Activation of Toll-like receptor 7 provides cardioprotection in septic cardiomyopathy-induced systolic dysfunction.

BACKGROUND: As a pattern recognition receptor, Toll-like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy. METHODS: We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7-knockout (TLR7-/- ), wild-type (WT) mice, cardiac-specific TLR7-transgenic (cTG-TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad-TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca2+ imaging, western blotting, immunostaining, and quantitative real-time polymerase chain reaction (qPCR). RESULTS: We found that TLR7 knockout markedly exacerbated sepsis-induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7-/- mice displayed weaker Ca2+ handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS-induced systolic dysfunction, and loxoribine (TLR7-specific agonist) improved LPS-induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)-protein kinase A (PKA) pathway, which upregulated phosphorylate-phospholamban (p-PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca2+ ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca2+ handling in response to sepsis. While improved Ca2+ handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG-TLR7 mice. Consistently, TLR7 overexpression improved LPS-induced Ca2+ -handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype. CONCLUSIONS: Our data demonstrated that activation of TLR7 protected against sepsis-induced cardiac dysfunction through promoting cAMP-PKA-PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis.

Intervention effect of the mode of monitoring-training-planning on rational use of antibacterials in upper respiratory infection in outpatient clinic of respiratory department / 中国实用内科杂志

Objective To study the effect of the intervention mode of MTP on use of antibacterials in upper respiratory infection.Methods Adopt retrospective method to select randomly prescriptions of upper respiratory infection from July to September in 2006 for baseline investigation in Outpatient Clinic of Respiratory Department of the First People's Hospital of the city of Zhuhai in Guangdong province.Then aim physicians was interfered by MTP and investigation of post-interference was carried out after a month.The process of intervention and investigation was carried out repeatedly until June in 2007.The ratio of antibacterials use,injection use percentage and average drug fee was observed in pre/post-interference.Results The ratio of antibacterials use in upper respiratory infection in our hospital was decreased from 81.33% to 0,and the ratio percentage of injection use and average drug fee decreased by 81.69% and 35.47% respectively after four MTP circulations.Conclusion The intervention mode of MTP is feasible and effective on promoting the rational use of antibacterials on upper respiratory infection in Outpatient Clinic of Respiratory Department of our hospital.