The local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes (LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and prostaglandin (PG) D2 from the cyclooxygenase pathway, were assessed clinically and histologically. In equimolar concentrations, LTC4, LTD4, and LTE4, elicited erythema and wheal formation, in which a wheal with central pallor was present up to 2 hr, and the erythema persisted as long as 6 hr. PGD2 elicited a wheal that lasted up to 1 hr and erythema that lasted up to 2 hr. The dermal vascular sites affected by LTD4 and PGD2 included capillaries, superficial and deep venules, and arterioles. LTB4 elicited a transient wheal and flare, followed in 3-4 hr by induration that was characterized by a dermal infiltrate comprised predominantly of neutrophils. The combination of LTB4 and PGD2 elicited tenderness and increased induration associated with a more intense neutrophil infiltration. Thus, the products of the 5-lipoxygenase pathway of arachidonic acid metabolism in nanomole amounts can induce cutaneous vasodilation with edema formation and a neutrophil infiltrate, and these responses are enhanced by a cyclooxygenase pathway product, PGD2.

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Relatively little information is available concerning the membrane structure of the mucosal cells of the small intestine. Hdber and Hober (1) and Schanker, Tocco, Brodie, and Hogben (2, 3) studied the absorption of a variety of substances in rats and found that absorption rate increased as lipid solubility increased. From this it has been deduced that mucosal cell membranes are lipoid in nature and that lipid-soluble substances are absorbed by dissolving in the cell membrane. However, it has been known for many years that small molecules, although lipid insoluble, can also be absorbed from the gastrointestinal tract. This has led to the hypothesis that, although essentially lipoidal, cell membranes are interspersed with water-filled pores, through which small molecules can diffuse. Hbber and Hdber (1) tested this hypothesis in the small intestine of the rat by correlating the absorption rate of nonlipid-soluble substances with their molecular size. Their results support the thesis that these molecules are absorbed by diffusion through water-filled pores, since small molecules were absorbed more rapidly than larger ones, and beyond a certain size (molecular weight about 180, which corresponds to a molecular radius of about 4 A) no penetration occurred. Lindemann and Solomon's studies (4) are in close agreement, since they experimentally determined, by an independent method, the pore radius of the luminal surface of the rat jejunal cells to be approximately 4 A. This is the only available estimate of intestinal pore size in any species. and no estimates at all are available for pore size at different levels of the small intestine.The purpose of our studies, therefore, was to evaluate the permeability of the human intestinal mucosa by measuring the effective pore size at different levels of the small intestine. The theoretical basis for the present studies rests on the demonstration by Staverman (5) and Solomon (6) that the ability of a nonlipid-soluble solute to exert an effective osmotic pressure gradient 1 across a membrane is a function of its molecular radius relative to the radius of the water-filled pores in that membrane. Thus, the degree to which a solute of known molecular size is capable of exerting its full theoretic osmotic pressure gradient, which is defined as the reflection coefficient (a), can be used to calculate the pore size of the membrane, which. in turn, determines the permeability of the membrane to nonlipid-soluble solutes.To

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