncertain how cigarette smoke induced MMP-9 and how simvastatin inhibited cigarette smoke-induced MMP-9 expression in alveolar macrophages (AMs), a major source of MMP-9 in the lungs of COPD patients. Presently, we examined the related signaling for MMP-9 induction and the inhibitory mechanism of simvastatin on MMP-9 induction in AMs exposed to cigarette smoke extract (CSE). In isolated rat AMs, CSE induced MMP-9 expression and phosphorylation of ERK and Akt. A chemical inhibitor of MEK1/2 or PI3K reduced phosphorylation of ERK or Akt, respectively, and also inhibited CSE-mediated MMP-9 induction. Simvastatin reduced CSE-mediated MMP-9 induction, and simvastatin-mediated inhibition was reversed by farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). Similar to simvastatin, inhibition of FPP transferase or GGPP transferase suppressed CSE-mediated MMP-9 induction. Simvastatin attenuated CSE-mediated activation of RAS and phosphorylation of ERK, Akt, p65, IkappaB, and nuclear AP-1 or NF-kappaB activity. Taken together, these results suggest that simvastatin may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of RAS in the signaling pathways, in which Raf-MEK-ERK, PI3K/Akt, AP-1, and IkappaB-NF-kappaB are involved.
1-Phosphatidylinositol 3-Kinase/metabolism
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Alkyl and Aryl Transferases/metabolism
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Animals
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Anticholesteremic Agents/pharmacology
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Cells, Cultured
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Enzyme Inhibitors/metabolism/pharmacology
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Extracellular Signal-Regulated MAP Kinases/metabolism
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Gene Expression Regulation, Enzymologic/*drug effects
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I-kappa B Kinase/antagonists & inhibitors/metabolism
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Macrophages, Alveolar/cytology/*drug effects/*enzymology
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Matrix Metalloproteinase 9/genetics/*metabolism
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Mitogen-Activated Protein Kinase Kinases/metabolism
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Polyisoprenyl Phosphates/metabolism
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Proto-Oncogene Proteins c-akt/metabolism
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Rats
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Sesquiterpenes/metabolism
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Signal Transduction/physiology
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Simvastatin/*pharmacology
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Smoke/*adverse effects
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*Tobacco/adverse effects/chemistry