Faculty Bibliography

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups

The ultraviolet-induced erythema reaction was investigated histologically and biochemically in four subjects, utilizing suction blister aspirates, analyzed for histamine and prostaglandin E2 (PGE2), and Epon-embedded 1-mu skin biopsy sections from control skin and from irradiated skin at intervals for 72 hours after exposure to a Hanovia lamp. Major histologic alterations in the epidermis included dyskeratotic and vacuolated keratinocytes (sunburn cells), and disappearance of Langerhans cells. In the dermis the major changes were vascular, involving both the superficial and deep venular plexuses. Endothelial cell enlargement was first apparent within 30 minutes of irradiation, peaked at 24 hours, and persisted throughout the 72-hour study period. Mast cell degranulation and associated perivenular edema were first apparent at 1 hour and striking at the onset of erythema, 3 to 4 hours postirradiation; edema was absent and mast cells were again normal in number and granule content at 24 hours. Histamine levels rose approximately fourfold above control values immediately after the onset of erythema and returned to baseline within 24 hours. PGE2 levels were statistically elevated even before the onset of erythema and reached approximately 150% of the control value at 24 hours. These data provide the first evidence that histamine may mediate the early phase of the human sunburn reaction and increase our understanding of its complex histologic and biochemical sequelae

In order to determine if there is a relationship among arterial histamine levels, state of disease activity, and the magnitude and site of obstruction in exercise-induced asthma, we recorded airway resistance, lung volumes, spirometry, and density dependence of maximum expiratory flow before and after an exercise challenge in 17 asymptomatic individuals. These observations were then related to the concentration of histamine in systemic arterial blood. This study demonstrates that those individuals whose disease process was the most active at the time of investigation had more depressed lung function and higher baseline histamine levels, and responded to the challenge with severe obstruction that involved the airways in the periphery of the lung. In contrast, those subjects whose underlying disease was more quiescent had lower histamine values and the response to provocation was less severe and predominated in the larger airways. In neither group did the postchallenge values for histamine increase. It is suggested that the factor that determines these patterns of response is the state of inflammation of the airways, for which histamine may serve as a marker

Urticaria and angioedema may occur in skin and mucus membranes when mast cells are activated by various physical stimuli, including trauma, pressure, vibration, light, cold, heat, and (in rare cases) water. Experimental challenge of patients with cold-induced and cholinergic urticaria/angioedema in particular provides an in vivo model of mast cell activation in humans. This model synthesizes observations of the evolution of clinical manifestations, histologic analysis of tissue alterations, measurement of mediators released into the circulation, and assessment of leukocyte motility. The model in turn allows a characterization of mediators that exist preformed in mast cell granules or that are generated through interactions with other cell types. Release of these mediators produces a variety of biologic effects, including elaboration of certain enzymes and alterations in venular permeability, smooth muscle contraction, leukocyte motility, and the release of substances from other cell types

The complement system was analysed in 14 asymptomatic patients with erythropoietic protoporphyria. In the majority of the sera studied the levels of complement components C1, C4, C2, and C3 were within the normal range. Upon ultraviolet light (330--460 nm) irradiation of the serum samples in vitro, a marked decrease in total hemolytic activity accompanied by reduction of C1, C4, C2, and C3 levels was observed. The loss of total hemolytic activity can be directly correlated with the levels of protoporphyrin (PP) and similar changes can be obtained in normal serum upon addition of PP followedf by ultraviolet light irradiation. It is postulated that after irradiation the excited PP develops the capacity to activate the complement sequence with the production of cleavage products, which may contribute to the skin changes observed in these patients upon sun exposure

Idiopathic acquired cold-induced urticaria has provided a model to study release of mast cell-derived chemical mediators into the blood and alterations of neutrophilic leukocyte motility. A factor chemotactic for neutrophilic leukocytes appeared in the circulation after local experimental challenge with ice. After partial purification by Sephadex G-200 gel filtration and by anion and cation exchange chromatography the neutrophil chemotactic activity was excluded on Sepharose 4B gel filtration, indicating a molecular weight in excess of 750,000. On isoelectric focusing it exhibited a neutral isoelectric point. This chemotactic factor showed preferential chemotactic activity for neutrophils and deactivated these cells in vitro and in vivo. HMW-NCF may prove to be a useful marker of mast cell activation and its release may modulate the capacity for motility of neutrophilic leukocytes in humans