Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction

Abstract

We hypothesized that progressive decline in myocardial performance would correlate with upregulation of markers for apoptotic mechanisms following increased duration of polymicrobial sepsis in the rat. Male Sprague-Dawley rats (350-400 g) were randomized into sham, 1-, 3-and 7-day sepsis groups. Each septic rat received 200 mg/kg cecal inoculum intraperitoneally (i.p). The post-mortem analysis showed a severely inflamed peritoneum with the presence of pus in all septic animals that was directly proportional to the duration of sepsis. We observed 10, 33 and 42% mortality in the 1-, 3-and 7-day sepsis groups, respectively. Septic animals at 3 and 7 days exhibited an increased wet lung/total body weight and heart weight/total body weight. A significant increase in total cardiac troponin I (cTnI) and C Reactive Protein (CRP) and endothelin-1 (ET-1) was also observed with an increased duration of sepsis. Myocardial ET-1 concentration in the 7-day postsepsis group was significantly elevated compared to the sham and 1-day post-sepsis groups. Sepsis also produced a significant decrease in the mean arterial pressure in the 7-day post-sepsis group and tachycardia in the 1-, 3-, and 7-day post-sepsis groups compared to the sham group. A significant prolongation of the left ventricular isovolumic relaxation rate constant, tau, and left ventricular enddiastolic pressure in the 1-, 3-and 7-day post-sepsis groups compared to the sham group was observed. In addition, a significant decrease in the rates of left ventricular relaxation (−dP/dt) and contraction (+dP/dt) in the 3-and 7-day post-sepsis groups compared to the sham and 1-day postsepsis group was observed. Sepsis produced a significant upregulation in the expression of myocardial TRADD, cytosolic active caspase-3, the Bax/Bcl 2 ratio, and the mitochondrial release of cytochrome C in the 3-and 7-day post-sepsis groups. We observed a progressive increase in the number of TUNEL positive nuclei, cytosolic caspase-3 activation and co-localization of PARP in the nuclei at 1, 3 and 7 days post-sepsis. These data suggest that the progression of sepsis from 1 day to 3-7 days produce distinct cardiodynamic characteristics with a more profound effect during later stages. The sepsis-induced decline in myocardial performance correlates with the induction of myocardial apoptosis.

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase*

“…Activation of p38MAPK has been demonstrated in myocardial, lung and brain tissue in sepsis [37][38][39][40], suggesting that p38MAPK has widespread effects in the pathophysiology of multi-organ dysfunction in septic shock. Inhibition of p38MAPK has been shown to attenuate LPS-induced acute lung injury through downregulation of the NFKB pathway [41].…”

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

“…43 In our study, LPS stimulation induced apoptosis that was associated with changes in protein levels of antiapoptotic Bcl-2 and Bax and caspase-3. Previous studies have tested the hypothesis that an increased duration of sepsis stimulates apoptosis in lung tissue, 44,45 whereas others have suggested a biphasic response where changes in Bax/Bcl-2 protein levels were found after sepsis onset. 40 Although NF-κB could have a role in apoptosis by regulating the expression of genes involved in cell death, a specific role of NF-κB on the apoptotic process cannot be ascertained from our data.…”

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

“…For example, in a septic rat model, up-regulated PARP-1 expression colocalized with DNA breaks and correlated with sepsis-induced inflammation and early and late stages of myocardial dysfunction. 41 In pulmonary inflammation models induced by intratracheal administration of lipopolysaccharide (LPS), PARP-1 suppression by genetic deletion or pharmacological inhibitors was beneficial in reducing the inflammatory cell recruitment to mouse airways. 42,43 Likewise, the absence of PARP-1 in a mouse model of enterocolitis induced by Salmonella typhimurium decreased NF-Bmediated proinflammatory gene expression and was associated with delayed gut inflammation.…”