Leukocyte adherence contributes to disruption of the blood-brain barrier during activation of mast cells.
The goal of this study was to examine the role of leukocytes in disruption of the blood-brain barrier during activation of mast cells using compound 48/80. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier (clearance of fluorescent-labeled dextran; molecular weight 10000 daltons; FITC-dextran-10 K) was determined while suffusing with vehicle or compound 48/80 (10 or 25 microg/ml). During superfusion with vehicle (saline), clearance of FITC-dextran-10 K from pial vessels was modest and remained relatively constant during the experimental period (0.52+/-0.05 ml/sx10(-6) at 80 min). In addition, diameter of pial arterioles remained constant (32+/-5 microm) while suffusing with vehicle. In contrast, topical application of compound 48/80 produced marked disruption of the blood-brain barrier to FITC-dextran-10 K. For example, suffusion with compound 48/80 (25 microg/ml) increased clearance of FITC-dextran-10 K about 4-fold to 2.26+/-0.25 ml/sx10(-6) at 80 min. In addition, superfusion with compound 48/80 (25 microg/ml) constricted pial arterioles by 26+/-9% at 80 min. To determine a potential role for leukocyte adhesion to endothelium in disruption of the blood-brain barrier during suffusion with compound 48/80, we examined permeability during suffusion with compound 48/80 (25 microg/ml) in the presence of WT.3 (2 mg/kg i.v.), a monoclonal antibody directed against the functional epitope of the leukocyte adhesive glycoprotein (CD18; LFA-1beta). We found that infusion of WT.3 markedly attenuated disruption of the blood-brain barrier to FITC-dextran-10 K in response to compound 48/80. The clearance of FITC-dextran-10 K during superfusion with compound 48/80 in the presence of WT.3 was 1.29+/-0.14 ml/sx10(-6) at 80 min (P<0.05). Thus, the findings of the present study suggest that application of compound 48/80, to degranulate mast cells, activates the adhesion of leukocytes to cerebral venular endothelium which contributes to disruption of the blood-brain barrier.
Mayhan
W G
WG
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-4575, USA. wgmayhan@unmc.edu
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002536:Cerebral Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002550:Cerebral Veins / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D003189:p-Methoxy-N-methylphenethylamine