CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Omatsu, Tatsushi; Cepinskas, Gediminas; Clarson, Cheril; Patterson, Eric K.; Alharfi, Ibrahim M.; Summers, Kelly L.; Couraud, Pierre‐Olivier; Romero, Ignacio A.; Weksler, Babette B.; Fraser, Douglas D.

doi:10.1152/ajpendo.00659.2013

Cited by 46 publications

(52 citation statements)

References 47 publications

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“…Specifically, our data suggest a potential mechanism for adhered leukocytes to facilitate human blood-brain barrier disruption in DKA (5). Clinician awareness is imperative as overaggressive fluid resuscitation will potentially exacerbate subclinical vasogenic edema via the compromised blood-brain barrier.…”

Section: Mmps In Pediatric Dkamentioning

confidence: 78%

“…MMPs have diverse actions that may involve exacerbation of existing inflammatory cascades (14), as well as direct actions on the microvasculature (15). This latter action of MMPs is particularly intriguing given that DKA induces leukocyte adherence to the brain microvasculature (5) and that the DKA-induced MMPs appear to be leukocyte derived.…”

Section: Mmps In Pediatric Dkamentioning

confidence: 99%

“…Additional enzymatic action could occur via the sequential addition of MMPs (i.e., MMP-8) that has been demonstrated to boost substrate degradation (38). We have previously demonstrated that reactive oxygen species (ROS) are elevated in human brain microvascular cells in vitro after DKA plasma application (5), and ROS are a common trigger for many downstream pathways that directly mediate blood-brain barrier compromise, including MMP activation (39).…”

Section: Mmps In Pediatric Dkamentioning

confidence: 99%

“…We recently reported that DKA elicits significant elevations in the chemokines CXCL1 (GROα) and CXCL8 (IL-8), resulting in leukocyte adhesion to human-derived cerebral microvascular endothelium (5). Adhered leukocytes can release substances that mediate endothelial damage and vascular destabilization (e.g., matrix metalloproteinases (MMP)) (6).…”

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confidence: 99%

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Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis

Woo

Patterson²,

Cepinskas

et al. 2015

Pediatr Res

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Background: Diabetic ketoacidosis (DKA) in children is associated with cerebrovascular-related complications. We recently reported that DKA facilitates leukocyte adherence to the brain microvascular endothelium. Adhered leukocytes can release enzymes that instigate vascular dysfunction. Our aims were to measure plasma levels of leukocyte-derived matrix metalloproteinases (MMPs) from DKA patients and to correlate plasma MMP concentrations with DKA severity. Methods: Plasma was obtained from children with type 1 diabetes, either in DKA (n = 16) or insulin controlled (CON; n = 16). Antibody microarray and gelatin zymography were used to quantify plasma MMPs and their endogenous tissue inhibitors (TIMPs). MMP concentrations were correlated with DKA severity (blood pH). Quantitative PCR of leukocyte mRNA was used to help determine the origin of plasma MMPs. results: DKA was associated with altered plasma levels of ↓MMP-2 (P < 0.001), ↑MMP-8 (P < 0.001), ↑MMP-9 (P < 0.05), and ↑TIMP-4 (P < 0.001), as compared with CON. Elevated MMP-8 and MMP-9 were both positively correlated with DKA severity (P < 0.05). DKA was associated with increased leukocyte mRNA for MMP-8, MMP-9, and TIMP-4 (P < 0.005). conclusion: MMPs are dynamically regulated during DKA. Plasma MMP-8 and MMP-9 concentrations correlate with DKA severity and are known to degrade brain microvascular endothelial cell tight junctions. Thus, leukocyte-derived MMPs might contribute to DKA-associated cerebrovascular complications.

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Section: Mmps In Pediatric Dkamentioning

confidence: 78%

Section: Mmps In Pediatric Dkamentioning

confidence: 99%

Section: Mmps In Pediatric Dkamentioning

confidence: 99%

mentioning

confidence: 99%

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Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis

Woo

Patterson²,

Cepinskas

et al. 2015

Pediatr Res

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“…BBB dysfunction may be secondary to DKA-associated inflammation and leukocyte adherence to the brain microvascular endothelium (16,45). DKA-induced BBB permeability may exacerbate increases in brain glucose, lactate, and ketone levels during DKA (13,28,55) and underlie the vasogenic edema observed on brain MRI with apparent diffusion coefficients (19, 23, 29).…”

Section: Discussionmentioning

confidence: 99%

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Rose

Watson

Drysdale

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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A common complication of type 1 diabetes mellitus is diabetic ketoacidosis (DKA), a state of severe insulin deficiency. A potentially harmful consequence of DKA therapy in children is cerebral edema (DKA-CE); however, the mechanisms of therapy-induced DKA-CE are unknown. Our aims were to identify the DKA treatment factors and membrane mechanisms that might contribute specifically to brain cell swelling. To this end, DKA was induced in juvenile mice with the administration of the pancreatic toxins streptozocin and alloxan. Brain slices were prepared and exposed to DKA-like conditions in vitro. Cell volume changes were imaged in response to simulated DKA therapy. Our experiments showed that cell swelling was elicited with isolated DKA treatment components, including alkalinization, insulin/alkalinization, and rapid reductions in osmolality. Methyl-isobutyl-amiloride, a nonselective inhibitor of sodium-hydrogen exchangers (NHEs), reduced cell swelling in brain slices elicited with simulated DKA therapy (in vitro) and decreased brain water content in juvenile DKA mice administered insulin and rehydration therapy (in vivo). Specific pharmacological inhibition of the NHE1 isoform with cariporide also inhibited cell swelling, but only in the presence of the anion transport (AT) inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid. DKA did not alter brain NHE1 isoform expression, suggesting that the cell swelling attributed to the NHE1 was activity dependent. In conclusion, our data raise the possibility that brain cell swelling can be elicited by DKA treatment factors and that it is mediated by NHEs and/or coactivation of NHE1 and AT.

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Frequency and Risk Factors of Acute Kidney Injury During Diabetic Ketoacidosis in Children and Association With Neurocognitive Outcomes

et al. 2020

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IMPORTANCEAcute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear. OBJECTIVE To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA. DESIGN, SETTING, AND PARTICIPANTSThis cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and venous pH less than 7.25 or serum bicarbonate level less than 15 mEq/L. EXPOSURES DKA requiring intravenous insulin therapy. MAIN OUTCOMES AND MEASURES AKI occurrence and stage were assessed using serum creatinine measurements using Kidney Disease: Improving Global Outcomes criteria. DKA episodes with and without AKI were compared using univariable and multivariable methods, exploring associated factors. RESULTS Among 1359 DKA episodes (mean [SD] patient age, 11.6 [4.1] years; 727 [53.5%] girls; 651 patients [47.9%] with new-onset diabetes), AKI occurred in 584 episodes (43%; 95% CI, 40%-46%).A total of 252 AKI events (43%; 95% CI, 39%-47%) were stage 2 or 3. Multivariable analyses identified older age (adjusted odds ratio [AOR] per 1 year, 1.05; 95% CI, 1.00-1.09; P = .03), higher initial serum urea nitrogen (AOR per 1 mg/dL increase, 1.14; 95% CI, 1.11-1.18; P < .001), higher heart rate (AOR for 1-SD increase in z-score, 1.20; 95% CI, 1.09-1.32; P < .001), higher glucose-corrected sodium (AOR per 1 mEq/L increase, 1.03; 95% CI, 1.00-1.06; P = .001) and glucose concentrations (AOR per 100 mg/dL increase, 1.19; 95% CI, 1.07-1.32; P = .001), and lower pH (AOR per 0.1 increase, 0.63; 95% CI, 0.51-0.78; P < .001) as variables associated with AKI. Children with AKI, compared with those without, had lower scores on tests of short-term memory during DKA (mean [SD] digit span recall: 6.8 [2.4] vs 7.6 [2.2]; P = .02) and lower mean (SD) IQ scores 3 to 6 months after recovery from DKA (100.0 [12.2] vs 103.5 [13.2]; P = .005). Differences persisted after adjusting for DKA severity and demographic factors, including socioeconomic status. (continued) Key Points Question What are the mechanisms, risk factors, and outcomes associated with acute kidney injury (AKI) during pediatric diabetic ketoacidosis (DKA)? Findings In this cohort study using data from 1359 DKA episodes in a large, multicenter, prospective study of fluid treatment during DKA, AKI occurred in 43% of episodes and was associated with greater acidosis and greater circulatory volume depletion. Children who had AKI were more likely to have subtle cognitive impairment during DKA and lower IQ at longer-term follow-up. Meaning These findings suggest that AKI is frequent in pediatric DKA and there is a pattern of multiorgan dysfunction during childhood DKA with the possibility of c...

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CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Cited by 46 publications

References 47 publications

Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis

Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Frequency and Risk Factors of Acute Kidney Injury During Diabetic Ketoacidosis in Children and Association With Neurocognitive Outcomes

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