The overall hypothesis is that adrenal regulation is dependent on a sequence of early cellular events that are characterized by phenotypic plasticity and mediated by interaction between local inflammatory and circulating endocrine factors. To test this hypothesis, three major questions will be addressed. First, what is the mechanism for ACTH-induced promotion of adrenal regeneration? Experiments will delineate the effect of ACTH suppression on phenotypic and proliferative changes in regenerating adrenals. Changes in expression of mRNA and protein for cytochrome P450 and aldosterone synthase, a P450 11beta-hydroxylase, will be used as phenotype markers of glomerulosa and fasiculata cells, respectively. Proliferation of specific cell phenotypes will be monitored using double-label immunohistochemistry that induces proliferation markers. Changes in adrenal melanocortin-2 receptor mRNA and protein will be examined using RNase protection and western analysis, respectively; immunohistochemistry will assess the cellular distribution of the receptor. Second, does the renin-angiotensin (AT) system act to suppress regeneration? Since AT upregulates adrenal P450 aldosterone synthase and promotes expansion of zona glomerulosa, studies will determine the role of specific AT receptor subtypes in regeneration using antagonists of the AT-1 and AT-2 receptors. Experiments will characterize the distribution and binding of AT-1 and AT-2 receptors in regenerating adrenals. Since AT has been implicated in models of fibrosis, studies will assess whether AT produces adrenal fibrosis. Third, what components of inflammatory responses affect adrenal regeneration? Since both adrenal and inflammatory cells can synthesize cytokines, the phenotype of cells expressing cytokine activity during regeneration will be delineated. Cytokines identified in regenerating adrenals including interleukin-1, interleukin-1 receptor antagonist, interleukin-18, macrophage migration inhibitory factory and transforming growth factor-beta will be examined in vitro. The effect of specific cytokines on adrenal cell differentiation and proliferation will be defined using short-term cultures of adrenal capsules with adherent cortical cells; potential cytokine modulation of ACTH and AT receptors will be evaluated. It is proposed that corticosteroids affect macrophage secretory activity at the site of adrenal inflammation. Studies using cultured regenerating adrenals or co-cultures of macrophages and adrenal capsules will assess macrophage-adrenal interactions. Since ACTH and AT may affect regeneration indirectly by altering the local inflammatory response, experiments will assess adrenal cytokine mRNA expression after in vivo blockade of ACTH or AT receptors. The proposed experiments should delineate the interaction between local inflammatory and endocrine factors responsible for adrenal regeneration and offer new perspective on injury-induced processes that result in tissue regeneration or fibrosis.
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