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Article: Editorial: Case reports in pediatric critical care 2022.

Stark, Ryan J / Yildizdas, Dinçer

2023 Volume 11, Page(s) 1176704

Language	English
Publishing date	2023-03-17
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2711999-3
ISSN	2296-2360
ISSN	2296-2360
DOI	10.3389/fped.2023.1176704
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Article ; Online: Endothelial-Dependent Responses Correlate with Pediatric SOFA Scores During Severe Sepsis and Septic Shock.

Stark, Ryan J

Journal of cardiovascular translational research

2022 Volume 15, Issue 4, Page(s) 903–905

Abstract: Sepsis is an exaggerated host response to an infectious challenge that is associated with significant alterations in vasomotor tone. We hypothesized that the endothelial dysfunction observed during severe sepsis and septic shock would correlate with the ... ...

Abstract	Sepsis is an exaggerated host response to an infectious challenge that is associated with significant alterations in vasomotor tone. We hypothesized that the endothelial dysfunction observed during severe sepsis and septic shock would correlate with the degree of organ failure as determined by the pediatric Sequential Organ Failure Assessment (pSOFA) score. Utilizing laser Doppler perfusion monitoring coupled with iontophoresis, we found that endothelium-dependent vascular reactivity to acetylcholine (ACh) stimulation significantly correlated with both total pSOFA scores and, more specifically, cardiovascular (CV) pSOFA scores. Alternatively, endothelium-independent vascular reactivity using sodium nitroprusside (SNP) did not demonstrate a significant relationship with pSOFA scores. These data suggest that endothelial-mediated vasculopathy may be a key driver of organ dysfunction during episodes of pediatric sepsis.
MeSH term(s)	Child ; Humans ; Shock, Septic/diagnosis ; Organ Dysfunction Scores ; Sepsis/diagnosis ; Acetylcholine ; Endothelium
Chemical Substances	Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2022-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2422411-X
ISSN	1937-5395 ; 1937-5387
ISSN (online)	1937-5395
ISSN	1937-5387
DOI	10.1007/s12265-021-10202-z
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Article ; Online: Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels.

Lamb, Fred S / Choi, Hyehun / Miller, Michael R / Stark, Ryan J

Hypertension (Dallas, Tex. : 1979)

2024 Volume 81, Issue 4, Page(s) 752–763

Abstract: Vascular inflammation underlies the development of hypertension, and the mechanisms by which it increases blood pressure remain the topic of intense investigation. Proinflammatory factors including glucose, salt, vasoconstrictors, cytokines, wall stress, ...

Abstract	Vascular inflammation underlies the development of hypertension, and the mechanisms by which it increases blood pressure remain the topic of intense investigation. Proinflammatory factors including glucose, salt, vasoconstrictors, cytokines, wall stress, and growth factors enhance contractility and impair relaxation of vascular smooth muscle cells. These pathways share a dependence upon redox signaling, and excessive activation promotes oxidative stress that promotes vascular aging. Vascular smooth muscle cell phenotypic switching and migration into the intima contribute to atherosclerosis, while hypercontractility increases systemic vascular resistance and vasospasm that can trigger ischemia. Here, we review factors that drive the initiation and progression of this vasculopathy in vascular smooth muscle cells. Emphasis is placed on the contribution of reactive oxygen species generated by the Nox1 NADPH oxidase which produces extracellular superoxide (O
MeSH term(s)	Humans ; Superoxides/metabolism ; Muscle, Smooth, Vascular/metabolism ; NADPH Oxidase 1/metabolism ; NADPH Oxidases/metabolism ; Reactive Oxygen Species/metabolism ; Hypertension/metabolism ; Myocytes, Smooth Muscle/metabolism ; Cells, Cultured
Chemical Substances	Superoxides (11062-77-4) ; NADPH Oxidase 1 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-) ; Reactive Oxygen Species
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.123.19434
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Article ; Online: Cell penetrating peptides coupled to an endothelial nitric oxide synthase sequence alter endothelial permeability.

Koch, Stephen R / Stark, Ryan J

Tissue barriers

2021 Volume 10, Issue 4, Page(s) 2017226

Abstract: Delivery of cargo to cells through the use of cell-penetrating peptide (CPP) sequences is an area of rich investigation for targeted therapeutics. Specific to the endothelium, the layer of cells that cover every blood vessel in the body, the loss or ... ...

Abstract	Delivery of cargo to cells through the use of cell-penetrating peptide (CPP) sequences is an area of rich investigation for targeted therapeutics. Specific to the endothelium, the layer of cells that cover every blood vessel in the body, the loss or alteration of a key enzyme, endothelial nitric oxide synthase (eNOS), is known to contribute to endothelial health during severe, infectious challenge. While the beneficial effects of eNOS are often thought to be mediated through the generation of nitric oxide, some protection is theorized to be through eNOS binding to regulatory pathways via a pentabasic RRKRK motif. We hypothesized that delivery of the eNOS-RRKRK peptide sequence using common CPPs would allow protection against gram-negative lipopolysaccharide (LPS). Combination of the eNOS-RRKRK sequence to the CPP antennapedia (AP) reduced the impact of LPS-induced permeability in cultured human microvascular endothelial cells (HMVECs) as measured by transendothelial electrical resistance (TEER). There was also a modest reduction in cytokine production, however it was observed that AP alone significantly impaired LPS-induced endothelial permeability and cytokine production. In comparison, the CPP trans-activator of transcription (TAT) did not significantly alter endothelial inflammation by itself. When TAT was coupled to the eNOS-RRKRK sequence, protection against LPS-induced permeability was still demonstrated, however cytokine production was not reduced. These data demonstrate that the RRKRK sequence of eNOS can offer some NO-independent protection against LPS-mediated endothelial inflammation, however the degree of protection is highly dependent on the type of CPP utilized for cargo delivery.
MeSH term(s)	Humans ; Nitric Oxide Synthase Type III/metabolism ; Nitric Oxide Synthase Type III/pharmacology ; Lipopolysaccharides/pharmacology ; Lipopolysaccharides/metabolism ; Cell-Penetrating Peptides/pharmacology ; Nitric Oxide/metabolism ; Nitric Oxide/pharmacology ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Permeability ; Inflammation/metabolism ; Cytokines/metabolism ; Trans-Activators/metabolism ; Trans-Activators/pharmacology
Chemical Substances	Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Lipopolysaccharides ; Cell-Penetrating Peptides ; Nitric Oxide (31C4KY9ESH) ; Cytokines ; Trans-Activators
Language	English
Publishing date	2021-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2168-8370
ISSN (online)	2168-8370
DOI	10.1080/21688370.2021.2017226
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Article: Case report: Temporal alterations in vascular function during the first 2 weeks of pediatric septic shock.

Wijers, Christiaan Diederik Mathijs / Stark, Ryan J

Frontiers in pediatrics

2022 Volume 10, Page(s) 939886

Abstract: Introduction: During sepsis and septic shock, the host's immune systems generate an overwhelming and often, detrimental, inflammatory response. Part of this response results in significant alterations in blood flow and vasomotor tone regulated in part ... ...

Abstract	Introduction: During sepsis and septic shock, the host's immune systems generate an overwhelming and often, detrimental, inflammatory response. Part of this response results in significant alterations in blood flow and vasomotor tone regulated in part by endothelial and vascular smooth muscle cells. Here, we report on a series of 3 pediatric patients for whom vascular response was assessed by laser doppler perfusion coupled to iontophoresis over the first 2 weeks after hospitalization for septic shock to demonstrate similarities and dissimilarities in the vascular response. Case presentations: A 12-year-old male with a history of Burkitt's Lymphoma, a 21-year-old male with congenital porencephaly and epilepsy, and a 7-year-old male with no significant past medical history all were admitted to a tertiary care children's hospital with a diagnosis of septic shock requiring vasoactive infusions to maintain mean arterial blood pressure. Non-invasive laser doppler perfusion coupled with iontophoresis of either acetylcholine (endothelial-dependent response) or sodium nitroprusside (endothelial-independent response) was performed on hospital days 1, 3, 7, and 14. Variability and heterogeneity were demonstrated by the temporal assessments of the vascular response to sodium nitroprusside, but all three patients showed significant similarity in the temporal responsiveness to acetylcholine. Conclusion: Assessment of baseline and temporal responsiveness to endothelial-dependent vascular reactivity may provide a predictable timeline to the resolution of pediatric septic shock.
Language	English
Publishing date	2022-07-22
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2711999-3
ISSN	2296-2360
ISSN	2296-2360
DOI	10.3389/fped.2022.939886
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Article ; Online: The Inverse Relationship Between Endothelium-Dependent Vasodilation and Blood Pressure is Lost After Cardiopulmonary Bypass.

Stark, Ryan J / Krispinsky, Luke T / Lamb, Fred S

Journal of cardiovascular translational research

2021 Volume 14, Issue 6, Page(s) 1114–1116

Abstract: Cardiopulmonary bypass (CPB) is required for the surgical correction of congenital heart defects and incites an acute inflammatory response that impairs endothelial function post-operatively. Therefore, we hypothesized that the pre-operative relationship ...

Abstract	Cardiopulmonary bypass (CPB) is required for the surgical correction of congenital heart defects and incites an acute inflammatory response that impairs endothelial function post-operatively. Therefore, we hypothesized that the pre-operative relationship between endothelial function and blood pressure would be impaired after CPB-mediated inflammation. Using laser Doppler perfusion monitoring coupled with iontophoresis, we found that while there was a significant inverse correlation between endothelium-dependent vascular reactivity to acetylcholine (ACh) stimulation and systolic blood pressure (SBP), this relationship was lost after CPB. No relationship was observed between endothelium-independent vascular reactivity using sodium nitroprusside (SNP) and SBP either pre-CPB or any point thereafter. Additionally, neither CPB time nor inflammatory cytokines correlated with the degree of responsiveness to ACh. These data suggest that the measurement of endothelium impairment after CPB may be more reflective of cardiovascular health than SBP alone.
MeSH term(s)	Acetylcholine/pharmacology ; Blood Pressure/drug effects ; Cardiopulmonary Bypass ; Endothelium, Vascular/physiopathology ; Female ; Heart Defects, Congenital/surgery ; Humans ; Infant ; Iontophoresis ; Laser-Doppler Flowmetry ; Male ; Nitroprusside/pharmacology ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology
Chemical Substances	Vasodilator Agents ; Nitroprusside (169D1260KM) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2021-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2422411-X
ISSN	1937-5395 ; 1937-5387
ISSN (online)	1937-5395
ISSN	1937-5387
DOI	10.1007/s12265-021-10124-w
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Article ; Online: Extracellular SOD modulates canonical TNFα signaling and α5β1 integrin transactivation in vascular smooth muscle cells.

Choi, Hyehun / Miller, Michael R / Nguyen, Hong-Ngan / Surratt, Victoria E / Koch, Stephen R / Stark, Ryan J / Lamb, Fred S

Free radical biology & medicine

2023 Volume 209, Issue Pt 1, Page(s) 152–164

Abstract: TNFα activates NADPH oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs). The extracellular superoxide anion ( ... ...

Abstract	TNFα activates NADPH oxidase 1 (Nox1) in vascular smooth muscle cells (VSMCs). The extracellular superoxide anion (O
MeSH term(s)	Mice ; Animals ; Muscle, Smooth, Vascular/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Superoxide Dismutase/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Hydrogen Peroxide/metabolism ; Transcriptional Activation ; Signal Transduction ; Integrins/genetics ; Integrins/metabolism
Chemical Substances	Tumor Necrosis Factor-alpha ; Superoxide Dismutase (EC 1.15.1.1) ; NF-kappa B ; Hydrogen Peroxide (BBX060AN9V) ; Integrins
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2023.10.397
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Article ; Online: Pediatric Persistent Inflammation, Immunosuppression, and Catabolism Syndrome Prevalence in Sepsis-Related Mortalities: A 23-Year Institutional History.

Patterson, Stephanie G / Lamb, Celia K / Gong, Wu / Resser, Jackson / Lindsell, Christopher J / Van Driest, Sara L / Stark, Ryan J

Chest

2023 Volume 164, Issue 5, Page(s) 1204–1215

Abstract: Background: Delayed mortality in sepsis often is linked to a lack of resolution in the inflammatory cascade termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Limited research exists on PICS in pediatric patients with ... ...

Abstract	Background: Delayed mortality in sepsis often is linked to a lack of resolution in the inflammatory cascade termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Limited research exists on PICS in pediatric patients with sepsis. Research question: What is the prevalence of pediatric PICS (pPICS) in patients who died of sepsis-related causes and what associated pathogen profiles and comorbidities did they have compared with those patients without pPICS who died from sepsis? Study design and methods: A retrospective study of a single institution using a de-identified database from 1997 through 2020 for all patients aged 21 years or younger who died of culture-positive sepsis from a known source and who had laboratory data available were evaluated for the presence of pPICS. Results: Among records extracted from the institutional database, 557 patients had culture-positive sepsis, with 262 patients having pPICS (47%). Patients with pPICS were more likely to have underlying hematologic or oncologic disease or cardiac disease. In addition, patients who had pPICS showed increased odds of associated fungal infection compared with those patients who did not (OR, 2.69; 95% CI, 1.59-4.61; P < .001). When assessing laboratory criteria, having a sustained absolute lymphocyte count of < 1.0 × 10 Interpretation: Pediatric patients who died of a sepsis-related cause have a pPICS phenotype nearly one-half of the time. These patients are more likely to be in the cardiac ICU than the pediatric ICU and have associated fungal infections. Special attention should be directed toward this population in future research.
MeSH term(s)	Humans ; Child ; Retrospective Studies ; Prevalence ; Syndrome ; Immunosuppression Therapy ; Sepsis ; Death
Language	English
Publishing date	2023-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1032552-9
ISSN	1931-3543 ; 0012-3692
ISSN (online)	1931-3543
ISSN	0012-3692
DOI	10.1016/j.chest.2023.05.002
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Article ; Online: Neuronal ASIC1A As a Cerebral pH Sensor: Bringing the Flow.

Stark, Ryan J / Choi, Hyehun / Lamb, Fred S

Circulation research

2019 Volume 125, Issue 10, Page(s) 921–923

MeSH term(s)	Acid Sensing Ion Channels ; Hydrogen-Ion Concentration ; Neurons
Chemical Substances	Acid Sensing Ion Channels
Language	English
Publishing date	2019-10-24
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.119.315925
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Article ; Online: PLAAT1 Exhibits Phosphatidylcholine:Monolysocardiolipin Transacylase Activity.

Bradley, Ryan M / Hashemi, Ashkan / Aristizabal-Henao, Juan J / Stark, Ken D / Duncan, Robin E

International journal of molecular sciences

2022 Volume 23, Issue 12

Abstract: Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified. We studied the enzyme phospholipase A and acyltransferase 1 (PLAAT1), and we report ... ...

Abstract	Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified. We studied the enzyme phospholipase A and acyltransferase 1 (PLAAT1), and we report the discovery that it has phosphatidylcholine (PC):monolysocardiolipin (MLCL) transacylase activity. Subcellular localization was analyzed by differential centrifugation and immunoblotting. Total levels of major phospholipids, and the fatty acyl profile of cardiolipin, were analyzed in HEK293 cells expressing murine PLAAT1 using gas chromatography. Apparent enzyme kinetics of affinity-purified PLAAT1 were calculated using radiochemical enzyme assays. This enzyme was found to localize predominantly to the endoplasmic reticulum (ER) but was detected at low levels in the mitochondria-associated ER matrix. Cells expressing PLAAT1 had higher levels of total cardiolipin, but not other phospholipids, and it was primarily enriched in the saturated fatty acids myristate, palmitate, and stearate, with quantitatively smaller increases in the n-3 polyunsaturated fatty acids linolenate, eicosatrienoate, and eicosapentanoate and the monounsaturated fatty acid erucate. Affinity-purified PLAAT1 did not catalyze the transacylation of MLCL using 1-palmitoyl-2-[
MeSH term(s)	Acyltransferases/metabolism ; Animals ; Cardiolipins/metabolism ; HEK293 Cells ; Humans ; Lecithins ; Lysophospholipids/metabolism ; Mice ; Phospholipases A/metabolism
Chemical Substances	Cardiolipins ; Lecithins ; Lysophospholipids ; monolysocardiolipin ; Acyltransferases (EC 2.3.-) ; PLAAT1 protein, human (EC 3.1.1.32) ; Phospholipases A (EC 3.1.1.32)
Language	English
Publishing date	2022-06-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23126714
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