The subcutaneous sponge implant model of acute
inflammation in the rat has been evaluated as a suitable test system for evaluating the potential anti-inflammatory efficacy of
5-lipoxygenase inhibitors. The inflammatory parameters measured were exudate volume and leukocyte recruitment. Specific radioimmunoassays were used to measure (1)
5-lipoxygenase (LPO) and
cyclo-oxygenase (CO) activity in exudate leukocytes stimulated ex vivo with
A23187, and (2) the
LTB4 and
PGE2 content of inflammatory exudate. The
NSAIDs flurbiprofen and
indomethacin inhibited cell recruitment, exudate volume and CO activity with ED50S of approximately 1 mg per kg p.o. but failed to inhibit LPO activity
at 10 mg per kg p.o.
Nafazatrom (Bayer 6575),
quercetin and NDGA, which inhibit LPO activity in vitro, were inactive against all parameters when dosed at 100 mg per kg p.o. The "mixed inhibitors"
BW755C and
phenidone were approximately equipotent inhibitors of LPO activity but
BW755C was 10 times more potent than
phenidone against CO activity.
BW755C was also greater than 10 times more potent at inhibiting cell recruitment and exudate volume than
phenidone suggesting that the anti-inflammatory efficacy of the mixed inhibitors reflect their potency against CO rather than LPO activity. Time course studies demonstrated that the inhibitor effects of
BW755C and
phenidone on leukocyte recruitment reflected a reduction in the
PGE2 but not the
LTB4 content of the inflammatory exudate.
Polyester sponges soaked in high concentrations of
LTB4 caused only a modest (2-fold) increase in leukocyte recruitment whilst physiological levels were inactive. The results taken together suggest that CO products make a major contribution to leukocyte recruitment in this model whilst the LPO product
LTB4 has little role. This model therefore is of little value for evaluating the anti-inflammatory efficacy of
5-lipoxygenase inhibitors. Moreover, the rat would appear to be unsuitable for evaluating the role of
LTB4 in acute
inflammation.