A Study of Possible Mediators of Inflammatory Reactions in the Mouse Foot

Abstract

A number of compounds have been studied for their ability to antagonize the inflammatory reaction produced by injections of formaldehyde and 5-hydroxytryptamine in the mouse foot. An attempt has been made to elucidate the ways in which certain hydroxybenzoates, pyrazolones, sympathomimetic amines, flavone and flavanone glycosides, local anaesthetics, antihistamines and anti-5-hydroxytryptamine substances produce their anti-inflammatory effect.Several substances occur in damaged tissues which have the ability to increase capillary permeability, the subject having been reviewed by Spector (1958). The presence of such substances does not prove their participation in the mediation of the symptoms observed, and it is difficult to differentiate between the causes and the effects of the process in many types of inflammation. Since Lewis (1927) demonstrated that part of the response of tissues to trauma is mediated by an axon-reflex there has been little work done to discover to what extent this process operates in different types of inflammation. Chambers & Zweifach (1947) have emphasized that little is known about the effect which local changes in blood flow have on the overall inflammatory reaction, and so we have attempted, in the experiments described here, to analyse the anti-inflammatory action of certain drugs which are known to alter blood flow in the skin. METHODSFormaldehyde-induced inflammation in the mouse foot. The details of the method have been described by Northover & Subramanian (1961a). Adult mice of either sex weighing between 25 and 35 g were used in groups of 6 animals. The animals were pretreated with the test substance, given subcutaneously, one injection 24 hr and another 30 min before the injection of formaldehyde. Where variations of this procedure were used they are indicated in the text. All premedicant injections were made in a dose-volume of 0.1 ml., and all compounds were given either as freshly prepared solutions or suspensions, adjusted, where required, to pH 7 with either sodium hydroxide or hydrochloric acid. Each mouse received 0.1 ml. of an aqueous solution containing 0.5% azovan blue and 0.9% sodium chloride through a lateral tail vein, and then immediately afterwards 0.05 ml. of an aqueous solution containing 4% formaldehyde and 0.9% sodium chloride subcutaneously in the dorsum of the right hind foot. The left hind foot received the same volume of saline alone and acted as a control for the formaldehyde-treated foot. The blue-dye accumulation and the swelling in the test foot compared with the control foot were given subjectively assigned scores of from 0 to 3 by

E. coli ENDOTOXIN SHOCK IN THE CAT; TREATMENT WITH INDOMETHACIN

“…*P<0.01; **P< 0.001. a tendency for the systemic blood pressure to be maintained for longer than in the control group (compare the diastolic blood pressure values at 2, 3 and 4 h in Tables 1 and 2) but this was certainly not as marked as when indomethacin was given prophylactically (Parratt & Sturgess, 1974). Cardiac output fell to the same extent as in the cats given endotoxin alone and there was no modification of the endotoxin-induced metabolic acidosis ( (Northover & Subramanian, 1962;Erdos, 1968;Culp, Erd6s, Hinshaw & Holmes, 1971). Clearly such studies are not relevant to the question whether such drugs might be used in the treatment of developed septic or bacteraemic shock in man although, because it prevents endotoxin-induced pulmonary changes in cats, the use of aspirin has been suggested as a therapeutic measure to help prevent further deterioration of established pulmonary damage in patients with gram-negative septicaemia (Murthy & Greenway, 1972 This is in contrast to the effect of pretreatment with indomethacin (Parratt & Sturgess, 1974) and suggests that the acute pulmonary changes (hypertension and decreased compliance) that occur in this species within a few minutes of endotoxin administration ultimately contribute to the severity of the shock phase.…”

MODIFICATION, BY ASPIRIN AND INDOMETHACIN, OF THE HAEMODYNAMIC AND PROSTAGLANDIN RELEASING EFFECTS OF E. coli ENDOTOXIN IN THE DOG

“…All previously reported studies (Northover & Subramanian, 1962;Hinshaw et al, 1967;Parratt & Sturgess, 1974;1975a,b,c) given at various times (30 min before to 2 h after endotoxin administration). Pharmacological doses of these drugs have a variety of effects as described earlier.…”

“…Treatment of endotoxin shock with antiinflammatory drugs was first introduced by Northover & Subramanian (1962). They showed that the administration of anti-inflammatory drugs either before or after endotoxin resulted in improved circulatory function.…”

“…Non-steroidal anti-inflammatory drugs decrease the haemodynamic responses in endotoxin shock and enhance survival (Northover & Subramanian, 1962;Hinshaw, Soloman, Erdos, Reins & Gunter, 1967;Culp, Erdos, Hinshaw & Holmes, 1971;Greenway & Murthy, 1971;Hall, Hodge, Irvine, Katic & Middleton, 1972;Parratt & Sturgess, 1974;1975a,b,c;Anderson, Jubiz, Tsagaris & Kuida, 1975a,b;Fletcher, Ramwell & Herman, 1976). …”

Anti-Inflammatory Activity of Taxifolin

“…The flavonoids viz hesperidin, neohesperidin and naringin have been shown to reduce formalin-induced oe dema in the mouse foot (4). The present investigation deals with the study of the anti inflammatory activity of taxifolin, a flavonoid obtained from <I>Madhuca Butyracea</I>, and the effect of taxifolin on the serum aminotransferase and tissue adenosine triphosphate (ATP) phosphohydrolase activity to elucidate the possible mechanism of its anti-inflamma tory activity.…”