Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis.
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).


CONCLUSIONS
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.
Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.|Children's Health Research Institute, London, Ontario, Canada.|Centre for Critical Illness Research, London, Ontario, Canada.
Martin
M
Woo
Centre for Critical Illness Research, London, Ontario, Canada.
Eric K
EK
Patterson
Centre for Critical Illness Research, London, Ontario, Canada.|Medical Biophysics, Western University, London, Ontario, Canada.
Gediminas
G
Cepinskas
Children's Health Research Institute, London, Ontario, Canada.|Pediatrics, Western University, London, Ontario, Canada.
Cheril
C
Clarson
Centre for Critical Illness Research, London, Ontario, Canada.|Pediatrics, Western University, London, Ontario, Canada.
Tatsushi
T
Omatsu
Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.|Children's Health Research Institute, London, Ontario, Canada.|Centre for Critical Illness Research, London, Ontario, Canada.|Pediatrics, Western University, London, Ontario, Canada.|Clinical Neurological Sciences, Western University, London, Ontario, Canada.|Translational Research Centre, London, Ontario, Canada.
Douglas D
DD
Fraser
D015415:Biomarkers / Q000097:blood; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications*; D016883:Diabetic Ketoacidosis / Q000097:blood / Q000201:enzymology* / Q000209:etiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020784:Matrix Metalloproteinase 8 / Q000097:blood* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood; D012720:Severity of Illness Index; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood; D000097792:Tissue Inhibitor of Metalloproteinase-4
D015415:Biomarkers; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C522361:MMP2 protein, human; C488762:MMP8 protein, human; C579270:MMP9 protein, human