(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Pneumonia

Statins have been reported to prevent adverse cardiovascular events in patients with myocardial infarction (MI). However, the association of statin use and the risk of pneumonia requiring hospitalization in MI patients remains unclear.. A nested case-control study was conducted by using data from the National Health Insurance Research Database of Taiwan. Among 24,975 patients with MI, 2686 case patients with pneumonia requiring hospitalization were age- and sex-matched with 10,726 control patients using the incidence density sampling approach. Duration and dosage of statin use were obtained from pharmaceutical claims. Conditional logistic regression analyses were used to estimate the risk of hospitalization for pneumonia associated with statin use adjusted for patient's demographics, medical conditions and prescribed medications.. Statin use was associated with a 15% reduced risk of pneumonia requiring hospitalization among MI patients (adjusted odds ratio [aOR] = 0.85, 95% confidence interval [CI] = 0.77-0.95, P = 0.004). The association was more significant for MI patients unexposed to statin pretreatment (aOR = 0.76, 95% CI = 0.64-0.90, P = 0.001). Statins also exhibited favorable benefits in a time- and dose-dependent manner. The results were consistent in various subgroup analysis of the patients who were female, age ≥ 65 years, a low CHADS2 (i.e. congestive heart failure, hypertension, diabetes mellitus, previous stroke and age > 75 years old) score, and fewer comorbidities. Atorvastatin, fluvastatin and simvastatin were the most common prescribed statins and had similar effects.. Statins might be considered as an adjunctive therapy to reduce the risk of hospitalization for pneumonia for MI patients under thorough evaluation of individual comorbidities, previous statin use and optimal dosage.

Topics: Aged; Atorvastatin; Case-Control Studies; Comorbidity; Diabetes Mellitus; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Indoles; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Pneumonia; Protective Factors; Retrospective Studies; Risk Factors; Simvastatin; Stroke; Taiwan

Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages.

Topics: Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Cells, Cultured; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipopolysaccharide Receptors; Lipopolysaccharides; Macrophages; Matrix Metalloproteinase 9; Membrane Microdomains; Mice; Mice, Inbred C57BL; Mice, Knockout; NIH 3T3 Cells; Pneumonia; Protein Transport; Reverse Transcriptase Polymerase Chain Reaction; Simvastatin; Tetraspanin 28; Tetraspanin 29; Tumor Necrosis Factor-alpha; Up-Regulation