N,N′,N′-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in Escherichia coli sepsis in dogs*

Mink, Steven N.; Jacobs, Hans; Duke, Krika; Böse, Dirk; Cheng, Zhao-Qin; Light, R. Bruce

doi:10.1097/01.ccm.0000104919.07538.04

Cited by 21 publications

(18 citation statements)

References 28 publications

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“…The in vivo contribution of Lzm-S to cardiovascular collapse in this condition was previously demonstrated in our E. coli sepsis model, in which chitotriose (N,NЈ,N"-triacetylchitotriose), an inhibitor of Lzm-S, prevented the fall in mean arterial blood pressure, cardiac output, and stroke work otherwise observed (29). We also found that chitotriose could inhibit the Lzm-S-induced decrease in FSR in the RVT preparation (28).…”

Section: Discussionsupporting

confidence: 61%

“…The mechanism seems to relate to relatively enhanced stimulation of the parasympathetic system that can be blocked by atropine. On the basis of our in vitro and in vivo experiments (18,(27)(28)(29), we therefore suggest that inhibitors of Lzm-S, by improving SS contraction and the neural adrenergic response, offer a potential strategy for the reversal of cardiovascular collapse in septic shock.…”

Section: Discussionmentioning

confidence: 94%

“…Among the physiological compensatory mechanisms that would potentially limit loss of cardiac function in this condition, stimulation of the cardiac sympathetic neurons, which leads to an increase in the release of norepinephrine (NE), would be expected to be important. In a previous study, we used pore filtration and mass spectroscopymass spectroscopy (MS) sequencing (MS-MS) to identify a myocardial depressant factor that developed after Escherichia coli infusion in a canine model of septic shock (18,(27)(28)(29). We found that the inflammatory mediator lysozyme (Lzm-S), released from neutrophils and macrophages (5,10,16), contributed to the development of myocardial dysfunction in this model.…”

mentioning

confidence: 93%

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Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling

Mink

Cheng²,

Bose³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas beta(1)- and beta(2)-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 93%

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Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling

Mink

Cheng²,

Bose³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…48 In extension of these findings, ultrafiltrates from patients with severe sepsis and simultaneously reduced left ventricular stroke work index (Ͻ30 g · m Ϫ1 · m Ϫ2 ) displayed cardiotoxic effects and contained significantly increased concentrations of interleu-kin (IL)-1, IL-8, and C3a. 49 Recently, Mink et al 50 demonstrated that lysozyme c, a bacteriolytic agent believed to originate mainly from disintegrating neutrophilic granulocytes and monocytes, mediates cardiodepressive effects during Escherichia coli sepsis and, importantly, that competitive inhibition of lysozyme c can prevent myocardial depression in the respective experimental sepsis model. Additional potential candidates for myocardial depressant substance include other cytokines, prostanoids, and nitric oxide (NO).…”

Section: Myocardial Depressant Substancementioning

confidence: 99%

Sepsis and the Heart

2007

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Abstract-Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Morbidity and mortality are high, resulting in sepsis and septic shock being the 10th most common cause of death in the United States. 5 The incidence of sepsis and sepsis-related deaths appears to be increasing by 1.5% per year. 6 In a recent study, 6 the total national hospital cost invoked by severe sepsis in the United States was estimated at approximately $16.7 billion on the basis of an estimated severe sepsis rate of 751 000 cases per year with 215 000 associated deaths annually. A recent study from Britain documented a 46% in-hospital mortality rate for patients presenting with severe sepsis on admission to the intensive care unit. 7 As an important organ system frequently affected by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. In 1951, Waisbren was the first to describe cardiovascular dysfunction due to sepsis. 8 He recognized a hyperdynamic state with full bounding pulses, flushing, fever, oliguria, and hypotension. In addition, he described a second, smaller patient group who presented clammy, pale, and hypotensive with low volume pulses and who appeared more severely ill. With hindsight, the latter group might well have been volume underresuscitated...

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“…We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in canine models of septic shock (21,(33)(34)(35). We showed that the mechanism by which Lzm-S caused myocardial depression was related to the binding of its catalytic site to the endocardial endothelium (EE) (33).…”

mentioning

confidence: 99%

Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation

Mink

Kasian

Martinez³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.

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N,N′,N′-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in Escherichia coli sepsis in dogs*

Abstract: We found that TAC, a competitive inhibitor of Lzm-S, prevented myocardial depression in experimental sepsis. Only specific NAG structures are inhibitory to Lzm-S's depressant activity. TAC may be useful in attenuating cardiovascular collapse in sepsis.

Cited by 21 publications

References 28 publications

Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling

Lysozyme, a mediator of sepsis, impairs the cardiac neural adrenergic response by nonendothelial release of NO and inhibitory G protein signaling

Sepsis and the Heart

Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation

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