PHOSPHODIESTERASE STUDIES IN ATOPIC DERMATITIS

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Atopic dermatitis is an inflammatory skin disease that comprises, along with asthma and allergic rhinitis, the triad of conditions known as the atopic diseases. These conditions are hereditary and are common causes of social and occupational morbidity. Disease mechanisms are uncertain and there are no satisfactory means of prevention or cure. Diagnosis is imprecise due to lack of distinct laboratory tests. Atopic dermatitis has the most pronounced immunologic and pharmacologic aberrancies and we have studied these abnormalities for clues as to basic causative factors. Our long-term objectives are to delineate the basic pathologic mechanisms and to identify a discrete laboratory indicator of the disease. Our studies have compared atopic and normal blood leukocytes. The latter show biochemical similarities to atopioc cells after exposure to mediators such as histamine, prostaglandin E1 and isoproterenol. This model led to our observation of abnormally high cyclic AMP-phosphodiesterase (PDE) in leukocytes of patients with atopic dermatitis and other atopic conditions. This project is focused upon biochemical characterization of the abnormal PDE in atopic leukocytes and on comparative studies of the PDE in normal lymphocytes and monocytes stimulated with histamine and other mediators. This model should provide a means for evaluating the role of phosphorylation and other mechanisms which may lead to abnormal PDE enzyme forms. Studies with inhibitors may provide insight into new pharmacologic modalities for treating atopic dermatitis. Recent investigations have utilized chromatofocusing as a novel means of biochemical identification and have shown two distinct abnormal fractions of PDE activity in atopic leukocytes. Future extensions of these studies should allow clarification of the exact cell source of these enzyme forms and whether they are identical with those in histamine stimulated cells. Collaborative studies of the Basenji-Greyhound dog model of asthma have shown leukocyte cyclic nucleotide abnormalities and elevated PDE similar to atopic humans. Biochemical identification of abnormal PDE along with newly developed specific antibodies to various PDE forms may provide a means of precise diagnostic, and predictive epidemiologic and genetic studies of atopic dermatitis and the other atopic diseases. Cyclic GMP synthesis and metabolism in these cells will be assessed to evaluate the possibility of imbalanced cyclic nucleotide regulation as an alternate cause of functional defects in atopy.