CRF plays a fundamental role in integrating stress-related responses throughout the neuro-immuno-endocrine axis. Its endocrine effects include actions at the pituitary level to stimulate the synthesis and release of POMC-derived peptides. CRF acts within the CNS to integrate the autonomic, behavioral, endocrine and immune responses to stress. Furthermore, recent evidence suggests that CRF may have direct actions on immunocytes to modulate immune function in the periphery. The actions of CRF in CNS, pituitary, and spleen are mediated by specific, high-affinity membrane receptors with similar kinetic and pharmacological properties. CRF receptors in these various tissues are functionally linked to a guanine nucleotide binding protein mediating stimulation of adenylate cyclase activity. Chemical affinity cross-linking studies demonstrated that the molecular weight of the CRF receptor-binding protein is different in central versus peripheral tissues and that the differences observed in molecular weights are due to the microheterogeneity of the carbohydrate moieties on the receptors in the two types of tissues. In autoradiographic studies, CRF receptors were localized in highest densities in anterior and intermediate lobes of the pituitary, and in brain regions involved in cognitive function, in limbic areas involved in emotion and in brain areas regulating autonomic and other stress-related responses. In spleen, CRF binding sites were localized in the macrophage-rich red pulp and marginal zones surrounding the white pulp regions. Studies examining the effects of CRF administration on local cerebral glucose utilization demonstrated differential changes in glucose utilization in brain regions that have been implicated in mediating the effects of CRF in a variety of homeostatic systems and the organism's ability to respond to stress. Overall, these data provide additional evidence for a physiological role for CRF in the brain-endocrine-immune axis and further support the importance of this neuro-peptide in coordinating the response to stress.
Physiologic stress results in significant alterations in the release of multiple cytokines. Increased production of interleukin-1 (IL-1) occurs following hemorrhage and thermal injury. Hemorrhage, accidental trauma and burns are followed by decreased interleukin-2 (IL-2) generation. Production of interleukin-3 (IL-3) and interleukin-5 (IL-5) is diminished following hemorrhage. Gamma-interferon release appears to be increased following hemorrhage. Stress secondary to infection is accompanied by marked elevations in serum levels of tumor necrosis factor (TNF), which contribute to hypotension and physiologic instability in this setting. Alterations in cytokine release probably play important roles in mediating alterations in immunologic, hemodynamic and cardiorespiratory function known to occur following physiologic stress. The production of all cytokines so far examined is altered by stress. Increased generation of IL-1, and probably of TNF and IL-6, contributes to the acute-phase reaction and hypermetabolic response which accompanies injury, burns, hemorrhage, and overwhelming infection. Severe immunosuppression, involving both T and B cell function, and contributing to the increased incidence of infection after injury may result, at least in part, from the multiple actions of stress-induced alterations in interleukin release. T cell activation is clearly affected by injury-induced decreases in IL-2, IL-3, and IFN-gamma release. Similarly, the depressed generation of systemic and mucosal antibodies to bacterial antigens following injury may be affected by alterations in the production of cytokines affecting B cell function, namely IL-1, IL-2, IL-3, IL-5 and IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
The recent discovery of several hypothalamic factors involved in the regulation of anterior pituitary function and the development of sensitive immunocytochemical techniques have greatly contributed to a better identification of the hypothalamic nuclei and individual neurons involved in the production of the hypophysiotropic factors. Each peptidergic factor is produced by a group of parvocellular neurons located in different hypothalamic areas and projecting to the external zone of the median eminence. These results obtained in the last few years fully confirm previous data obtained on the basis of lesion experiments which had established that the hypophysiotropic areas were localized in the hypothalamus. Studies performed at the electron-microscopic level indicate that hypophysiotropic peptidergic factors are contained in dense core vesicles within the cytoplasm of neuronal cell bodies. From there, the dense core vesicles migrate along the axons to reach the external zone of the median eminence where they are stored in endings. On appropriate stimulation, the hormones are released into the capillaries of the pituitary portal plexus. These parvocellular neurosecretory systems then appear to be very similar to the classic magnocellular neurosecretory systems involved in the secretion of vasopressin and oxytocin (fig. 1).
The relationships between emotional status, neurohormonal control and the cardiovascular function are reviewed. In the first part of this paper, we reviewed (1) the pathways between brain and heart, physiology of the defense reaction and the role of the autonomic nervous system in the mediation of the effects of stress; (2) the cardiac manifestations of emotional stress, and (3) the role of stress and the influence of circadian variations in the occurrence and development of myocardial ischemia, myocardial infarction and sudden death. In the second part, we discussed the relationship between behavior, coronary heart disease and particularly the role of the so-called type A behavior and hostility. Finally, we emphasize the importance of life-style changes to improve the prognosis of coronary disease and to limit the progression and ultimately to cause a regression of atherosclerosis. Thus, it appears that a transdisciplinary approach associating cardiologists, neuroscientists and behavior scientists will help to devise more effective strategies for the prevention and early therapy of cardiovascular disease.
This chapter presents the methodology as well as various applications of a silicone rubber (Microfil) prefusion technique for evaluation of the microcirculation. In the heart, Microfil perfusion has been used in conjunction with clearing techniques to elucidate normal anatomic relationships, to identify areas of myocardium at risk following vascular occlusion, and to observe dynamic events in the development of various cardiomyopathies. Advantages of the technique include in vivo applicability, ease of vascular filling, and ability to discriminate between adjacent vascular fields. Preliminary data from work in other organ systems including skeletal muscle, brain, liver, and lung are also presented.
Cell death takes two distinct forms, necrosis and apoptosis. Necrosis is a degenerative phenomenon that follows irreversible injury. Apoptosis, in contrast, appears to be an active process requiring protein synthesis for its execution; it is implicated in physiological regulation of tissue size, and, where it occurs pathologically, a homeostatic role for the death is often evident. Morphologically, apoptosis involves condensation of the nuclear chromatin and cytoplasm, fragmentation of the nucleus, and budding of the whole cell to produce membrane-bounded bodies in which organelles are initially intact. These bodies are disposed of by adjacent cells without inflammation. Biochemically, there is distinctive internucleosome cleavage of DNA in apoptosis, which is quite different from the random DNA degradation observed in necrosis.
