Gender differences in sepsis

Angele, Martin K.; Pratschke, Sebastian; Hubbard, William J.; Chaudry, Irshad H.

doi:10.4161/viru.26982

Cited by 264 publications

(136 citation statements)

References 80 publications

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“…In the present study we used male mice to evaluate the effect of Ang-(1-7) on LPS-induced muscle wasting; however, there is evidence that indicates sex-dependent differences in: (i) muscle composition and its functionality [51,52]; (ii) prognosis in sepsis [53,54]; and (iii) the expression and activation of the Ang-(1-7)/Mas receptor axis in cardiovascular pathologies [55][56][57][58]. For this reason, further studies could be performed in female mice to elucidate the different sex-related response to Ang-(1-7) on muscle wasting induced by LPS.…”

Section: Discussionmentioning

confidence: 98%

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

et al. 2015

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Skeletal muscle atrophy induced during sepsis syndrome produced by endotoxin in the form of LPS (lipopolysaccharide), is a pathological condition characterized by the loss of strength and muscle mass, an increase in MHC (myosin heavy chain) degradation, and an increase in the expression of atrogin-1 and MuRF-1 (muscle-specific RING-finger protein 1), two ubiquitin E3 ligases belonging to the ubiquitin-proteasome system. Ang-(1-7) [Angiotensin-(1-7)], through its Mas receptor, has beneficial effects in skeletal muscle. We evaluated in vivo the role of Ang-(1-7) and Mas receptor on the muscle wasting induced by LPS injection into C57BL/10J mice. In vitro studies were performed in murine C2C12 myotubes and isolated myofibres from EDL (extensor digitorum longus) muscle. In addition, the participation of p38 MAPK (mitogen-activated protein kinase) in the Ang-(1-7) effect on the LPS-induced muscle atrophy was evaluated. Our results show that Ang-(1-7) prevents the decrease in the diameter of myofibres and myotubes, the decrease in muscle strength, the diminution in MHC levels and the induction of atrogin-1 and MuRF-1 expression, all of which are induced by LPS. These effects were reversed by using A779, a Mas antagonist. Ang-(1-7) exerts these anti-atrophic effects at least in part by inhibiting the LPS-dependent activation of p38 MAPK both in vitro and in vivo. We have demonstrated for the first time that Ang-(1-7) counteracts the skeletal muscle atrophy induced by endotoxin through a mechanism dependent on the Mas receptor that involves a decrease in p38 MAPK phosphorylation. The present study indicates that Ang-(1-7) is a novel molecule with a potential therapeutic use to improve muscle wasting during endotoxin-induced sepsis syndrome.

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Section: Discussionmentioning

confidence: 98%

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

et al. 2015

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“…There are numerous known sex differences in sepsis (93), which, in experimental models, usually confer a certain degree of protection to females (93). However, this protection is only partially seen in humans, in whom sepsis is indeed less prevalent in women, but is associated with higher mortality (94).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Intracellular Calcium Transporters in Animal Models of Sepsis-Induced Cardiomyopathy

Hobai

Edgecomb

LaBarge³

et al. 2015

Shock

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Sepsis induced cardiomyopathy (SIC) develops as the result of myocardial calcium (Ca2+) dysregulation. Here we reviewed all published studies that quantified the dysfunction of intracellular Ca2+ transporters and the myofilaments in animal models of SIC. Cardiomyocytes isolated from septic animals showed, invariably, a decreased twitch amplitude, which is frequently caused by a decrease in the amplitude of cellular Ca2+ transients (ΔCai) and sarcoplasmic reticulum (SR) Ca2+ load (CaSR). Underlying these deficits, the L-type Ca2+ channel is downregulated, through mechanisms that may involve adrenomedullin-mediated redox signaling. SR Ca2+ pump (SERCA) is also inhibited, through oxidative modifications (sulphonylation) of one reactive thiol group (on Cys674), and/or modulation of phospholamban. Diastolic Ca2+ leak of ryanodine receptors is frequently increased. In contrast, Na+/Ca2+ exchange inhibition may play a partially compensatory role by increasing CaSR and ΔCai. The action potential is usually shortened. Myofilaments show a bidirectional regulation, with decreased Ca2+ sensitivity in milder forms of disease (due to troponin I hyperphosphorylation) and a (redox mediated) increase in more severe forms. Most deficits occurred similarly in two different disease models, induced by either intraperitoneal administration of bacterial lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). In conclusion, substantial cumulative evidence implicates various Ca2+ transporters and the myofilaments in SIC pathology. What is less clear, however, is the identity and interplay of the signaling pathways that are responsible for Ca2+ transporters dysfunction. With few exceptions, all studies we found used solely male animals. Identifying sex differences in Ca2+ dysregulation in SIC becomes, therefore, another priority.

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“…However, this first in vitro study had to follow the mass of information already existing in in vivo models. Identifying sex differences (43) in SIC must remain for the future. For this goal, our in vitro model offers distinct promises, since it will allow the direct comparison of cells isolated from male vs. female rats after identical challenge with Cytomix in vitro , as well as studying the effects of sex hormones on modulating Ca 2+ handling dysregulation induced by Cytomix.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide and cytokines inhibit rat cardiomyocyte contractility in vitro

Hobai

Morse

Siwik

et al. 2015

Journal of Surgical Research

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Background Sepsis-induced cardiomyopathy (SIC) is thought to be the result of detrimental effects of inflammatory mediators on cardiac muscle. Here we studied the effects of prolonged (24 ± 4 h) exposure of adult rat ventricular myocytes (ARVM) to bacterial lipopolysaccharide (LPS) and inflammatory cytokines tumor necrosis factor (TNF) and interleukins-1 (IL-1) and -6 (IL-6). Materials and methods We measured sarcomere shortening (SS) and cellular calcium (Ca2+) transients (ΔCai, with fura-2AM) in isolated cardiomyocytes externally paced at 5Hz at 37 °C. Results SS decreased after incubation with LPS (100 µg/ml), IL-1 (100 ng/ml) and IL-6 (30 ng/ml), but not with lesser doses of these mediators, or TNF (10 –100 ng/ml). A combination of LPS (100 µg/ml), TNF, IL-1 and IL-6 (each 100 ng/ml; i.e. “Cytomix-100”) induced a maximal decrease in SS and ΔCai. Sarcoplasmic reticulum (SR) Ca2+ load (CaSR, measured with caffeine) was unchanged by Cytomix-100, however, SR fractional release (ΔCai/CaSR) was decreased. Underlying these effects, Ca2+ influx into the cell (via L-type Ca2+ channels) and Ca2+ extrusion via Na+/Ca2+ exchange were decreased by Cytomix-100. SR Ca2+ pump (SERCA) was not affected. Conclusions Prolonged exposure of ARVM to a mixture of LPS and inflammatory cytokines inhibits cell contractility. The effect is mediated by the inhibition of Ca2+ influx via LTCC, and partially opposed by the inhibition of Na+/Ca2+ exchange. Since both mechanisms are commonly seen in animal models of SIC, we conclude that prolonged challenge with Cytomix-100 of ARVM may represent an accurate in vitro model for SIC.

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Gender differences in sepsis

Cited by 264 publications

References 80 publications

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

Dysregulation of Intracellular Calcium Transporters in Animal Models of Sepsis-Induced Cardiomyopathy

Lipopolysaccharide and cytokines inhibit rat cardiomyocyte contractility in vitro

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