Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 10, Issue 3, 2010

A series of clinical studies have shown that thiazide diuretics (TD) might reduce the risk of bone fractures. We also recently demonstrated that angiotensin receptor blockers (ARB) ameliorated ovariectomy (OVX)-induced osteoporosis in a hypertensive rat model. In this study, we examined whether a combination of TD and ARB might have additional effects on osteoporosis in a hypertensive rat model. In spontaneous hypertensive rats, estrogen deficiency induced by OVX resulted in a significant increase in osteoclast activation as assessed by tartrate-resistant acid phosphatase (TRAP) activity in the tibia, accompanied by a significant decrease in bone mineral density (BMD) evaluated by dual-energy X-ray absorptiometry and an increase in urinary deoxypyridinoline. Treatment with high-dose ARB, valsartan (3 mg Kg-1day-1), attenuated the OVX-induced decrease in BMD and increased TRAP activity and urinary deoxypyridinoline, whereas low-dose ARB, valsartan (1 mg Kg-1day-1), or low-dose TD, hydrochlorothiazide (0.2 mg Kg-1day-1), did not. Of importance, administration of low-dose valsaltan in combination with hydrochlorothiazide significantly decreased the magnitude of bone mineral loss compared with the effect of administration of high-dose valsartan alone. These results demonstrated that treatment with TD in combination with ARB attenuated osteoporosis additionally in a hypertensive rat model.

Several epidemiological, pathophysiologic and clinical data demonstrate the interrelationship between upper and lower airways, and common features between inflammatory pathways and disorders of the nasal and bronchial mucosa have been emphasized both in the clinic (ARIA guidelines [1]) and in basic science, and reflected by numerous reviews on this topic. In contrast, detailed comparative analysis of basic defence mechanisms in upper versus lower airways and its clinical relevance is lacking. It is becoming increasingly clear that airway epithelium plays a key role in driving key initiating steps of immune defence (either protective or deleterious) against inhaled antigens and particles. Epithelial cells respond to changes in the external environment by secreting a large array of antimicrobial host defence molecules, cytokines and chemokines following exposure to and activation by pathogen molecular patterns, and link in concert with dendritic cells innate to antigen-specific adaptive immunity. However, the type of epithelial response to ‘pathogens’ and danger signals may differ between upper and lower airways, as well as according to genetic background. This review provides an updated, extensive and comparative review of immune defence mechanisms of the respiratory tract, in upper versus lower airways, including most relevant changes observed during chronic airway diseases and how these may translate into different clinical features.

The sex hormones that play major roles in the neuroimmune regulatory network include gonadotropins, prolactin, estrogens, progestogens, androgens and their agonists and antagonists. The steroid hormones listed above have membrane and cytoplasmic or nuclear receptors. Nuclear receptors are transcription factors that directly regulate gene expression. Luteinizing hormone releasing hormone and gonadotropins exert a direct regulatory influence on the immune system, in addition to the regulation of sex steroid hormones. In turn immune-derived cytokines regulate the production of gonadotropins. These mechanisms insure the coordination of reproduction with health status and prevent inopportune conception. Prolactin maintains adaptive immunocompetence and is a powerful stimulant of adaptive immune reactions. It plays a role in autoimmune disease, hematopoiesis and in host resistance to infectious disease. Estrogens regulate the thymus and suppress cell-mediated immune reactions. The antibody response and natural immunity (NK cytotoxicity, phagocytosis) are augmented by estradiol. Testosterone is immunosuppressive during trauma and shock. Many of the immunological effects of testosterone are due to its conversion to estradiol by aromatase in the thymus and in other lymphoid organs. The adrenal androgen, dehydroepiandrosterone stimulates immune reactions in experimental animals and in man. It antagonizes the immunosuppressive effect of glucocorticoids and its age-related decline may contribute to the immunodeficiency that develops in elderly individuals. Progesterone is a powerful immunosuppressive hormone. It plays a major role in the protection of the foetus during mammalian reproduction. Progesterone also contributes to the generation of self tolerance and protects against the excessive activation of the immune system. In this article the above listed hormones, their agonists and antagonists are discussed from the point of view of treating human diseases. By now autoimmune disease and cancer are routinely treated with sex hormones and their analogues. Additional opportunities may open up in infectious disease and in parasitic infestations