Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

Chung, Ha-Yeun; Hupe, Daniel C; Otto, Gordon P.; Sprenger, Marcel; Bunck, Alexander C.; Dorer, Michael J.; Bockmeyer, Clemens L.; Deigner, Hans‐Peter; Gräler, Markus H.; Claus, Ralf A.

doi:10.2119/molmed.2016.00140

Cited by 27 publications

(28 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An increased activity of SMPD1 has been observed in response to exogenous and endogenous mediators including oxidative stress, cytokines or invading microorganisms [ 37 ]. However, our experiments were based on the observation that increased plasma levels of SMPD1 have been found in patients with sepsis as well as patients with chronic heart failure [ 13 , 14 , 15 , 16 , 38 ]. Furthermore, numerous studies have described ceramide-induced caspase-3 and -8-like protease activation in cardiomyocytes [ 39 ] and cardiomyocyte apoptosis in ischemia/reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

“…Enhancement of activity and increase in concentration in plasma correlates with disease severity of septic patients and discriminates with respect to outcome [13,14,15]. Patients with chronic heart failure also have increased activity, associated with decreased vascular functional capacity and poor long-term outcome [16].…”

Section: Introductionmentioning

confidence: 99%

“…The plasma-secreted isoform of acid sphingomyelinase (SMPD1) is a conserved enzyme in cellular stress response playing a detrimental role in sepsis and remote organ failure [ 12 ]. Enhancement of activity and increase in concentration in plasma correlates with disease severity of septic patients and discriminates with respect to outcome [ 13 , 14 , 15 ]. Patients with chronic heart failure also have increased activity, associated with decreased vascular functional capacity and poor long-term outcome [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

Chung

Kollmey

Schrepper

et al. 2017

IJMS

Self Cite

View full text Add to dashboard Cite

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

Chung

Kollmey

Schrepper

et al. 2017

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Various studies suggested that sepsis is closely associated with the pathological processes of inflammation (12,13), which may require further elucidation. Sepsis is thought to result from acute and postponed inflammatory responses via the increasing of plasma inflammatory cytokines levels and leukocytes in affected patients (14,15).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory cytokine expression in patients with sepsis at an intensive care unit

2018

View full text Add to dashboard Cite

Abstract. Sepsis is a systemic inflammatory response syndrome caused by infection of bacteria, fungi and/or viruses in clinical patients. It is known that inflammatory cytokine levels have an essential role in the progression of sepsis. The present study investigated the role of inflammatory markers in human peripheral blood mononuclear cells (hPBMCs) of patients with sepsis at an intensive care unit. In addition, the plasma levels of inflammatory cytokines were compared between sepsis patients and healthy individuals. The results demonstrated that the serum levels of interleukin-1, -17 and -6, as well as tumor necrosis factor-α, were upregulated in sepsis patients. The serum levels of high mobility group box 1 and C-reactive protein were increased in sepsis patients compared with those in healthy individuals. The expression levels of nuclear factor-κB-p65 and its inhibitor IκBα, as well as the ratio of CD25 + cells, and the levels of neutrophil gelatinase-associated lipocalin and peptidoglycan recognition protein were higher in hPBMCs in sepsis patients compared with those in healthy individuals. It was also indicated that balance of T helper type 1/2 cytokines was also disturbed in patients with sepsis compared with that in healthy individuals. In conclusion, these results indicated that inflammation is involved in the progression of sepsis by interfering with the expression of various molecules, suggesting a potential therapeutic strategy for the treatment of sepsis patients.

show abstract

“…This process further leads to local ceramide accumulation in so called lipid rafts which is mediated by its biophysical properties [ 21 ]. The plasma activity of acid sphingomyelinase correlates with the severity of the disease and allows for the discrimination of patient outcomes [ 16 , 22 , 23 ]. In the course of endotoxemia and Staphylococcus aureus induced sepsis [ 24 ], functional inhibition of SMPD1 exerted protective effects and improved survival rates [ 16 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

Chung

Hurtado-Oliveros

Wickel

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1+/− mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated.

show abstract

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

Cited by 27 publications

References 65 publications

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

Inflammatory cytokine expression in patients with sepsis at an intensive care unit

Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

Contact Info

Product

Resources

About