Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: effect of lipocortin 1.
In this study we investigated, using intravital microscopy, how neutrophil extravasation across mouse mesenteric postcapillary venules is inhibited by the glucocorticoid-regulated protein lipocortin (LC; also termed annexin) 1. Intraperitoneal injection of 1 mg of zymosan into mice induced neutrophil rolling on the activated mesenteric endothelium followed by adhesion (maximal at 2 hr: 5-6 cells per 100-micrometers of vessel length) and emigration (maximal at 4 hr: 8-10 cells per high-powered field). Treatment of mice with human recombinant LC1 (2 mg/kg s.c.) or its mimetic peptide Ac2-26 (13 mg/kg s.c.) did not modify cell rolling but markedly reduced (>/=50%) the degree of neutrophil adhesion and emigration (P < 0.05). Intravenous treatment with peptide Ac2-26 (13 mg/kg) or recombinant human LC1 (0.7-2 mg/kg) promoted detachment of neutrophils adherent to the endothelium 2 hr after zymosan administration, with adherent cells detaching within 4.12 +/- 0.75 min and 2.36 +/- 0.31 min, respectively (n = 20-25 cells). Recruitment of newly adherent cells to the endothelium was unaffected. The structurally related protein LC5 was inactive in this assay, whereas a chimeric molecule constructed from the N terminus of LC1 (49 aa) attached to the core region of LC5 produced cell detachment with kinetics similar to LC1. Removal of adherent neutrophils from activated postcapillary endothelium is a novel pharmacological action, and it is at this site where LC1 and its mimetics operate to down-regulate this aspect of the host inflammatory response.
Lim
L H
LH
Department of Biochemical Pharmacology, William Harvey Research Institute, London EC1M 6BQ, United Kingdom.
Solito
E
E
Russo-Marie
F
F
Flower
R J
RJ
Perretti
M
M
D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000494:pharmacology* / Q000502:physiology; D001783:Blood Flow Velocity; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D004912:Erythrocytes / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013152:Splanchnic Circulation; D013329:Structure-Activity Relationship; D014699:Venules / Q000502:physiology* / Q000503:physiopathology
D017305:Annexin A1; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins