A comparison of the anti-inflammatory activity of selective 5-lipoxygenase inhibitors with dexamethasone and colchicine in a model of zymosan induced inflammation in the rat knee joint and peritoneal cavity

Abstract

Intraperitoneal and intra-articular (knee joint) injection of zymosan in the rat caused two phases of increased vascular permeability, a rapid increase (0.25-0.5 h) and a secondary increase (2-3 h) which was temporally associated with the onset of leukocyte infiltration. Intraperitoneal injection of zymosan led to a single peak of eicosanoid production (LTB4, C4, D4, E4 and 6-oxo-PGF1 alpha) which was maximal at 0.125-0.25 h. Intra-articular injection led to an initial peak of LTB4 production (maximal at 0.25 h) and a secondary peak of LTB4 and PGE2 production (maximal at 3 h). Oral administration of the 5-lipoxygenase (5-LO) inhibitors phenidone, BW A4C (N-hydroxy-N-[3-(3-phenoxyphenyl)-2-propenyl] acetamide), A63162 (N-hydroxy-N-[1-(4-(phenylmethoxy) phenyl)ethyl] acetamide and ICI 207 968 (2-[3-pyridylmethyl]-indazolinone inhibited LTB4 production in A23187 stimulation blood ex vivo. The glucocorticosteroid dexamethasone had no effect in this model. The initial phase of increased vascular permeability in the peritoneal cavity and LTB4 production was dose dependently inhibited by the 5-LO inhibitors phenidone, BW A4C, A63162, and ICI 207 968 but not by dexamethasone or colchicine. The initial phase of increased permeability in the joint was unaffected by phenidone, BW A4C, dexamethasone or colchicine. However the latter two drugs inhibited the later phase of increased permeability and leukocyte infiltration in the joint and peritoneal cavity. These results demonstrate that zymosan induces eicosanoid production in vivo but the relative importance of these mediators varies depending on the inflammatory site.(ABSTRACT TRUNCATED AT 250 WORDS)

Tulathromycin Exerts Proresolving Effects in Bovine Neutrophils by Inhibiting Phospholipases and Altering Leukotriene B4, Prostaglandin E2, and Lipoxin A4Production

“…In view of its multifaceted roles in airway inflammation, future studies will examine the impact of tulathromycin on PGE 2 production and the consequence of this effect on airway inflam- mation. Using the experimental protocol described here, zymosan was found to significantly increase PGE 2 production 24 h postchallenge, consistent with previous studies using other models in vivo (43)(44)(45) or in vitro (46), an effect that was blocked by tulathromycin. Another immunomodulating antibiotic for cattle and pigs, tilmicosin, also blocks PGE 2 production in LPS-stimulated bovine alveolar macrophages via a decrease in COX-2 expression and/or partial inhibition of secretory phospholipase A 2 activity (47,48).…”

Post-capillary venules in the “milky spots” of the greater omentum are the major site of plasma protein and leukocyte extravasation in rodent models of peritonitis

“…2A). These data correspond to the initial decrease in cells (mostly resident macrophages) followed by an influx of neutrophils that has been reported previously in both mice [10] and rats [15]. The increased number of neutrophils in the peritoneal lavage was preceded by an increase in the omentum, as measured by myeloperoxidase content (Fig.…”

“…Rats were used for these experiments because larger animals are required in order to make cardiovascular monitoring possible. Previous studies indicate that the vascular leak in response to zymosan A is similar in rats and mice [10,15,24]. The microsphere studies demonstrated that a clear increase in blood flow occurred in the omentum following intraperitoneal injection of zymosan A while flow to other abdominal organs showed no change or decreased.…”

“…However, monocytes/ macrophages also contain this activity albeit at much lower levels [13,14]. In some experiments zymosan A induced peritonitis (2ml of a 5mg/ml suspension) or arthritis (0.05ml of a 20mg/ml suspension) was studied in rats (Male, Charles River CD outbred, 200-300 g) as described by Griffiths et al [15]. Pleurisy was induced in rats by the injection of 0.1ml of a 10mg/ml suspension of zymosan A, using the injection technique described by Vinegar et al…”

Central mediators of the zymosan-induced febrile response

“…The inflammatory process is different in the joints and other sites of the body. For example, Griffiths et al compared the effectiveness of 5-lipooxygenase inhibitors against zymosan-induced inflammation in the rat knee joint and peritoneal cavity [41]. An i.p.…”