Kinetics of the generation and action of chemical mediators in zymosan‐induced inflammation of the rabbit peritoneal cavity

Abstract

Acute inflammation was induced by intraperitoneal injection of zymosan (yeast cell walls) in the rabbit. Peritoneal inflammation was monitored by the local accumulation of intravenously‐injected Evans blue dye (which binds to plasma albumin) and of polymorphonuclear leukocytes (PMNLs). The zymosan‐induced exudate fluid contained a microvascular permeability‐increasing factor or factors which, unlike histamine and bradykinin, had a long duration of action when tested in rabbit skin and was dependent on circulating PMNLs. Using radioimmunossay, high levels of rabbit C5a, or C5a des Arg, were detected in the exudate fluid and accounted for much of the permeability‐increasing activity, as judged by skin bioassay after separation on Sephadex G‐100. The vasodilator prostaglandin, prostaglandin I2 (PGI2), was generated in the inflammatory reaction, as judged by the presence of high levels of 6‐oxo‐PGF1α detected in the exudate by radioimmunossay. However, in contrast to observations in rabbit skin, inhibition of prostaglandin generation had a relatively small effect on peritoneal oedema formation. C5a and C5a des Arg increase microvascular permeability by a PMNL‐dependent mechanism in the rabbit. However, in response to zymosan, protein leakage was detected considerably earlier than PMNL accumulation. A hypothesis to account for this difference is proposed.

Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit. Evidence for a role for C5a and interleukin-8.

“…Chemotactic activity, neutralized by an anti-CSa antibody, has also been detected in cardiac lymph in a dog model (17). In a peritonitis model in the rabbit we detected high levels of CSa in exudate (18,19) followed, after a delay, by high levels of interleukin-8 (20,21) and a related cytokine, melanoma growth-stimulatory activity (MGSA) (22). The possibility of a similar relationship was investigated in the present study.…”

Evidence that neutrophil accumulation induced by interleukin‐1 requires both local protein biosynthesis and neutrophil CD18 antigen expression in vivo

“…We have previously presented evidence that the inflammatory response to locally-injected zymosan involves the generation of C5a and C5a des Arg in extravascular tissue fluid (Jose et al, 1983;Forrest et al, 1986). Interestingly, a further component of this reaction is suggested by the experiments presented here.…”

“…These mediators can arise either from complement activation in extravascular tissue fluid or from activation of cells, such as macrophages. The 73 amino acid complement fragment C5a des Arg, detected in high concentrations in inflammatory exudates (Williams & Jose, 1981;Jose et al, 1983;Forrest et al, 1986), has potent chemotactic properties for neutrophils in vitro. C5a des Arg induces neutrophil accumulation 1 Present address: Department of Experimental Pharmacology, University of Antwerp, B-2610 Wilrijk, Belgium. 2 Author for correspondence.…”

Time‐dependent synergistic interactions between the vasodilator neuropeptide, calcitonin gene‐related peptide (CGRP) and mediators of inflammation

“…C5a des Arg, has been detected in high concentrations in inflammatory exudates (Ward & Zvaifler, 1971;Jose et al, 1983;1990;Forrest et al, 1986) and has been implicated in many inflammatory disease processes such as rheumatoid arthritis and lung injury (Ward & Zvaifler, 1971;Henson et al, 1982). In a previous study Rampart & Williams (1988), by centrifugation over a two-layer discontinuous (50:70%0) Percoll-plasma gradient after an initial red blood cell sedimentation with 3% hydroxyethyl starch.…”