Anaphylactoid Edema: 1937-1967

ANAPHYLACTOID EDEMA: 1937-1967 HANS SELYE* Since its first description in 1937, almost 1,000 publications have dealt with the anaphylactoid edema (AE), particularly its mechanism and the factors capable ofinfluencing its course [1]. The reaction has been shown always to be closely related to the function ofthe mast cell (MC). Despite this common factor, the AE can give rise to a great variety ofstructurally distinct lesions (serous inflammation, thrombohemorrhagic lesions, calcification , necrosis, delayed tissue clearance of various substances) whose localization in different organs (skin, gastrointestinal tract, endocrine and exocrine glands, nerves) can be predictably regulated. It appears, furthermore , that many ofthe lesions which depend upon the AE have clinical equivalents in man and that the AE of the rat represents a reliable test object for the screening ofantihistamines, antiserotonins, and related antiallergic and antiphlogistic drugs. It may be useful, therefore, to summarize the salient results ofthe first thirtyyears ofinvestigations on this phenomenon . Classical AnaphylactoidEdema In 1937 weattempted to explorethepossible role ofhistamine liberation in the development of the then newly discovered general adaptation syndrome. In the course ofthis work, it was noted that, unlike most nonspecific stressors, intraperitoneally injected egg white produces a unique hypersensitivity reaction in the rat [2]. This response was characterized by an acute hyperemia and edema, especially ofthe "aerai regions" (lips, nose, tongue, ears, paws) and genitalia , the swelling being accompanied by intense pruritus, asjudged by the fact that theanimals scratchedthemselves violently. It strikinglyresembled "angioneurotic" edema and urticaria. It also exhibited certain characteristics ofhistamine liberation (edema, hyperemia) and anaphylaxis, but, since * Institut de Médecine et de Chirurgie expérimentales, Université de Montréal, Montreal, Canada. This work was supported by the Medical Research Council ofCanada (Block Term grant MT-1829). 247 it was produced without any previous sensitization, we called it first the "anaphylactoid inflammation" and later "anaphylactoid edema" (AE). The response evidently differed from the non-specific alarm reaction to stress; indeed, it could be prevented by previous exposure to a stressor of sufficient intensity to produce adrenocortical enlargement. On the other hand, adrenalectomy aggravated the AE to such an extent that the affected regions became deeply cyanotic. Furthermore, adrenalectomized rats died after treatment with small doses ofegg white which were well tolerated by intact controls. Upon repeated daily injections, the AE diminished progressively [2]. About ten years later, J. Légerjoined our Institute and selected the anaphylactoid inflammatory edema as a subject for his Ph.D. thesis [3]. He demonstrated that the active principle in egg white is ovomucoid and that the AE-G (produced by egg white i.p. in the rat) is prevented by various antihistamines [4]. This latter finding was especially important because it came just after the discovery by O'Leary and Färber ofthe Mayo Clinic that antihistamines often give spectacular relief from urticaria and angioneurotic edema in man [5,6]. Hence, it called attention to the close relationship between these clinical syndromes and the AE response. Thereupon the AE became one ofthe most commonly used pharmacologic tests for the assay ofhistamine antagonists ofpotential clinical value. In 1948, Ivy, Tanturi, Hernandez, and Baroso [7] noted that sorbitol monolaurate (Tween 20) i.e. or i.v. causes urticaria in the dog through the release ofsome histamine-like substance and that this response can also be prevented by antihistamines. During the following year, Elster et al. [8-10] showed that hyaluronidase i.v. produces a typical AE-G in the rat which was likewise preventable by antihistamines. Finally, in 1951, Morrison, Voorhees, and their coworkers produced an AE-G in rats by dextran i.v. or i.p., again noting that the response diminishes following repeated daily injections [11, 12]. These findings clearly showed that egg white is not the only compound capable ofproducing an AE. They also called attention to an earlier observation made by Duran-Reynals in 1939. In studying the effect oftesticular hyaluronidase upon capillary permeability in mice, he found that systemic treatment with this enzyme causes Evans' blue to stain selectively the skin around the ears and foot pads. Although the author was apparently un248 Hans Selye · Anaphylactoid Edema Perspectives in Biology and Medicine · Winter 1968 aware ofthe very existence ofthe AE (and did not mention...