title: Beta 2 integrin independent neutrophil recruitment and injury in anti-GBM glomerulonephritis in rabbits.
abstract: The role of the beta 2 integrin cell adhesion molecules (CAM) in directing neutrophil accumulation and injury in acute anti-glomerular basement membrane antibody induced glomerulonephritis (anti-GBM GN) was assessed in rabbits by in vivo inhibition of CD18 dependent neutrophil/endothelial cell interactions using a monoclonal anti-CD18 antibody. Rabbits given horse anti-rabbit GBM antibody developed significant glomerular neutrophil influx (2.9 +/- 0.1 neutrophils per glomerular cross-section [c/gcs], normal 0.1 +/- 0.1 c/gcs, P = 0.002) and proteinuria (1389 +/- 257 mg/16 h, normal 15 +/- 4 mg/16 h, P = 0.0015) after 16 h. Rabbits rendered neutropenic (< 500 neutrophils/microL) by mustine hydrochloride, or complement depleted by cobra venom factor, did not develop glomerular neutrophil accumulation and had markedly reduced proteinuria after anti-GBM antibody, demonstrating complement-induced neutrophil recruitment is a major mechanism of glomerular injury in this model. Anti-CD18 antibody treatment of rabbits developing anti-GBM GN abrogated dermal neutrophil influx in response to intradermal injection of fMLP and zymosan activated serum. Treated rabbits achieved levels of anti-CD18 antibody in their serum which saturated the binding sites on rabbit neutrophils in vitro, and their circulating neutrophils had saturated anti-CD18 antibody binding in vivo. However, glomerular neutrophil influx (3.5 +/- 0.4 c/gcs) and proteinuria (1210 +/- 428 mg/16 h) were both unaffected. Thus, in this model of antibody-initiated complement and neutrophil-dependent glomerular injury, in which neutrophil transmigration across the endothelium is not required, effective functional inhibition of beta 2 integrin CAM in vivo did not reduce glomerular injury or glomerular neutrophil influx. These studies demonstrate that beta 2 integrin CAM are not a requirement for neutrophil accumulation and glomerular injury in anti-GBM GN in rabbits.
authors.affiliation: Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: P G
authors.initials: PG
authors.lastname: Tipping
authors.forename: L J
authors.initials: LJ
authors.lastname: Cornthwaite
authors.forename: S R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D004727:Endothelium / Q000166:cytology; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology*; D016023:Integrins / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology*; D011817:Rabbits
chemical_list: D018845:CD11 Antigens; D018821:CD18 Antigens; D016023:Integrins