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Diabetic Ketoacidosis Elicits Systemic Inflammation Associated with Cerebrovascular Endothelial Cell Dysfunction
Author(s) -
Close Taylor E.,
Cepinskas Gediminas,
Omatsu Tatsushi,
Rose Keeley L.,
Summers Kelly,
Patterson Eric K.,
Fraser Douglas D.
Publication year - 2013
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1111/micc.12053
Subject(s) - inflammation , endocrinology , medicine , diabetic ketoacidosis , endothelial activation , systemic inflammation , endothelial dysfunction , proinflammatory cytokine , immunology , diabetes mellitus
Objective To determine if the DKA ‐induced inflammation in juvenile mice provokes activation and dysfunction of CVEC s. Methods DKA in juvenile mice was induced with administration of STZ and ALX. Blood from DKA mice was assessed for cytokines and soluble cell adhesion proteins, and either DKA plasma or exogenous compounds were applied to immortalized bEND 3. Results DKA increased circulating levels of IL‐6, IL‐8(KC), MCP‐1, IL‐10, sE‐selectin, sICAM ‐1, and sVCAM ‐1. Stimulation of bEND 3 with DKA plasma caused cellular activation (increased ROS and activation of NF‐κΒ), upregulation of a proadhesive phenotype (E‐selectin, ICAM‐1, and VCAM‐1), and increased leukocyte‐ bEND 3 interaction (leukocyte rolling/adhesion). TEER, a measure of bEND 3 monolayer integrity, was decreased by DKA plasma. Activation and dysfunction of bEND 3 with DKA plasma were suppressed by plasma heat treatment (56°C, 1 hour) and replicated with the application of DKA recombinant cytomix (IL‐6, IL‐8[KC], MCP‐1, and IL‐10), implicating circulating inflammatory protein(s) as mediators. Treatment of bEND 3 with β‐OH‐butyrate, the main ketone elevated in DKA, failed to mimic the DKA plasma–induced activation and dysfunction of bEND 3. Conclusions DKA elicits systemic inflammation associated with CVEC activation and dysfunction, possibly contributing to DKA ‐associated intracranial microvascular complications.