interleukin-8 and Diabetic-Ketoacidosis

Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under "flow" conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

Topics: Brain; Case-Control Studies; Cells, Cultured; Chemokine CXCL1; Chemotaxis, Leukocyte; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Electric Impedance; Endothelium, Vascular; Female; Humans; Interleukin-8; Male

In human beings, diabetes mellitus (DM) and diabetic ketoacidosis (DKA) are recognized as proinflammatory states and dysregulation of cytokines has been linked to some potentially fatal complications. Cytokine profiles of dogs with DM or DKA have not been reported. The objectives of this study were to compare cytokine and hormone concentrations in dogs with DKA before and after resolution of ketoacidosis, to compare these concentrations before treatment of DKA to those measured in dogs with uncomplicated DM and healthy dogs, and to compare concentrations in dogs with uncomplicated DM to those measured in healthy dogs. 27 dogs were included in this prospective clinical study. 18 dogs had naturally-occurring disease (9 DKA and 9 DM) and 9 dogs were healthy. Serum GMCSF, IL-2, IL-4, IL-6, IL-7, CXCL8, IL-10, IL-15, IL-18, IFNγ, IP-10, TNFα, Monocyte Chemoattractant Protein-1 (MCP-1), Keratinocyte Chemoattractant (KC), glucagon, leptin, adiponectin, and resistin were assayed using Milliplex MAP Canine kits.(2)(,)(3) IL-18, resistin, and GMCSF concentrations were significantly higher in dogs with DKA before treatment compared to after resolution of ketoacidosis. CXCL8, MCP-1, KC, and resistin were significantly higher in DKA dogs compared to healthy controls, and KC was also significantly higher in DKA compared to DM dogs. Additionally, CXCL8 and MCP-1 were significantly higher in dogs with DM compared to healthy controls. Significant differences were not detected in concentrations of the other measured analytes, including glucagon. It is concluded that IL-18, resistin, GMCSF, and KC may be involved in the pathogenesis of canine DKA, and their importance in this pathogenesis may be as great as that of glucagon. Dysregulation of CXCL8 and MCP-1 may be involved in the pathogenesis of DM in dogs.

Topics: Animals; Chemokine CCL2; Cytokines; Diabetes Mellitus; Diabetic Ketoacidosis; Dog Diseases; Dogs; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Insulin; Interleukin-18; Interleukin-8; Male

It has been suggested that cytokine release during DKA may result in capillary perturbation and thus may contribute to the development of its acute clinical complications (i.e.cerebral or pulmonary edema). We studied in 38 newly diagnosed T1DM children with DKA, aged 7.68±3.07 years, plasma levels of cytokines IL-1β (interleukin-1β), IL-2, IL-6, IL-8, IL-10, TNF-α (tumour necrosis factor-α) and also WBC (white blood cell count), hs-CRP (high sensitivity C-reactive protein), GH (growth hormone) and cortisol, prior to, during and 120h after DKA management, with the aim to monitor their levels at different time-points and in different degrees of DKA severity. Prior to DKA management the levels of IL-6, IL-8, IL-10, WBC and cortisol were elevated, but were all reduced within 120 h after DKA management. Then the patients were divided into two groups: a. moderate/severe: pH≤7.2, b. mild DKA: pH>7.2. In the group with moderate/severe DKA (ph≤7.2), IL-10 levels were the highest of all cytokines, but were significantly decreased after 6h (91.76 vs 18.04 pg/mL, p=0.008), with no further change, while IL-6 levels were decreased at 120 h (28.32 vs 11.9 pg/mL, p=0.003). The above were not observed in the group with mild DKA. In conclusion, in the children with DKA of our study, in the group with moderate/severe DKA the IL-10 levels were prematurely reduced at 6 hours, while the IL-6 levels remained high and were reduced at 120 hours after the DKA management. These changes may be responsible for increased capillary perturbation, which could lead to the subsequent development of acute DKA complications.

Topics: Adolescent; C-Reactive Protein; Child; Child, Preschool; Cytokines; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Interleukin-10; Interleukin-1beta; Interleukin-2; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Tumor Necrosis Factor-alpha

The objectives of this study were to monitor plasma cytokines as markers of cellular activation and as potential markers for the progression of the acute complications of diabetic ketoacidosis (DKA). Blood samples were obtained prior to, during and after treatment of severe DKA (pH < 7.2) in six children and adolescents. Plasma IL-10, IL-1beta, TNF-alpha, IL-6, IL-8 and IL-2 cytokine levels were assayed by ELISA at each of the time points. Prior to treatment, elevations of multiple cytokines were found, the highest being IL-10. Treatment of DKA resulted in a significant decrease of IL-10 at 6-8 h (p = 0.0062), and further increases in the inflammatory cytokines at 6-8 h and/or 24 h vs 120 h (baseline): IL-1beta (p =.0048); TNF-alpha (p =.0188) and IL-8 (p =.0048). This study strengthens the hypothesis that the metabolic crisis of DKA, and its treatment, have differential effects on cellular activation and cytokine release. The time frame for the increase in inflammatory cytokines correlates with the reported progression of subclinical brain edema, interstitial pulmonary edema and the development of clinical brain edema.

Topics: Adolescent; Child; Cytokines; Diabetic Ketoacidosis; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-8; Male; Time Factors; Tumor Necrosis Factor-alpha

As our previous studies had shown that human neutrophils could kill Rhizopus oryzae hyphae in vitro, interactions of these hyphae with neutrophils and serum were further explored. Heated or fresh normal human sera suppressed hyphal metabolic activity as determined by [14C]uracil uptake, but severe ketoacidosis (8 X 10(-3) M beta-hydroxybutyric acid plus 2 X 10(-3) M acetoacetic acid at pH 7.0) negated this effect. Hyperglycemia (500 mg/dl) and severe ketoacidosis did not affect damage to hyphae by human neutrophils. Hyphae generated factors from sera which induced comparable chemotactic responses by neutrophils obtained from both normal and diabetic subjects, using a leading front assay performed in modified Boyden chambers. Zymosan-stimulated neutrophil chemotaxis was marginally depressed only by the combined elevation of both glucose (500 mg/dl) and ketoacids (10(-2)M) irrespective of pH (7.0 to 7.4), but not by any of these factors alone. Protein-containing supernatants from live or killed hyphae were chemotactic in the absence of serum based upon "checkerboard" assays varying the concentrations of hyphal supernatants above and below filters in the Boyden chambers. The supernatant-induced chemotactic response by neutrophils from diabetic subjects was minimally less than that of normal neutrophils (P less than 0.05). These findings indicate that R. oryzae hyphae can generate chemotactic factors which might prove to influence the inflammatory response to infections in vivo, and that severe hyperglycemia and ketoacidosis might affect interaction between the host and invading hyphae in mucormycosis.

Topics: Chemotactic Factors; Chemotaxis, Leukocyte; Complement Pathway, Alternative; Diabetic Ketoacidosis; Humans; Hydrogen-Ion Concentration; Hyperglycemia; Interleukin-8; Neutrophils; Rhizopus