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Reply to letter by Siracusano & Girasole
- Melanie Marshall, Jonathon C. Kentish (23 April 2009)
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PP2A activity in sepsis and the importance of the experimental model
- Luca Siracusano, V. Girasole (30 March 2009)
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Melanie Marshall, Post-Doctoral Research Assistant Dept of Cardiology, King's College London, 125, Coldharbour Lane, London SE5 9NU, Jonathon C. Kentish
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We would like to thank Siracusano & Girasole (1) for their interest in our paper (2). We agree that it would be very interesting to examine PP2A activity in another model of sepsis such as the cecal ligation puncture (CLP) model. However, the endotoxin-induced model of sepsis is a well-established and useful model that has been employed extensively in sepsis research (3-5). We used this model in our study as it is a very robust model of sepsis-associated cardiac dysfunction. Furthermore, we were particularly interested in the hypodynamic stage of sepsis because, in the experimental setting, many drugs appear to reduce myocardial dysfunction when given as a pre-treatment, but few seem to have a significant impact when sepsis is already well developed. Our study shows one way in which endotoxaemia-induced myocardial dysfunction can be reversed by drug treatment several hours after the onset of sepsis. Nevertheless, we agree that the pathophysiology of sepsis is complex and translation of the results from any animal model of sepsis (whether endotoxin- or CLP-induced) to humans should always be undertaken with caution. 1) Luca Siracusano, & V. Girasole: PP2A activity in sepsis and the importance of the experimental model. Cardiovasc Res. 2009; E-letter from 30 March. 2) Marshall M, Anilkumar N, Layland J, Walker SJ, Kentish JC, Shah AM, Cave AC: Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia. Cardiovasc Res. 2009; 82:67-76. 3) Aoshiba K, Onizawa S, Tsuji T, Nagai A: Therapeutic effects of erythropoietin in murine models of endotoxin shock. Crit. Care Med. 2009; 37(3): 889-98. 4) Tsai WH, Cheng PY, Lee YM, Jiau SS, Wu ES, Yen MH: Anti-inflammatory effects of LK- 3 on LPS-induced sepsis in rats. Chin J. Physiol. 2008; 51(5): 291-300. 5) Nacira S, Meziani F, Dessebe O, Cattan V, Collins S, Montemont C, Gibot S, Asfar P, Ramaoson A, Regnault V, Slama M, Lecompte T, Lacolley P, Levy B: Activated protein C improves lipopolysaccharide-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress. Crit. Care Med. 2009 37(1); 246-255. Conflict of Interest:None declared |
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Luca Siracusano, associate professor Policlinico of Messina via Consolare Valeria 98121 Messina, V. Girasole
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We read with great interest the article by Marshall et al (1) underlining the role of the Protein Phosphatase 2A (PP2A) and of the balance between kinases and phosphatases in the phosphorylation of cardiac Troponin I (cTnI) at Ser 23\24 leading to the reduced contractile function observed in sepsis. The pathogenesis of the myocardial dysfunction in sepsis is not definitively explained even though several concomitant causes of the contractile alteration have been recognized: along with the increased phosphorylation of cTnI and the consequent reduction in contractile efficiency, the increase in TNFalpha and other proinflammatory ILs, the downregulation of beta receptors in the later phases of sepsis, myocardiocytes death by apoptosis, the excess of nitric oxide systemic and\or in some critical cell compartments (2-3). However the choice of the model used in this study may give rise to some doubt. It is well known that the degree of cTnI phosphorylation at Ser 23\24, the related calcium sensitivity of myocardiocytes and the beta adrenergic function have a different behaviour in the early hyperdynamic and the late hypodynamic phase of the sepsis with an initial increase followed by a reduction (4); also, the calcium content of the sarcoplasmic reticulum undergoes modifications during sepsis showing a reduction only in the hypodynamic phase (5). In the experimental model of sepsis elicited by endotoxin administration, in contrast to the cecal ligation and puncture(CLP) model, there is only the presence of a hypodynamic phase (6), making difficult the translation of the important data obtained in this study to the setting of human sepsis, characterized by a biphasic course. We think it would be very intriguing, in future studies, to control the course of the PP2A activity in a CLP model of sepsis. References. 1)Marshall M, Anilkumar N, Layland J, Walker SJ, Kentish JC, Shah AM, Cave AC: Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia. Cardiovasc Res. 2009; 82:67-76. 2)Fernandes CJ Jr, Akamine N, Knobel E: Myocardial depression in sepsis. Shock. 2008;30 Suppl 1:14-7. 3) Flierl MA, Rittirsch D, Huber-Lang MS, Sarma JV, Ward PA.: Molecular Events in the Cardiomyopathy of Sepsis. Mol Med 2008 ; 14:327-36. 4)Wu LL, Tang C, Liu MS: Altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins during sepsis. Am J Physiol Regul Integr Comp Physiol. 2001 Aug;281:R408-16 5)Dong LW, Wu LL, Ji Y, Liu MS. Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock. 2001 Jul;16(1):33-9. 6)Esmon CT: Why do animal models (sometimes) fail to mimic human sepsis? Crit Care Med. 2004 May;32(5 Suppl):S219-22. Conflict of Interest:None declared |
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