Evidence for the role of platelet-activating factor in immune complex vasculitis in the rat.
These studies were designed to determine the role of platelet-activating factor (PAF) in the pathogenesis of immune complex (IgG) induced dermal vasculitis in the rat. In vitro, very low (pM and nM) concentrations of PAF "primed" rat neutrophils for enhanced O2-. responses to IgG immune complexes while higher concentrations were directly stimulatory. The PAF receptor antagonist, L-652,731, blocked responses (O2-. production and enzyme release) of rat neutrophils stimulated with PAF but did not block responses triggered by immune complexes, formyl chemotactic peptide or opsonized zymosan particles. When L-652,731 was added to the antibody employed in the reversed passive Arthus reaction, the injury resulting from immune complex-induced vasculitis was significantly attenuated. In order to determine if in vivo protection provided by L-652,731 was related to neutrophils, we developed a new model in which rats are systemically depleted of neutrophils by cyclophosphamide and then locally reconstituted with intact neutrophils in a manner that allows restoration of immune complex-induced vascular injury. With this model, we demonstrated that the effects of neutrophil reconstitution are substantially diminished if the cells are pretreated with L-652,731 and then washed. By priming neutrophils with substimulatory concentrations of PAF, we have also provided in vivo evidence that neutrophil priming can increase the magnitude of vascular injury. These data provide evidence that vascular injury associated with immune complex dermal vasculitis is related to availability of PAF receptors on neutrophils, suggesting a mechanism through which PAF may function as a mediator in the pathogenesis of immune complex vasculitis.
Warren
J S
JS
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Mandel
D M
DM
Johnson
K J
KJ
Ward
P A
PA
D000818:Animals; D002199:Capillary Permeability; D005663:Furans / Q000494:pharmacology; D006878:Hydroxides; D017665:Hydroxyl Radical; D007105:Immune Complex Diseases / Q000209:etiology*; D008213:Lymphocyte Activation; D008854:Microscopy, Electron; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology; D010101:Oxygen Consumption; D010972:Platelet Activating Factor / Q000502:physiology*; D051381:Rats; D014657:Vasculitis / Q000209:etiology*
D005663:Furans; D006878:Hydroxides; D010972:Platelet Activating Factor; D017665:Hydroxyl Radical; D009240:N-Formylmethionine Leucyl-Phenylalanine; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran