Publications by authors named "Hjalmar R Bouma"

37 Publications

Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.

Front Physiol 2021 1;12:624950. Epub 2021 Apr 1.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their 'great slumbers.'
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http://dx.doi.org/10.3389/fphys.2021.624950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047423PMC
April 2021

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney.

Redox Biol 2021 Apr 2;43:101961. Epub 2021 Apr 2.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Hydrogen sulfide (HS) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, HS is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. HS-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, HS is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of HS are not precisely understood. HS modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, HS affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by HS. HS enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of HS anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal HS levels. Together, HS is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of HS not only expands fundamental insight in the regulation of functional effects mediated by HS, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.
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http://dx.doi.org/10.1016/j.redox.2021.101961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065217PMC
April 2021

Use of sepsis-related diagnostic criteria in primary care: a survey among general practitioners.

Fam Pract 2021 Mar 23. Epub 2021 Mar 23.

Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Use of sepsis-criteria in hospital settings is effective in realizing early recognition, adequate treatment and reduction of sepsis-associated morbidity and mortality. Whether general practitioners (GPs) use these diagnostic criteria is unknown.

Objective: To gauge the knowledge and use of various diagnostic criteria. To determine which parameters GPs associate with an increased likelihood of sepsis.

Methods: Two thousand five hundred and sixty GPs were invited and 229 agreed to participate in a survey, reached out to through e-mail and WhatsApp groups. The survey consisted of two parts: the first part aimed to obtain information about the GP, training and knowledge about sepsis recognition, and the second part tested specific knowledge using six realistic cases.

Results: Two hundred and six questionnaires, representing a response rate of 8.1%, were eligible for analysis. Gut feeling (98.1%) was the most used diagnostic method, while systemic inflammatory response syndrome (37.9%), quick Sequential Organ Failure Assessment (qSOFA) (7.8%) and UK Sepsis Trust criteria (UKSTc) (1.5%) were used by the minority of the GPs. Few of the responding GPs had heard of either the qSOFA (27.7%) or the UKSTc (11.7%). Recognition of sepsis varied greatly between GPs. GPs most strongly associated the individual signs of the qSOFA (mental status, systolic blood pressure, capillary refill time and respiratory rate) with diagnosing sepsis in the test cases.

Conclusions: GPs mostly use gut feeling to diagnose sepsis and are frequently not familiar with the 'sepsis-criteria' used in hospital settings, although clinical reasoning was mostly in line with the qSOFA score. In order to improve sepsis recognition in primary care, GPs should be educated in the use of available screening tools.
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http://dx.doi.org/10.1093/fampra/cmab020DOI Listing
March 2021

Reversible thrombocytopenia during hibernation originates from storage and release of platelets in liver sinusoids.

J Comp Physiol B 2021 May 4;191(3):603-615. Epub 2021 Mar 4.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Immobility is a risk factor for thrombosis due to low blood flow, which may result in activation of the coagulation system, recruitment of platelets and clot formation. Nevertheless, hibernating animals-who endure lengthy periods of immobility-do not show signs of thrombosis throughout or after hibernation. One of the adaptations of hemostasis in hibernators consists of a rapidly reversible reduction of the number of circulating platelets during torpor, i.e., the hibernation phase with reduction of metabolic rate, low blood flow and immobility. It is unknown whether these platelet dynamics in hibernating hamsters originate from storage and release, as suggested for ground squirrel, or from breakdown and de novo synthesis. A reduction in detaching forces due to low blood flow can induce reversible adhesion of platelets to the vessel wall, which is called margination. Here, we hypothesized that storage-and-release by margination to the vessel wall induces reversible thrombocytopenia in torpor. Therefore, we transfused labeled platelets in hibernating Syrian hamster (Mesocricetus auratus) and platelets were analyzed using flow cytometry and electron microscopy. The half-life of labeled platelets was extended from 20 to 30 h in hibernating animals compared to non-hibernating control hamsters. More than 90% of labeled platelets were cleared from the circulation during torpor, followed by emergence during arousal which supports storage-and-release to govern thrombocytopenia in torpor. Furthermore, the low number of immature platelets, plasma level of interleukin-1α and normal numbers of megakaryocytes in bone marrow make platelet synthesis or megakaryocyte rupture via interleukin-1α unlikely to account for the recovery of platelet counts upon arousal. Finally, using large-scale electron microscopy we revealed platelets to accumulate in liver sinusoids, but not in spleen or lung, during torpor. These results thus demonstrate that platelet dynamics in hibernation are caused by storage and release of platelets, most likely by margination to the vessel wall in liver sinusoids. Translating the molecular mechanisms that govern platelet retention in the liver, may be of major relevance for hemostatic management in (accidental) hypothermia and for the development of novel anti-thrombotic strategies.
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http://dx.doi.org/10.1007/s00360-021-01351-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043940PMC
May 2021

Ensemble machine learning prediction and variable importance analysis of 5-year mortality after cardiac valve and CABG operations.

Sci Rep 2021 Feb 10;11(1):3467. Epub 2021 Feb 10.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Despite having a similar post-operative complication profile, cardiac valve operations are associated with a higher mortality rate compared to coronary artery bypass grafting (CABG) operations. For long-term mortality, few predictors are known. In this study, we applied an ensemble machine learning (ML) algorithm to 88 routinely collected peri-operative variables to predict 5-year mortality after different types of cardiac operations. The Super Learner algorithm was trained using prospectively collected peri-operative data from 8241 patients who underwent cardiac valve, CABG and combined operations. Model performance and calibration were determined for all models, and variable importance analysis was conducted for all peri-operative parameters. Results showed that the predictive accuracy was the highest for solitary mitral (0.846 [95% CI 0.812-0.880]) and solitary aortic (0.838 [0.813-0.864]) valve operations, confirming that ensemble ML using routine data collected perioperatively can predict 5-year mortality after cardiac operations with high accuracy. Additionally, post-operative urea was identified as a novel and strong predictor of mortality for several types of operation, having a seemingly additive effect to better known risk factors such as age and postoperative creatinine.
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http://dx.doi.org/10.1038/s41598-021-82403-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876023PMC
February 2021

Phase specific suppression of neutrophil function in hibernating Syrian hamster.

Dev Comp Immunol 2021 Jun 24;119:104024. Epub 2021 Jan 24.

Department Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Internal Medicine, Section Acute Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address:

Hibernation consists of alternating periods of reduced metabolism (torpor) with brief periods of metabolism similar to summer euthermia (arousal). The function of the innate immune system is reduced during hibernation, of which the underlying mechanisms are incompletely understood. Here, we studied neutrophil functionality during hibernation in Syrian hamsters. The inflammatory response to LPS-induced endotoxemia is inhibited in hibernation, partly mediated by reduced IL-6 production in early arousal. Furthermore, neutrophil pathogen binding, phagocytosis and oxidative burst is profoundly reduced in early arousal. Functionality of both summer and early arousal neutrophils was repressed in plasma from early arousal and mixed plasma from early arousal and summer euthermic, but restored by summer euthermic plasma, signifying that a plasma factor in early arousal inhibits TLR-recognition. Identification of the inhibiting factor may offer a target to modulate neutrophil function with relevance to (auto-)inflammatory diseases.
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http://dx.doi.org/10.1016/j.dci.2021.104024DOI Listing
June 2021

Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI.

Crit Care 2021 01 25;25(1):36. Epub 2021 Jan 25.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands.

Background: Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI.

Methods: We conducted a clinical laboratory study using "warm" postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro.

Results: Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels.

Conclusion: Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.
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http://dx.doi.org/10.1186/s13054-020-03424-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831178PMC
January 2021

Acute Kidney Injury is Associated with Lowered Plasma-Free Thiol Levels.

Antioxidants (Basel) 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands.

Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH) are crucial components of the extracellular antioxidant machinery and reliably reflect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this preliminary study, we hypothesized that plasma-free thiols are associated with AKI upon admission to the intensive care unit (ICU). In this study, 301 critically ill patients were included. Plasma samples were taken upon admission, and albumin-adjusted plasma-free thiols were determined. Albumin-adjusted plasma-free thiols were lower in patients with AKI (n = 43, median (interquartile range) 7.28 µmol/g (3.52, 8.95)) compared to patients without AKI (8.50 μmol/g (5.82, 11.28); < 0.05) upon admission to the ICU. Higher age (B = -0.72), higher levels of neutrophil gelatinase-associated lipocalin (B = -0.002), creatinine (B = -0.01) and lower serum albumin (B = 0.47) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were significantly reduced in patients with sepsis (8.30 (5.52-10.64) µmol/g) compared to patients without sepsis (6.95 (3.72-8.92) µmol/g; < 0.05). Together, albumin-adjusted plasma-free thiols were significantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis.
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http://dx.doi.org/10.3390/antiox9111135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696918PMC
November 2020

Exploring the pathophysiology of post-sepsis syndrome to identify therapeutic opportunities.

EBioMedicine 2020 Nov 8;61:103044. Epub 2020 Oct 8.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, , P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address:

Sepsis is a major health problem worldwide. As the number of sepsis cases increases, so does the number of sepsis survivors who suffer from "post-sepsis syndrome" after hospital discharge. This syndrome involves deficits in multiple systems, including the immune, cognitive, psychiatric, cardiovascular, and renal systems. Combined, these detrimental consequences lead to rehospitalizations, poorer quality of life, and increased mortality. Understanding the pathophysiology of these issues is crucial to develop new therapeutic opportunities to improve survival rate and quality of life of sepsis survivors. Such novel strategies include modulating the immune system and addressing mitochondrial dysfunction. A sepsis follow-up clinic may be useful to identify long-term health issues associated with post-sepsis syndrome and evaluate existing and novel strategies to improve the lives of sepsis survivors.
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http://dx.doi.org/10.1016/j.ebiom.2020.103044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544455PMC
November 2020

A high urea-to-creatinine ratio predicts long-term mortality independent of acute kidney injury among patients hospitalized with an infection.

Sci Rep 2020 09 24;10(1):15649. Epub 2020 Sep 24.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Acute kidney injury (AKI) occurs frequently in patients with sepsis. Persistent AKI is, in contrast to transient AKI, associated with reduced long-term survival after sepsis, while the effect of AKI on survival after non-septic infections remains unknown. As prerenal azotaemia is a common cause of transient AKI that might be identified by an increased urea-to-creatinine ratio, we hypothesized that the urea-to-creatinine ratio may predict the course of AKI with relevance to long-term mortality risk. We studied the association between the urea-to-creatinine ratio, AKI and long-term mortality among 665 patients presented with an infection to the ED with known pre-existent renal function. Long-term survival was reduced in patients with persistent AKI. The urea-to-creatinine ratio was not associated with the incidence of either transient or non-recovered AKI. In contrast, stratification according to the urea-to-creatinine-ratio identifies a group of patients with a similar long-term mortality risk as patients with persistent AKI. Non-recovered AKI is strongly associated with all-cause long-term mortality after hospitalization for an infection. The urea-to-creatinine ratio should not be employed to predict prerenal azotaemia, but identifies a group of patients that is at increased risk for long-term mortality after infections, independent of AKI and sepsis.
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http://dx.doi.org/10.1038/s41598-020-72815-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515888PMC
September 2020

Thyroid function and risk of all-cause and cardiovascular mortality: a prospective population-based cohort study.

Endocrine 2021 Feb 6;71(2):385-396. Epub 2020 Jul 6.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Purpose: Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality.

Methods: We included community-dwelling individuals aged 28-75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors.

Results: Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92-1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (<72 years) participants (1.31, 1.00-1.72) and decreased risk in elderly (≥72 years) (0.77, 0.56-1.06). Higher free thyroxine (FT) was associated with all-cause mortality (1.18, 1.07-1.30) and with cardiovascular mortality only in elderly (1.61, 1.19-2.18), but not in younger participants (1.03, 0.78-1.34). Higher free triiodothyronine (FT) was associated with all-cause mortality in females only (1.18, 1.02-1.35). FT was not associated with cardiovascular mortality (0.91, 0.70-1.18).

Conclusions: Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.
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http://dx.doi.org/10.1007/s12020-020-02397-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881952PMC
February 2021

Metabolic Resuscitation Strategies to Prevent Organ Dysfunction in Sepsis.

Antioxid Redox Signal 2019 07 23;31(2):134-152. Epub 2019 Jan 23.

1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Sepsis is the main cause of death among patients admitted to the intensive care unit. As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis, and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of adenosine triphosphate-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, that is, cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy-sensing pathways (, sirtuins and AMP-activated protein kinase) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulfide (HS). In addition HS may also confer beneficial effects through upregulation of antioxidant mechanisms, similar to the other gasotransmitters nitric oxide and carbon monoxide, which display antioxidant and anti-inflammatory effects in sepsis. In addition, oxidative stress may be averted by systemic or mitochondria-targeted antioxidants, of which a wide range are able to lower inflammation, as well as reduce organ dysfunction and mortality from sepsis. Mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis.
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http://dx.doi.org/10.1089/ars.2018.7537DOI Listing
July 2019

Reply.

Ann Thorac Surg 2018 12 11;106(6):1891-1892. Epub 2018 Aug 11.

Department of Anesthesiology, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.athoracsur.2018.07.006DOI Listing
December 2018

Torpor-arousal cycles in Syrian hamster heart are associated with transient activation of the protein quality control system.

Comp Biochem Physiol B Biochem Mol Biol 2018 09 9;223:23-28. Epub 2018 Jun 9.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.

Hibernation consists of torpor, with marked suppression of metabolism and physiological functions, alternated with arousal periods featuring their full restoration. The heart is particularly challenged, exemplified by its rate reduction from 400 to 5-10 beats per minute during torpor in Syrian hamsters. In addition, during arousals, the heart needs to accommodate the very rapid return to normal function, which lead to our hypothesis that cardiac function during hibernation is supported by maintenance of protein homeostasis through adaptations in the protein quality control (PQC) system. Hereto, we examined autophagy, the endoplasmic reticulum (ER) unfolded protein (UPR) response and the heat shock response (HSR) in Syrian hamster hearts during torpor and arousal. Transition from torpor to arousal (1.5 h) was associated with stimulation of the PQC system during early arousal, demonstrated by induction of autophagosomes, as shown by an increase in LC3B-II protein abundance, likely related to the activation of the UPR during late torpor in response to proteotoxic stress. The HSR was not activated during torpor or arousal. Our results demonstrate activation of the cardiac PQC system - particularly autophagosomal degradation - in early arousal in response to cardiac stress, to clear excess aberrant or damaged proteins, being gradually formed during the torpor bout and/or the rapid increase in heart rate during the transition from torpor to arousal. This mechanism may enable the large gain in cardiac function during the transition from torpor to arousal, which may hold promise to further understand 'hibernation' of cardiomyocytes in human heart disease.
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http://dx.doi.org/10.1016/j.cbpb.2018.06.001DOI Listing
September 2018

Acute Kidney Injury Classification Underestimates Long-Term Mortality After Cardiac Valve Operations.

Ann Thorac Surg 2018 07 1;106(1):92-98. Epub 2018 Mar 1.

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, The Netherlands.

Background: Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented.

Methods: Perioperative renal injury and long-term all-cause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference.

Results: In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p < 0.05 for valve; HR, 1.65, p < 0.05 for valve+CABG; HR, 1.56, p < 0.05 for CABG). Notably, the mortality risk increased already substantially at serum creatinine increases of 10% to 25%-that is, far below the threshold for AKI stage 1 after valve operations (HR, 1.39, p < 0.05), but not after valve operations combined with CABG or CABG only.

Conclusions: An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations.
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http://dx.doi.org/10.1016/j.athoracsur.2018.01.066DOI Listing
July 2018

A Hibernation-Like State for Transplantable Organs: Is Hydrogen Sulfide Therapy the Future of Organ Preservation?

Antioxid Redox Signal 2018 06 29;28(16):1503-1515. Epub 2017 Aug 29.

3 Matthew Mailing Center for Translational Transplant Studies, Western University , London, Canada .

Significance: Renal transplantation is the treatment of choice for end-stage renal disease, during which renal grafts from deceased donors are routinely cold stored to suppress metabolic demand and thereby limit ischemic injury. However, prolonged cold storage, followed by reperfusion, induces extensive tissue damage termed cold ischemia/reperfusion injury (IRI) and puts the graft at risk of both early and late rejection. Recent Advances: Deep hibernators constitute a natural model of coping with cold IRI as they regularly alternate between 4°C and 37°C. Recently, endogenous hydrogen sulfide (HS), a gas with a characteristic rotten egg smell, has been implicated in organ protection in hibernation.

Critical Issues: In renal transplantation, HS also seems to confer cytoprotection by lowering metabolism, thereby creating a hibernation-like environment, and increasing preservation time while allowing cellular processes of preservation of homeostasis and tissue remodeling to take place, thus increasing renal graft survival.

Future Directions: Although the underlying cellular and molecular mechanisms of organ protection during hibernation have not been fully explored, mammalian hibernation may offer a great clinical promise to safely cold store and reperfuse donor organs. In this review, we first discuss mammalian hibernation as a natural model of cold organ preservation with reference to the kidney and highlight the involvement of HS during hibernation. Next, we present recent developments on the protective effects and mechanisms of exogenous and endogenous HS in preclinical models of transplant IRI and evaluate the potential of HS therapy in organ preservation as great promise for renal transplant recipients in the future. Antioxid. Redox Signal. 28, 1503-1515.
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http://dx.doi.org/10.1089/ars.2017.7127DOI Listing
June 2018

The influence of sex and diet on the characteristics of hibernation in Syrian hamsters.

J Comp Physiol B 2017 Jul 21;187(5-6):725-734. Epub 2017 Mar 21.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Research on deep hibernators almost exclusively uses species captured from the wild or from local breeding. An exception is Syrian hamster (Mesocricetus auratus), the only standard laboratory animal showing deep hibernation. In deep hibernators, several factors influence hibernation quality, including body mass, sex and diet. We examined hibernation quality in commercially obtained Syrian hamsters in relation to body mass, sex and a diet enriched in polyunsaturated fatty acids. Animals (M/F:30/30, 12 weeks of age) were obtained from Harlan (IN, USA) and individually housed at 21 °C and L:D 14:10 until 20 weeks of age, followed by L:D 8:16 until 27 weeks. Then conditions were changed to 5 °C and L:D 0:24 for 9 weeks to induce hibernation. Movement was continuously monitored with passive infrared detectors. Hamsters were randomized to control diet or a diet 3× enriched in linoleic acid from 16 weeks of age. Hamsters showed a high rate of premature death (n = 24, 40%), both in animals that did and did not initiate torpor, which was unrelated to body weight, sex and diet. Time to death (31.7 ± 3.1 days, n = 12) or time to first torpor bout (36.6 ± 1.6 days, n = 12) was similar in prematurely deceased hamsters. Timing of induction of hibernation and duration of torpor and arousal was unaffected by body weight, sex or diet. Thus, commercially obtained Syrian hamsters subjected to winter conditions showed poor survival, irrespective of body weight, sex and diet. These factors also did not affect hibernation parameters. Possibly, long-term commercial breeding from a confined genetic background has selected against the hibernation trait.
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http://dx.doi.org/10.1007/s00360-017-1072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486544PMC
July 2017

Renal Mitochondrial Response to Low Temperature in Non-Hibernating and Hibernating Species.

Antioxid Redox Signal 2017 Sep 26;27(9):599-617. Epub 2017 Apr 26.

1 Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, the Netherlands .

Significance: Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is believed to be a key event triggering loss of cellular homeostasis, and potentially cell death. Subsequent rewarming generates large amounts of reactive oxygen species that aggravate organ injury. Recent Advances: Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature ("torpor"), interspersed by brief periods of rewarming ("arousal") without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress, and protect against cell death. These adaptations consist of active suppression of mitochondrial function and upregulation of anti-oxidant enzymes and anti-apoptotic pathways.

Critical Issues: Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit IRI in patients.

Future Directions: Although the precise signaling routes involved in natural hibernation are not yet fully understood, torpor-like hypothermic states with increased resistance to ischemia/reperfusion can be induced pharmacologically by 5'-adenosine monophosphate (5'-AMP), adenosine, and hydrogen sulfide (HS) in non-hibernators. In this review, we compare the molecular effects of hypothermia in non-hibernators with natural and pharmacologically induced torpor, to delineate how safe and reversible metabolic suppression may provide resistance to renal IRI. Antioxid. Redox Signal. 27, 599-617.
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http://dx.doi.org/10.1089/ars.2016.6705DOI Listing
September 2017

Hydrogen sulfide: A novel nephroprotectant against cisplatin-induced renal toxicity.

Nitric Oxide 2016 07 16;57:15-20. Epub 2016 Apr 16.

Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON, Canada; Department of Microbiology and Immunology, London Health Sciences Center, Western University, London, ON, Canada; Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, ON, Canada; Department of Surgery, Division of Urology, University of Manitoba, Winnepeg, MB, Canada; Multi-Organ Transplant Program, Western University, London Health Sciences Center, Western University, London, ON, Canada.

Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury.
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http://dx.doi.org/10.1016/j.niox.2016.04.005DOI Listing
July 2016

Dopamine treatment attenuates acute kidney injury in a rat model of deep hypothermia and rewarming - The role of renal H2S-producing enzymes.

Eur J Pharmacol 2015 Dec 21;769:225-33. Epub 2015 Nov 21.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Hypothermia and rewarming produces organ injury through the production of reactive oxygen species. We previously found that dopamine prevents hypothermia and rewarming-induced apoptosis in cultured cells through increased expression of the H2S-producing enzyme cystathionine β-Synthase (CBS). Here, we investigate whether dopamine protects the kidney in deep body cooling and explore the role of H2S-producing enzymes in an in vivo rat model of deep hypothermia and rewarming. In anesthetized Wistar rats, body temperature was decreased to 15°C for 3h, followed by rewarming for 1h. Rats (n≥5 per group) were treated throughout the procedure with vehicle or dopamine infusion, and in the presence or absence of a non-specific inhibitor of H2S-producing enzymes, amino-oxyacetic acid (AOAA). Kidney damage and renal expression of three H2S-producing enzymes (CBS, CSE and 3-MST) was quantified and serum H2S level measured. Hypothermia and rewarming induced renal damage, evidenced by increased serum creatinine, renal reactive oxygen species production, KIM-1 expression and influx of immune cells, which was accompanied by substantially lowered renal expression of CBS, CSE, and 3-MST and lowered serum H2S levels. Infusion of dopamine fully attenuated renal damage and maintained expression of H2S-producing enzymes, while normalizing serum H2S. AOAA further decreased the expression of H2S-producing enzymes and serum H2S level, and aggravated renal damage. Hence, dopamine preserves renal integrity during deep hypothermia and rewarming likely by maintaining the expression of renal H2S-producing enzymes and serum H2S.
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http://dx.doi.org/10.1016/j.ejphar.2015.11.022DOI Listing
December 2015

Induction of a Torpor-Like State by 5'-AMP Does Not Depend on H2S Production.

PLoS One 2015 21;10(8):e0136113. Epub 2015 Aug 21.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Therapeutic hypothermia is used to reduce ischemia/reperfusion injury (IRI) during organ transplantation and major surgery, but does not fully prevent organ injury. Interestingly, hibernating animals undergo repetitive periods of low body temperature called 'torpor' without signs of organ injury. Recently, we identified an essential role of hydrogen sulfide (H2S) in entrance into torpor and preservation of kidney integrity during hibernation. A torpor-like state can be induced pharmacologically by injecting 5'-Adenosine monophosphate (5'-AMP). The mechanism by which 5'-AMP leads to the induction of a torpor-like state, and the role of H2S herein, remains to be unraveled. Therefore, we investigated whether induction of a torpor-like state by 5-AMP depends on H2S production.

Methods: To study the role of H2S on the induction of torpor, amino-oxyacetic acid (AOAA), a non-specific inhibitor of H2S, was administered before injection with 5'-AMP to block endogenous H2S production in Syrian hamster. To assess the role of H2S on maintenance of torpor induced by 5'-AMP, additional animals were injected with AOAA during torpor.

Key Results: During the torpor-like state induced by 5'-AMP, the expression of H2S- synthesizing enzymes in the kidneys and plasma levels of H2S were increased. Blockade of these enzymes inhibited the rise in the plasma level of H2S, but neither precluded torpor nor induced arousal. Remarkably, blockade of endogenous H2S production was associated with increased renal injury.

Conclusions: Induction of a torpor-like state by 5'-AMP does not depend on H2S, although production of H2S seems to attenuate renal injury. Unraveling the mechanisms by which 5'-AMP reduces the metabolism without organ injury may allow optimization of current strategies to limit (hypothermic) IRI and improve outcome following organ transplantation, major cardiac and brain surgery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546583PMC
May 2016

Aging and Immunopathology in Primary Sjögren's Syndrome.

Curr Aging Sci 2015 ;8(2):202-13

Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1 (AA21), 9713 GZ, Groningen, The Netherlands.

Sicca complaints (sensation of dry mouth and/or eyes) are present in about a quarter of the individuals above the age of 65 years old and are mainly due to medication. However, physiological changes that occur during aging might also lead to a diminished glandular function. These age-related changes are, at least in part, to be the consequence of decreased androgen levels. In addition to these physiological effects that occur during normal aging, sicca complaints can also be caused by Sjögren's syndrome (SS): a systemic auto-inflammatory disorder mainly affecting exocrine glands. Genetic factors, lowered levels of gonadal hormones and (viral) infections appear to contribute to the etiology of the syndrome. The incidence of SS is higher among aged individuals, which might be due to earlier diagnosis, as the onset of SS in an individual with age-related exocrine gland dysfunction lowers the threshold for sicca complaints. On the other hand, physiological aging might be considered as a risk factor for development of SS, resulting in a faster development of the syndrome. Differentiating physiological sicca complaints from SS in the elderly can be challenging, since apparently healthy individuals might present with auto-antibodies and lymphocytic infiltrates in salivary glands might be present as well. The drop in the level of androgens and estrogens upon aging, immunosenescence and pro-inflammatory features of the aging immune system may all contribute to the etiology of pSS in the elderly. In this review, we describe the physiological effects of aging and the influence of SS on exocrine gland morphology and function.
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http://dx.doi.org/10.2174/1874609808666150727112826DOI Listing
August 2016

S1P1 receptor modulation preserves vascular function in mesenteric and coronary arteries after CPB in the rat independent of depletion of lymphocytes.

PLoS One 2014 12;9(5):e97196. Epub 2014 May 12.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.

Background: Cardiopulmonary bypass (CPB) may induce systemic inflammation and vascular dysfunction. Sphingosine 1-phosphate (S1P) modulates various vascular and immune responses. Here we explored whether agonists of the S1P receptors, FTY720 and SEW2871 improve vascular reactivity after CPB in the rat.

Methods: Experiments were done in male Wistar rats (total n = 127). Anesthesia was induced by isoflurane (2.5-3%) and maintained by fentanyl and midazolam during CPB. After catheterization of the left femoral artery, carotid artery and the right atrium, normothermic extracorporeal circulation was instituted for 60 minutes. In the first part of the study animals were euthanized after either 1 hour, 1 day, 2 or 5 days of the recovery period. In second part of the study animals were euthanized after 1 day of postoperative period. We evaluated the contractile response to phenylephrine (mesenteric arteries) or to serotonin (coronary artery) and vasodilatory response to acethylcholine (both arteries).

Results: Contractile responses to phenylephrine were reduced at 1 day recovery after CPB and Sham as compared to healthy control animals (Emax, mN: 7.9 ± 1.9, 6.5 ± 1.5, and 11.3 ± 1.3, respectively). Mainly FTY720, but not SEW2871, caused lymphopenia in both Sham and CPB groups. In coronary and mesenteric arteries, both FTY720 and SEW2871 normalized serotonin and phenylephrine-mediated vascular reactivity after CPB (p<0.05) and FTY720 increased relaxation to acetylcholine as compared with untreated rats that underwent CPB.

Conclusion: Pretreatment with FTY720 or SEW2871 preserves vascular function in mesenteric and coronary artery after CPB. Therefore, pharmacological activation of S1P1 receptors may provide a promising therapeutic intervention to prevent CPB-related vascular dysfunction in patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018292PMC
June 2015

Platelet dynamics during natural and pharmacologically induced torpor and forced hypothermia.

PLoS One 2014 10;9(4):e93218. Epub 2014 Apr 10.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Hibernation is an energy-conserving behavior in winter characterized by two phases: torpor and arousal. During torpor, markedly reduced metabolic activity results in inactivity and decreased body temperature. Arousal periods intersperse the torpor bouts and feature increased metabolism and euthermic body temperature. Alterations in physiological parameters, such as suppression of hemostasis, are thought to allow hibernators to survive periods of torpor and arousal without organ injury. While the state of torpor is potentially procoagulant, due to low blood flow, increased viscosity, immobility, hypoxia, and low body temperature, organ injury due to thromboembolism is absent. To investigate platelet dynamics during hibernation, we measured platelet count and function during and after natural torpor, pharmacologically induced torpor and forced hypothermia. Splenectomies were performed to unravel potential storage sites of platelets during torpor. Here we show that decreasing body temperature drives thrombocytopenia during torpor in hamster with maintained functionality of circulating platelets. Interestingly, hamster platelets during torpor do not express P-selectin, but expression is induced by treatment with ADP. Platelet count rapidly restores during arousal and rewarming. Platelet dynamics in hibernation are not affected by splenectomy before or during torpor. Reversible thrombocytopenia was also induced by forced hypothermia in both hibernating (hamster) and non-hibernating (rat and mouse) species without changing platelet function. Pharmacological torpor induced by injection of 5'-AMP in mice did not induce thrombocytopenia, possibly because 5'-AMP inhibits platelet function. The rapidness of changes in the numbers of circulating platelets, as well as marginal changes in immature platelet fractions upon arousal, strongly suggest that storage-and-release underlies the reversible thrombocytopenia during natural torpor. Possibly, margination of platelets, dependent on intrinsic platelet functionality, governs clearance of circulating platelets during torpor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982955PMC
January 2015

Reduction of body temperature governs neutrophil retention in hibernating and nonhibernating animals by margination.

J Leukoc Biol 2013 Sep 13;94(3):431-7. Epub 2013 Jun 13.

Department of Clinical Pharmacology, University Medical Center Groningen, The Netherlands.

Hibernation consists of periods of low metabolism, called torpor, interspersed by euthermic arousal periods. During deep and daily (shallow) torpor, the number of circulating leukocytes decreases, although circulating cells, is restored to normal numbers upon arousal. Here, we show that neutropenia, during torpor, is solely a result of lowering of body temperature, as a reduction of circulating also occurred following forced hypothermia in summer euthermic hamsters and rats that do not hibernate. Splenectomy had no effect on reduction in circulating neutrophils during torpor. Margination of neutrophils to vessel walls appears to be the mechanism responsible for reduced numbers of neutrophils in hypothermic animals, as the effect is inhibited by pretreatment with dexamethasone. In conclusion, low body temperature in species that naturally use torpor or in nonhibernating species under forced hypothermia leads to a decrease of circulating neutrophils as a result of margination. These findings may be of clinical relevance, as they could explain, at in least part, the benefits and drawbacks of therapeutic hypothermia as used in trauma patients and during major surgery.
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http://dx.doi.org/10.1189/jlb.0611298DOI Listing
September 2013

5'-AMP impacts lymphocyte recirculation through activation of A2B receptors.

J Leukoc Biol 2013 Jul 16;94(1):89-98. Epub 2013 May 16.

University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5'-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5'-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5'-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5'-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5'-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5'-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5'-AMP. In conclusion, 5'-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs.
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http://dx.doi.org/10.1189/jlb.1212613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685012PMC
July 2013

Microarray analysis of gene expression profiles in the rat kidney demonstrates a local inflammatory response induced by cardiopulmonary bypass.

Eur J Anaesthesiol 2013 Aug;30(8):492-500

Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.

Context: Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery but is associated with acute, transient, renal dysfunction that has a negative impact on long-term survival.

Objective: To unravel the molecular pathogenesis of renal injury following CPB.

Design: To obtain insight into the pathogenesis of renal dysfunction following CPB, we performed a microarray analysis of renal gene expression in the rat.

Setting: University Medical Centre Groningen.

Intervention: Rats underwent CPB or a sham procedure for 60 min and were sacrificed at 60 min, 1 and 5 days after the procedure.

Main Outcome Measures: Renal gene expression profile as determined by microarray analysis.

Results: Expression of 420 genes was significantly altered in CPB compared to the sham procedure, and in 407 genes, this was evident in the acute phase (60 min) following CPB. Gene ontology analysis revealed 28 of these genes were involved in inflammatory responses, with high expression of genes downstream of mitogen-activated protein-kinase (MAP-kinase) signalling pathways. Potent inducers identified are from the interleukin-6 cytokine family that consists of interleukin-6 and oncostatin M (OSM), which signal through the gp130-cytokine receptor complex. The plasma concentration of interleukin-6 was hugely increased by CPB as measured by ELISA. Expression of genes downstream of these signalling pathways that lead to production of chemokines, adhesion molecules and molecules involved in coagulative pathways, was upregulated.

Conclusion: CPB induces an acute and local inflammatory response in the kidney, which might contribute to renal injury. The signalling pathways involved identified by gene expression analysis may represent pharmacological targets to limit renal injury following CPB.
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http://dx.doi.org/10.1097/EJA.0b013e32835ce530DOI Listing
August 2013

Troubleshooting the rat model of cardiopulmonary bypass: effects of avoiding blood transfusion on long-term survival, inflammation and organ damage.

J Pharmacol Toxicol Methods 2013 Mar-Apr;67(2):82-90. Epub 2013 Jan 14.

Dept. of Anesthesiology, University Medical Centre Groningen, University of Groningen, The Netherlands.

Introduction: Rat models of cardiopulmonary bypass (CPB) have been used to examine the mechanisms of associated organ damage and to test intervention strategies. However, these models only partly mimic the clinical situation, because of the use of blood transfusion and arterial inflow via the tail artery. Thus a model using arterial inflow in the aorta and a miniaturized CPB circuit without need of transfusion was validated by examining intra-procedure characteristics, mortality and the effects of CPB on biomarkers of inflammation and cerebral injury during 5days follow-up.

Methods: Male Wistar rats (n=95) were anesthetized with isoflurane (2.5%) and fentanyl/midazolam during CPB. Animals were assigned to Control (n=6), Sham (n=40) or normothermic CPB (n=49) groups. Both Sham and CPB were cannulated in the aorta via the left carotid artery and in the right common jugular vein for access into the right heart. Extracorporeal circulation (ECC) was instituted for 60min only in CPB at a flow rate of 120mLkg(-1)min(-1) employing a CPB circuit of 15ml primed with 6% hydroxyethyl starch 60mgml(-1) solution. Rats were sacrificed at either 1h or 1, 2 or 5days after Sham or weaning from CPB. Plasma IL-6 and s100Beta levels were measured and blood cell counts were performed.

Results: Mortality in CPB animals (3 out of 49) and Sham (4 out of 40) did not differ (chi-square=0.46, dF=1, P>0.5). Compared to baseline (1.87±0.46∗10^9cells/L), Sham procedure (cannulation and anesthesia) significantly increased blood neutrophil count at the end of the period matching ECC (6.34±2.36∗10^9cells/L, P<0.05). CPB induced neutrophilia which persisted during 24h recovery. Also, CPB caused a rapid and prominent increase in plasma IL-6 from the first hour of the postoperative period (~1200pg/ml) with continuation (50-90pg/ml) up to 5th day of recovery. S100Beta levels were above detection level only in 3 out of 42 samples from CPB animals.

Discussion: Our rat model of CPB without homologous blood transfusion produces a reproducible and reliable systemic inflammatory response, with low mortality rates on long term follow up. The model more closely mimics the human situation in respect to arterial inflow site and avoidance of blood transfusion. Thus, our CPB model is suitable to study its influence on systemic inflammation, ischemia-reperfusion injury, microcirculation and vascular dysfunction in vivo, and to evaluate potential therapeutic interventions.
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http://dx.doi.org/10.1016/j.vascn.2013.01.002DOI Listing
August 2013

Hibernation is associated with depression of T-cell independent humoral immune responses in the 13-lined ground squirrel.

Dev Comp Immunol 2013 Mar 24;39(3):154-60. Epub 2012 Nov 24.

Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, The Netherlands.

Mammalian hibernation consists of periods of low metabolism and body temperature (torpor), interspersed by euthermic arousal periods. The function of both the innate and adaptive immune system is suppressed during hibernation. In this study, we analyzed the humoral adaptive immune response to a T-cell independent (TI-2) and a T-cell dependent (TD) antigen. Thirteen-lined ground squirrels were immunized in summer or during hibernation with either a TI-2 or TD antigen on day 0 and day 14. Blood was drawn on day 0, 7, 14, 21 and 28. Both types of antigens induced a significant rise in antibody titer in summer animals. Much to our surprise, however, only immunization with the TD antigen, and not with the TI-2 antigen induced a humoral response in hibernators. Flow cytometric analysis of CD4 (helper T-lymphocytes), CD8 (cytotoxic T-lymphocytes) and CD45RA (B-lymphocytes) in blood, spleen and lymph nodes ruled out massive apoptosis as explanation of the absent TI humoral response during hibernation. Rather, reduced TI-2 stimulation of B-lymphocytes, possibly due to lowered serum complement during torpor, may explain the reduced antibody production in response to a TI-2 antigen. These results demonstrate that hibernation diminishes the capacity to induce a TI-2 humoral immune response, while the capacity to induce a humoral response to a TD antigen is maintained.
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http://dx.doi.org/10.1016/j.dci.2012.11.004DOI Listing
March 2013

The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster.

J Exp Biol 2012 Aug;215(Pt 16):2912-9

Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 196, 9700 RB Groningen, The Netherlands.

During hibernation, small mammals alternate between periods of metabolic suppression and low body temperature ('torpor') and periods of full metabolic recovery with euthermic temperatures ('arousal'). Previously, we demonstrated marked structural remodeling of the lung during torpor, which is rapidly reversed during arousal. We also found that cooling of hamster cells increased endogenous production of H(2)S through the enzyme cystathionine-β-synthase (CBS). H(2)S suppresses the immune response and increases deposition of collagen. Therefore, we examined inflammatory markers and matrix metalloproteinase (MMP) activity in relation to CBS expression and H(2)S levels in lungs of euthermic and hibernating Syrian hamsters. Lung remodeling during torpor was confirmed by a strong increase in both collagenous and non-collagenous hydroxyproline content. The number of leukocytes in lung was unchanged in any phase of hibernation, while adhesion molecules VCAM-1 and ICAM-1, and the inflammatory marker NF-κB (P65) were modestly upregulated in torpor. Gelatinase activity was decreased in lungs from torpid animals, indicating inhibition of the Zn(2+)-dependent MMP-2 and MMP-9. Moreover, expression of CBS and tissue levels of H(2)S were increased in torpor. All changes normalized during arousal. Inhibition of gelatinase activity in torpor is likely caused by quenching of Zn(2+) by the sulphide ion of H(2)S. In accord, inhibition of CBS normalized gelatinase activity in torpid animals. Conversely, NaHS decreased the gelatinase activity of euthermic animals, which was attenuated by excess Zn(2+). Similar results were obtained on the activity of the Zn(2+)-dependent angiotensin converting enzyme. Our data indicate that increased production of H(2)S through CBS in hamster lungs during torpor contributes to remodeling by inhibition of gelatinase activity and possibly by suppression of the inflammatory response. Although administration of H(2)S is known to induce metabolic suppression in non-hibernating mammals ('suspended animation'), this is the first report implying endogenous H(2)S production in natural hibernation.
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http://dx.doi.org/10.1242/jeb.067363DOI Listing
August 2012