A special adaptation of the rabbit ear chamber has been devised to study in vivo, under high magnification, the acute inflammatory reaction to thermal injury. Systematic observations of the cellular response have led to the following conclusions. 1. Contrary to the commonly accepted view, vasodilatation does not always precede the adherence of leucocytes to vascular endothelium. 2. The fact that leucocytes often adhere to one another as well as to the endothelium indicates that the increased adhesiveness characteristic of the early stages of inflammation is not limited to the surfaces of the endothelial cells. 3. The sharing of erythrocytes and platelets in this increased stickiness suggests that a "plasma factor" is involved. There is indirect but as yet inconclusive evidence that the plasma factor may concern the clotting mechanism of the blood. 4. The adherence of leucocytes to the endothelium is usually first noted on the side of the vessel closest to the site of injury. This previously undescribed phenomenon of "unilateral sticking" is in keeping with the concept that the vascular reaction is caused by products of cellular damage which diffuse to the vessel from the site of injury. 5. Leucocytes always become adherent to the endothelium before penetrating the vessel wall. They often migrate about for some time on the endothelial surface before undergoing diapedesis. 6. Although no definite stomata are at any time visible in the endothelium, penetrating leucocytes may leave behind temporary defects through which other leucocytes and even erythrocytes may pass. 7. The diapedesis of leucocytes appears to depend primarily upon cellular motility. It may occur in static vessels where there is presumably little if any hydrostatic pressure. 8. The diapedesis of erythrocytes, on the other hand, is a passive process depending upon intravascular pressure. Its occurrence is greatly exaggerated in areas in which intravascular pressure becomes elevated. Such elevations occur as the result of proximal arteriolar dilatation and distal occlusion of vessels. 9. Once they have reached the extravascular tissues the leucocytes move about more or less at random, apparently uninfluenced by any compelling chemotactic force. Their resultant migration, however, is toward the site of injury around which they eventually tend to congregate. 10. The histiocytes normally present in the connective tissue appear to play no role in the type of acute inflammatory reaction produced in these experiments.

The mode of action of cortisone as an antipyretic has been studied in rabbits challenged with intravenous injections of bacterial pyrogens. The fever induced by pyromen or dextran was found to be markedly suppressed when cortisone was administered in liberal amounts (25 mg. twice daily) for 3 days prior to the challenge. Although the cortisone effectively blocked the febrile response to both pyrogens, it failed to influence the transient but marked leucopenia which characteristically precedes the onset of fever. The antipyretic action of the drug also was shown to bear no relation to the activity of the serum factor recently demonstrated by Farr, Grant, and others to be involved in the production of pyrogen-induced fever. In preliminary experiments with typhoid vaccine as the inciting pyrogen, the presence of serum factor activity in normal blood and its absence in the blood of pyrogen-tolerant rabbits was confirmed. Subsequently the blood of rabbits treated with antipyretically effective doses of cortisone was shown to contain just as much serum factor activity as that of normal rabbits. In addition, previous incubation of the pyrogen with serum factor failed to influence the antipyretic effect of the drug. It is concluded from these findings that in suppressing pyrogen fever, cortisone acts neither upon the leucopenic reaction nor upon the fever-accelerating factor of the serum. By exclusion it would appear that the drug must influence some later stage of the fever-producing process. The mechanisms involved in the later stages of the response to exogenous pyrogen remain undefined, and the need for determining whether they are related to the prefebrile leucopenia is emphasized.

The relation of intravascular fibrin to the leucocytic sticking reaction in ear chambers of rabbits injured by heat was investigated in two ways. First, attempts were made to destroy the thin layer of fibrin believed to coat the surfaces of cells involved in the sticking reaction. Second, white cell sticking was studied after fibrinogen had been removed from the blood stream. The results of these experiments were as follows:— 1. Activation of fibrinolysin in vivo by streptokinase did not impair sticking of white blood cells. 2. Administration of streptokinase parenterally did not lower fibrinogen blood levels appreciably even when the amount used was large. 3. Thromboplastin infusions alone reduced circulating fibrinogen to low levels but leucocytic sticking was not prevented. Furthermore, frequent death of animals due to pulmonary embolism made such experiments prohibitive. 4. Addition of streptokinase to thromboplastin infusions protected against embolic deaths but did not influence sticking even though the fibrinogen levels achieved were quite low. 5. Finally, when thrombin was added to infusions of thromboplastin and streptokinase, no circulating fibrinogen could be detected. Under such circumstances leucocytic sticking following heat injury occurred without reduction. These findings were interpreted as evidence against a primary role of the blood clotting mechanism in causing the sticking of white blood cells to injured endothelium. Alternative explanations were discussed.

The anti-inflammatory action of cortisone upon the acute cellular response to thermal injury has been systematically studied in the rabbit ear chamber. The hormone has been shown to suppress the reaction of acute inflammation in its earliest recognizable phase; i.e., that involving vasodilatation and the adherence of leucocytes to the vascular endothelium. Evidence has been presented that the anti-inflammatory effect of the hormone cannot be explained on the basis of its vasoconstrictive properties alone. The experimental observations support the hypothesis that cortisone exerts a direct protective action upon endothelial cells and leucocytes, and that in so doing, it renders them refractory to the tissue products which initiate inflammation.

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