Abstract
Cardiac depression in sepsis is associated with the increased morbidity and mortality. Although myofilaments damage, autonomic dysfunction, and apoptosis play roles in sepsis-induced myocardial dysfunction, the underlying mechanism is not clear. All of these possible factors are related to NFκB signaling, which plays the main role in sepsis signaling. Thaliporphine was determined to possess anti-inflammatory and cardioprotective activity by suppressing NFκB signaling in rodents. The purpose of this study is to further prove this protective effect in larger septic animals, and try to find the underlying mechanisms. The systolic and diastolic functions were evaluated in vivo by pressure-volume analysis at different preloads. Both preload-dependent and -independent hemodynamic parameters were performed. Inflammatory factors of whole blood and serum samples were analyzed. Several sepsis-related signaling pathways were also determined at protein level. Changes detected by conductance catheter showed Thaliporphine could recover impaired left ventricular systolic function after 4 hours LPS injection. It could also reverse the LPS induced steeper EDPVR and gentler ESPVR, thus improve Ees, Ea, and PRSW. Thaliporphine may exert this protective effect by decreasing TNFα and caspase3 dependent cell apoptosis, which was consistent with the decreased serum cTnI and LDH concentration. Thaliporphine could protect sepsis-associated myocardial dysfunction in both preload-dependent and -independent ways. It may exert these protective effects by both increase of “good”-PI3K/Akt/mTOR and decrease of “bad”-p38/NFκB pathways, which followed by diminishing TNFα and caspase3 dependent cell apoptosis.
Highlights
Septic shock is an increasingly severe clinical syndrome and the primary cause of death in intensive care units characterized by hemodynamic dysfunction of several organs [1,2]
Some evidences suggest that LPS involved in the PI3K pathway followed by mammalian target of rapamycin signaling [11], which could negatively regulate p38 dependent matrix metalloproteinase-9 (MMP9) activation
There was no significant difference of mean body weight between four groups, but blood pH and glucose level were both lower after 4 hours LPS injection than were sham (7.4560.01, 68.17613.54 mg/dl vs. 7.5160.02, 157.00612.73 mg/dl, respectively)
Summary
Septic shock is an increasingly severe clinical syndrome and the primary cause of death in intensive care units characterized by hemodynamic dysfunction of several organs [1,2]. This is due to more and more uses of diagnostic or therapeutic invasive procedures and the application of immunosuppressive chemotherapy. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram negative bacteria, activates several intracellular signaling pathways including mainly NFkB and MAP kinase signaling, leading cells to a proinflammatory state with the secretion of cytokines and overexpression of several markers of the immune response [10]. Some evidences suggest that LPS involved in the PI3K pathway followed by mammalian target of rapamycin (mTOR) signaling [11], which could negatively regulate p38 dependent matrix metalloproteinase-9 (MMP9) activation
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