title: CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro.
abstract: 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.
authors.affiliation: Centre for Critical Illness Research, London, Ontario, Canada;
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Omatsu
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
authors.forename: Cheril
authors.initials: C
authors.lastname: Clarson
authors.forename: Eric K
authors.initials: EK
authors.lastname: Patterson
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Alharfi
authors.forename: Kelly
authors.initials: K
authors.lastname: Summers
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fraser
mesh_terms: D001921:Brain / Q000098:blood supply* / Q000276:immunology; D016022:Case-Control Studies; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000097:blood* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications; D016883:Diabetic Ketoacidosis / Q000097:blood* / Q000276:immunology; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000097:blood* / Q000494:pharmacology; D008297:Male
chemical_list: C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D016209:Interleukin-8
keywords: CXC chemokine ligand; brain; cell trafficking; chemokines; diabetes; growth-regulated oncogene-α; human; inflammation; ketoacidosis; neutrophils; pediatric