Federation proceedings最新文献

Oxygen-derived free radicals (superoxide and hydroxyl) and related species (hydrogen peroxide and hypohalous acids) have well-defined roles in the inflammatory process. Their actions include the killing of microorganisms as well as participation in cell-to-cell communication among phagocytes via the activation of a superoxide-dependent chemoattractant. The active oxygen species also have roles in postischemic injury brought about by the conversion during ischemia of the enzyme xanthine dehydrogenase (EC 1.1.1.204) to the radical-producing xanthine oxidase (EC 1.1.3.22). Although the enzymes responsible for producing superoxide in inflammation and ischemia are quite distinct, and are triggered by very different events, there are points of interplay in the two mechanisms whereby an ischemia/reperfusion-induced injury would lead to inflammation, and conversely whereby inflammation could lead to impairment of the circulation and hence to ischemic injury.

Granulocytes are large, stiff viscoelastic cells that adhere naturally to the vascular endothelium. On their passage through the capillary network they have to be deformed, and recent evidence indicates that they may impose a significant hemodynamic resistance. The entry time of granulocytes into capillaries is about three orders of magnitude longer than that for red cells. Inside the capillary the granulocytes move with a lower velocity than red cells. Under conditions when the capillary perfusion pressure is reduced and/or elevated levels of inflammatory products are present that increase the adhesion stress to the endothelium, granulocytes may become stuck in the capillary. In such a situation, the granulocytes form a large contact area with the capillary endothelium, they obstruct the lumen, and they may initiate tissue injury. After the restoration of the perfusion pressure the granulocytes may not be removed from the capillary owing to the adhesion to the endothelium. Capillary plugging by granulocytes appears to be the mechanism responsible for the no-reflow phenomenon, and together with oxygen free radical formation and lysosomal enzyme activity may constitute the origin for ischemic injury as well as other microvascular occlusive diseases.

Rat and mouse heparin-containing connective tissue mast cells (CTMC) are stained by both alcian blue and safranin, whereas the chondroitin sulfate-containing mucosal mast cells (MMC) are stained by alcian blue but not by safranin. Mouse bone marrow-derived mast cells (BMMC) (the presumptive in vitro counterpart of the in vivo-differentiated MMC) were derived by culture of progenitors in the presence of 50% WEHI-3-conditioned medium and 10% fetal calf serum and were then cultured for up to 14 days with confluent skin-derived mouse 3T3 fibroblasts in the same culture medium. Although the BMMC adhered to the fibroblast monolayer, they continued to divide, probably because of the presence of interleukin 3 in the conditioned medium. After 14 days of coculture, their cellular histamine content increased approximately 15-fold, and greater than 50% of the BMMC changed histochemically from safranin negative to safranin positive. At this time 30-50% of the glycosaminoglycans of the proteoglycans synthesized by these cocultured mast cells were heparin, whereas the initial BMMC synthesized proteoglycans containing chondroitin sulfate E. When activated immunologically, the cocultured mast cells generated approximately fivefold more prostaglandin D2 than did the activated starting BMMC. Thus, interleukin 3-dependent mouse BMMC can be induced to undergo phenotypic changes in staining characteristics, histamine content, glycosaminoglycan structure, and metabolism of arachidonic acid to resemble heparin-containing CTMC. These findings suggest that the tissue microenvironment determines the phenotypic characteristics of mast cells. This demonstration of the functional diversity of different populations of mast cells adds an important dimension to the understanding of the role of mast cells in biological processes.

Measurements of cardiac performance for humans at various ages is influenced by the variable examined, the population and techniques employed, and the factors that co-vary with age, including the presence of disease and physical conditioning. Interstudy differences in the extent to which occult coronary disease is present in older subjects and in the level of physical conditioning among subjects may underlie the variable perspectives contained in the literature of how aging affects cardiovascular function. In carefully screened, highly motivated but not athletically trained community-dwelling subjects, resting cardiovascular parameters are not age related except for systolic blood pressure, which increases with age. During vigorous exercise the mechanisms used to achieve a high level of cardiac output shift from a dependence on a catecholamine-mediated increase in heart rate and inotropy to a dependence on the Frank Starling mechanism. One reason for the age difference in cardiovascular response to exercise may be a diminished responsiveness to beta-adrenergic stimulation in these subjects. In other elderly subjects who cannot exercise to high work loads, a decline in stroke volume as well as heart rate at peak exercise has been observed. Whether the inability of these individuals to augment stroke volume is caused by a decrease in the ability of the heart to increase diastolic filling, by a decrease in systolic pump function caused by an increased afterload, by intrinsic myocardial contractile defects, or by a greater diminution of the cardiovascular response to beta-adrenergic stimuli is presently unknown.

The nonsteroidal antiestrogen tamoxifen exhibits a paradoxical species-specific pharmacology. The drug is a full estrogen in the mouse, a partial estrogen/antiestrogen in humans and the rat, and an antiestrogen in the chick oviduct. Inasmuch as tamoxifen has antiestrogenic effects in vitro, differential metabolism of tamoxifen to estrogens might occur in the species in which it has an estrogenic pharmacology. Tamoxifen or its metabolite 4-hydroxytamoxifen could lose the alkylaminoethane side chain to form the estrogenic compound metabolite E or bisphenol. Sensitive metabolic studies with [3H]tamoxifen in chicks, rats, and mice identified 4-hydroxytamoxifen as the major metabolite, but no potentially estrogenic metabolites were observed. Athymic mice with transplanted human breast tumors can be used to study the ability of tamoxifen to stimulate target tissue or tumor growth. Estradiol caused the growth of transplanted MCF-7 breast cancer cells into solid tumors and a uterotrophic response. However, tamoxifen does not support tumor growth when administered alone, although it stimulates uterine growth. Since a similar profile of metabolites is sequestered in human and mouse tissues, these studies strongly support the concept that the drug can selectively stimulate or inhibit events in the target tissues of different species without metabolic intervention.

Photodegradation of vitamins in vitro is responsible for large losses of these nutrients in foods, beverages, and semisynthetic liquid formula diets. In vivo photodegradation of vitamins has been reported for riboflavin in jaundiced infants exposed to blue light and for folate in patients with chronic psoriasis given photochemotherapy. Two recent studies of normal subjects have also shown that photodegradation of carotenoids in plasma occurs with cumulative exposure of the skin to an artificial light source having maximal spectral emission in the UVA range. Females showed a larger effect of the UV light on their plasma carotenoid levels than males. These observations have identified a need for further investigation of the role of sunlight exposure as a determinant of plasma carotenoid levels and vitamin A status in human subjects.

Nearly 50 years ago the first reports appeared that cast suspicion on lipids, or peroxidative products thereof, as being involved in the expression of actinically induced cancer. Whereas numerous studies have implicated lipids as potentiators of specific chemical-induced carcinogenesis, only recently has the involvement of these dietary constituents in photocarcinogenesis been substantiated. It has now been demonstrated that both level of dietary lipid intake and degree of lipid saturation have pronounced effects on photoinduced skin cancer, with increasing levels of unsaturated fat intake enhancing cancer expression. The level of intake of these lipids is also manifested in the level of epidermal lipid peroxidation. Conversely, dietary antioxidants inhibit both lipid peroxidation and photocarcinogenesis, the degree of inhibition of the latter being roughly equivalent to the degree of cancer enhancement evoked by the respective level of dietary lipid. The apparent similarities of lipid effects on both chemical and photoinduced carcinogenesis suggest a common underlying role for these dietary constituents in the carcinogenic process. This role may involve free radical-mediated lipid peroxidative reactions. Regardless of the mechanism, it is obvious that both dietary lipid and antioxidants can modify the photocarcinogenic response of skin.

Exposure to sunlight continues to play a major role in providing adequate vitamin D nutrition for most of the population of the world, including those who live in countries that practice fortification of dairy, margarine, and cereal products with vitamin D. During exposure to sunlight, the high-energy UV photons (290-315 nm) penetrate the epidermis and photolyze 7-dehydrocholesterol (provitamin D3) to previtamin D3. Once formed, previtamin D3 undergoes a thermally induced isomerization to vitamin D3 that takes 2-3 days to reach completion. Melanin effectively competes with provitamin D3 for the UV radiation that enters the epidermis and limits its photolysis to previtamin D3. However, this is not the major factor that prevents excess production of vitamin D in the skin of people who are constantly exposed to sunlight. During the initial exposure to sunlight, provitamin D3 is efficiently converted to previtamin D3. However, because previtamin D3 is photolabile, continued exposure to sunlight causes the isomerization of previtamin D3, principally to lumisterol. Thus, no more than 10-20% of the initial provitamin D3 concentrations ultimately end up as previtamin D3. Aging, sunscreens, seasonal changes, time of day, and latitude also significantly affect the cutaneous production of this vitamin-hormone.

It has been proposed that continued exercise training may slow the rate of decline of VO2max that occurs as a person ages. Although little evidence has been available in the past to support this belief, recently published data appear to indicate that older persons who maintain their activity levels decrease their VO2max at a rate of 5% per decade rather than the 10% per decade decline found in sedentary persons. It was also believed that men and women over the age of 60 either showed minimal or no increase in VO2max as a result of exercise training. Recent data from our laboratory and others indicate that individuals in this age range can increase their VO2max in response to training and that their adaptive capacity, at least on a relative basis, is similar to that of younger persons. It also appears that older persons may require a lower relative training intensity to elicit increases in VO2max. Thus it appears that older persons can minimize the reduction in VO2max that occurs as they age if they maintain high levels of physical activity and that they retain the ability to adapt to exercise training.