uPA modulates the age-dependent effect of brain injury on cerebral hemodynamics through LRP and ERK MAPK.
We hypothesized that urokinase plasminogen activator (uPA) contributes to age-dependent early hyperemia after fluid percussion brain injury (FPI) by activating extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK), leading to histopathologic changes in the underlying cortex. Both cerebrospinal fluid (CSF) uPA and phosphorylation of CSF ERK MAPK was increased at 1 min after FPI in newborn pigs, but was unchanged in juvenile pigs. uPA and phosphorylated ERK MAPK, detectable in sham piglet brain by immunohistochemistry, was markedly elevated and associated with histopathology 4 h after FPI in the newborn but there was minimal staining and histopathology in the juvenile. EEIIMD, a peptide derived from PA inhibitor-1 that does not affect proteolysis, blunted FPI-induced phosphorylation of ERK MAPK. FPI produced pial artery dilation and increased cerebral blood flow at 1 min after insult in the newborn, but not in the juvenile. Antilipoprotein-related protein (LRP) antibody, EEIIMD, a soluble uPA antagonist, and the ERK MAPK antagonist U 0126 inhibited FPI-associated hyperemia. These data indicate that uPA is upregulated after FPI and produces an age-dependent early hyperemia followed by histopathology through an LRP- and ERK MAPK-dependent pathway.
Armstead
William M
WM
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. armsteaw@uphs.upenn.edu
Cines
Douglas B
DB
Bdeir
Khalil H
KH
Bdeir
Yasmina
Y
Stein
Sherman C
SC
Higazi
Abd Al-Roof
AA
D000375:Aging / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006439:Hemodynamics / Q000502:physiology*; D008297:Male; D011973:Receptors, LDL / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000502:physiology*
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D011973:Receptors, LDL; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator