Publications by authors named "Stephen W Standage"

12 Publications

  • Page 1 of 1

The application of omic technologies to research in sepsis-associated acute kidney injury.

Pediatr Nephrol 2021 May 30;36(5):1075-1086. Epub 2020 Apr 30.

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Acute kidney injury (AKI) is common in critically ill children and adults, and sepsis-associated AKI (SA-AKI) is the most frequent cause of AKI in the ICU. To date, no mechanistically targeted therapeutic interventions have been identified. High-throughput "omic" technologies (e.g., genomics, proteomics, metabolomics, etc.) offer a new angle of approach to achieve this end. In this review, we provide an update on the current understanding of SA-AKI pathophysiology. Omic technologies themselves are briefly discussed to facilitate interpretation of studies using them. We next summarize the body of SA-AKI research to date that has employed omic technologies. Importantly, omic studies are helping to elucidate a pathophysiology of SA-AKI centered around cellular stress responses, metabolic changes, and dysregulation of energy production that underlie its clinical features. Finally, we propose opportunities for future research using clinically relevant animal models, integrating multiple omic technologies and ultimately progressing to translational human studies focusing therapeutic strategies on targeted disease mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04557-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606209PMC
May 2021

PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis.

Physiol Rep 2019 05;7(10):e14078

Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Sepsis-associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis-associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator-activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan-kynurenine-NAD and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome-wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis-associated AKI and PPARα-driven fatty acid metabolism that merit further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.14078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525329PMC
May 2019

PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.

Am J Physiol Heart Circ Physiol 2017 Feb 23;312(2):H239-H249. Epub 2016 Nov 23.

Department of Pediatrics (Cardiology), University of Washington School of Medicine, Seattle, Washington.

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality.

New & Noteworthy: In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00457.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734063PMC
February 2017

The Relationship Between KLF5 and PPARα in the Heart: It's Complicated.

Circ Res 2016 Jan;118(2):193-5

From the Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington School of Medicine, Seattle (N.D.R., R.T.); and Department of Pediatrics, University of Washington School of Medicine, Seattle (S.W.S.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.115.308069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743553PMC
January 2016

Nonhematopoietic Peroxisome Proliferator-Activated Receptor-α Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis.

Crit Care Med 2016 08;44(8):e594-603

1Center for Lung Biology, Department of Medicine, University of Washington School of Medicine, Seattle, WA. 2Department of Pediatrics (Critical Care Medicine), University of Washington School of Medicine, Seattle, WA. 3Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA. 4Department of Medicine, University of Washington School of Medicine, Seattle, WA.

Objectives: Peroxisome proliferator-activated receptor-α is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-α null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-α in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-α confers a survival advantage.

Design: Prospective randomized preclinical study.

Setting: Laboratory investigation.

Subjects: Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.

Interventions: Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.

Measurements And Main Results: Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-α status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.

Conclusions: Peroxisome proliferator-activated receptor-α expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-α expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-α-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940302PMC
August 2016

High-dose rosuvastatin treatment for multifocal stroke in trauma-induced cerebral fat embolism syndrome: a case report.

Pediatr Neurol 2014 Sep 28;51(3):410-3. Epub 2014 Apr 28.

Department of Pediatric Critical Care Medicine, Seattle Children's Hospital, Seattle, Washington.

Background: Fat embolism syndrome is a life-threatening condition with treatment centering on the provision of excellent supportive care and early fracture fixation. No pharmacologic intervention has yet shown any clear benefit. We used high-dose rosuvastatin specifically for its anti-inflammatory effects to treat a patient with severe fat embolism syndrome. We also suggest that magnetic resonance imaging and transcranial Doppler studies are helpful in establishing the diagnosis and for monitoring the patient's course.

Patient: A 17-year-old boy developed severe cerebral fat embolism syndrome with multifocal strokes after sustaining bilateral femur fractures.

Results: In spite of profound and prolonged neurological impairment, our patient experienced dramatic recovery by the time he was discharged from inpatient rehabilitation several weeks after his initial injury. Magnetic resonance imaging revealed the classic "starfield" pattern of infarcts on diffusion-weighted sequences early in the illness. Additionally, serial transcranial Doppler studies demonstrated dramatically elevated microembolic events that resolved completely during the course of treatment.

Conclusion: We feel that the acute administration of high-dose rosuvastatin early in the development of our patient's illness may have contributed to his ultimate recovery. Therapeutic guidelines cannot be extrapolated from a single patient, but our experience suggests that statin therapy could be potentially beneficial for individuals with severe fat embolism syndrome, and this approach deserves further clinical evaluation. Additionally, the diagnosis and monitoring of cerebral involvement in fat embolism syndrome is facilitated by both magnetic resonance imaging and transcranial Doppler studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2014.04.025DOI Listing
September 2014

Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children.

J Pediatr Intensive Care 2014 Mar;3(1):23-28

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/PIC-14080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530737PMC
March 2014

Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray.

Crit Care 2011 18;15(6):R273. Epub 2011 Nov 18.

Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45223, USA.

Introduction: Septic-shock-associated acute kidney injury (SSAKI) carries high morbidity in the pediatric population. Effective treatment strategies are lacking, in part due to poor detection and prediction. There is a need to identify novel candidate biomarkers of SSAKI. The objective of our study was to determine whether microarray data from children with septic shock could be used to derive a panel of candidate biomarkers for predicting SSAKI.

Methods: A retrospective cohort study compared microarray data representing the first 24 hours of admission for 179 children with septic shock with those of 53 age-matched normal controls. SSAKI was defined as a >200% increase of baseline serum creatinine, persistent to 7 days after admission.

Results: Patients with SSAKI (n = 31) and patients without SSAKI (n = 148) were clinically similar, but SSAKI carried a higher mortality (45% vs. 10%). Twenty-one unique gene probes were upregulated in SSAKI patients versus patients without SSAKI. Using leave-one-out cross-validation and class prediction modeling, these probes predicted SSAKI with a sensitivity of 98% (95% confidence interval (CI) = 81 to 100) and a specificity of 80% (95% CI = 72 to 86). Serum protein levels of two specific genes showed high sensitivity for predicting SSAKI: matrix metalloproteinase-8 (89%, 95% CI = 64 to 98) and elastase-2 (83%, 95% CI = 58 to 96). Both biomarkers carried a negative predictive value of 95%. When applied to a validation cohort, although both biomarkers carried low specificity (matrix metalloproteinase-8: 41%, 95% CI = 28 to 50; and elastase-2: 49%, 95% CI = 36 to 62), they carried high sensitivity (100%, 95% CI = 68 to 100 for both).

Conclusions: Gene probes upregulated in critically ill pediatric patients with septic shock may allow for the identification of novel candidate serum biomarkers for SSAKI prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/cc10554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388679PMC
June 2013

Reduced peroxisome proliferator-activated receptor α expression is associated with decreased survival and increased tissue bacterial load in sepsis.

Shock 2012 Feb;37(2):164-9

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

The peroxisome proliferator-activated receptor α (PPAR-α) is a member of the nuclear receptor family with many important physiologic roles related to metabolism and inflammation. Previous research in pediatric patients with septic shock revealed that genes corresponding to the PPAR-α signaling pathway are significantly downregulated in a subgroup of children with more severe disease. In this study, PPAR-α expression analysis using whole-blood derived RNA revealed that PPAR-α expression was decreased in patients with septic shock and that the magnitude of that decrement correlated with the severity of disease. In a mouse model of sepsis, induced by cecal ligation and puncture, knockout mice lacking PPAR-α had decreased survival compared with wild-type animals. Plasma cytokine analysis demonstrated decreased levels of interleukin 1β (IL-1β), IL-6, IL-17, keratinocyte-derived cytokine, macrophage chemoattractant protein 1, macrophage inflammatory protein 2, and tumor necrosis factor α at 24 h in PPAR-α knockout animals. Cell surface markers of activation on splenic dendritic cells, macrophages, and CD8 T cells were reduced in PPAR-α null animals, and the bacterial load in lung and splenic tissues was increased. These data indicate that reduced or absent PPAR-α expression confers a survival disadvantage in sepsis and that PPAR-α plays a role in maintaining appropriate immune functions during the sepsis response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0b013e31823f1a00DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261332PMC
February 2012

Biomarkers for pediatric sepsis and septic shock.

Expert Rev Anti Infect Ther 2011 Jan;9(1):71-9

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.

Sepsis is a clinical syndrome defined by physiologic changes indicative of systemic inflammation, which are likely attributable to documented or suspected infection. Septic shock is the progression of those physiologic changes to the extent that delivery of oxygen and metabolic substrate to tissues is compromised. Biomarkers have the potential to diagnose, monitor, stratify and predict outcome in these syndromes. C-reactive protein is elevated in inflammatory and infectious conditions and has long been used as a biomarker indicating infection. Procalcitonin has more recently been shown to better distinguish infection from inflammation. Newer candidate biomarkers for infection include IL-18 and CD64. Lactate facilitates the diagnosis of septic shock and the monitoring of its progression. Multiple stratification biomarkers based on genome-wide expression profiling are under active investigation and present exciting future possibilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1586/eri.10.154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033193PMC
January 2011

Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC).

J Leukoc Biol 2011 Jan 19;89(1):3-10. Epub 2010 Aug 19.

Temple University School of Medicine, 3307 North Broad St., PAH-206, Philadelphia, PA 19140, USA.

Inflammation and proinflammatory mediators are activators of δ-PKC. In vitro, δ-PKC regulates proinflammatory signaling in neutrophils and endothelial and epithelial cells, cells that can contribute to lung tissue damage associated with inflammation. In this study, a specific δ-PKC TAT peptide inhibitor was used to test the hypothesis that inhibition of δ-PKC would attenuate lung injury in an animal model of ARDS. Experimental ARDS was induced in rats via 2CLP, a model of polymicrobial sepsis. Following 2CLP surgery, the δ-PKC TAT inhibitory peptide (2CLP+δ-PKC TAT in PBS) or PBS (2CLP+PBS) was administered intratracheally. Controls consisted of SO, where animals underwent a laparotomy without 2CLP. Twenty-four hours after SO or 2CLP, blood, BALF, and lung tissue were collected. 2CLP induced δ-PKC phosphorylation in the lung within 24 h. Treatment with the δ-PKC TAT inhibitory peptide significantly decreased pulmonary δ-PKC phosphorylation, indicating effective inhibition of δ-PKC activation. Plasma and BALF levels of the chemokines CINC-1 and MIP-2 were elevated in 2CLP + PBS rats as compared with SO rats. Treatment with δ-PKC TAT reduced 2CLP-induced elevations in chemokine levels in BALF and plasma, suggesting that δ-PKC modulated chemokine expression. Most importantly, intratracheal administration of δ-PKC TAT peptide significantly attenuated inflammatory cell infiltration, disruption of lung architecture, and pulmonary edema associated with 2CLP. Thus, δ-PKC is an important regulator of proinflammatory events in the lung. Targeted inhibition of δ-PKC exerted a lung-protective effect 24 h after 2CLP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1189/jlb.0510281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004522PMC
January 2011

Duration of mechanical ventilation in life-threatening pediatric asthma: description of an acute asphyxial subgroup.

Pediatrics 2004 Sep;114(3):762-7

Division of Pediatric Critical Care, Strong Children's Research Center of the University of Rochester, Rochester, New York, USA.

Objective: Acute asphyxial asthma (AAA) is well described in adult patients and is characterized by a sudden onset that may rapidly progress to a near-arrest state. Despite the initial severity of AAA, mechanical ventilation often restores gas exchange promptly, resulting in shorter durations of ventilation. We believe that AAA can occur in children and can lead to respiratory failure that requires mechanical ventilation. Furthermore, children with rapid-onset respiratory failure that requires intubation in the emergency department (ED) are more likely to have AAA and a shorter duration of mechanical ventilation than those intubated in the pediatric intensive care unit (PICU).

Methods: An 11-year retrospective chart review (1991-2002) was conducted of all children who were aged 2 through 18 years and had the primary diagnosis of status asthmaticus and required mechanical ventilation.

Results: During the study period, 33 (11.4%) of 290 PICU admissions for status asthmaticus required mechanical ventilation. Thirteen children presented with rapid respiratory failure en route, on arrival, or within 30 minutes of arrival to the ED versus 20 children who progressed to respiratory failure later in their ED course or in the PICU. Mean duration of mechanical ventilation was significantly shorter in the children who presented with rapid respiratory failure versus those with progressive respiratory failure (29 +/- 43 hours vs 88 +/- 72 hours). Children with rapid respiratory failure had greater improvements in ventilation and oxygenation than those with progressive respiratory failure as measured by pre- and postintubation changes in arterial carbon dioxide pressure, arterial oxygen pressure/fraction of inspired oxygen ratio, and alveolar-arterial gradient. According to site of intubation, 23 children required intubation in the ED, whereas 10 were intubated later in the PICU. Mean duration of mechanical ventilation was significantly shorter in the ED group versus the PICU group (42 +/- 63 hours vs 118 +/- 46 hours). There were significantly greater improvements in ventilation and oxygenation in the ED group versus the PICU group as measured by pre- and postintubation changes in arterial carbon dioxide pressure and arterial oxygen pressure/fraction of inspired oxygen ratio.

Conclusions: AAA occurs in children and shares characteristics seen in adult counterparts. Need for early intubation is a marker for AAA and may not represent a failure to maximize preintubation therapies. AAA represents a distinct form of life-threatening asthma and requires additional study in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2004-0294DOI Listing
September 2004