Inducible nitric oxide synthase gene expression in the brain during systemic inflammation.

Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (LPS). The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We know that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.

IL-1 beta, IL-1 receptor type I and iNOS gene expression in rat brain vasculature and perivascular areas.

The mechanism by which IL-1 beta exerts its actions in the brain during systemic inflammation is not fully understood, as neither IL-1 receptor gene expression nor IL-1 binding have been identified in significant levels in key areas that respond to IL-1 beta. Having hypothesized that perivascular nitric oxide (NO) might modulate the effects of systemic IL-1 beta in the brain, we studied the expression of the genes encoding for IL-1 beta, the signal-transducing IL-1 receptor type I (IL-1RI) and inducible NO synthase (iNOS) constitutively and during systemic inflammation in vascular and perivascular regions of the rat brain. Our results show that IL-1RI is constitutively expressed at the interface of the vascular wall and perivascular glia. During systemic inflammation there is induction of IL-1 beta gene expression in the vascular wall, accompanied by perivascular induction of iNOS mRNA. We conclude that during systemic inflammation vascular IL-1 beta, binding to vascular and perivascular IL-1RI receptors, may induce perivascular iNOS gene expression, leading to the production of NO and modulation of the effects of IL-1 beta in the brain. We propose that the vascular and peri-vascular induction of iNOS mRNA by IL-1 beta might represent a mechanism for the modulation of the central nervous system effects of peripheral inflammatory mediators.

Sensory Mononeuropathy Multiplex in Chronic Graft versus Host Disease.

Graft versus host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). Peripheral neuropathies in association with chronic GVHD are uncommon. We report a patient with BHT for chronic myeloid leukemia, and chronic GVHD with severe sclerodermatitis resulting in bilateral medial antebrachial and saphenous sensory mononeuropathies.

Localization of urocortin messenger RNA in rat brain and pituitary.

Pituitary function is regulated by hypothalamic releasing hormones secreted into hypophyseal-portal blood. A new hypothesis is that pituitary function might also be regulated at the local level by releasing hormones synthesized within the pituitary. Here we show that the pituitary expresses high levels of the gene encoding for urocortin. We suggest that urocortin synthesized by the pituitary may modulate pituitary function, and that adrenocorticotropic hormone (ACTH) secretion is dependent on input not only from the hypothalamus as previously described, but it may also be regulated by urocortin synthesized locally. Urocortin binds to the corticotropin-releasing hormone (CRH) receptor type 1 (CRH-R1) with high affinity and potently stimulates pituitary-adrenal function. Our group and others have previously localized high levels of CRH-R1 mRNA in the pituitary. Using a 35S-labeled rat urocortin riboprobe we have now localized urocortin mRNA in rat brain and pituitary. The finding of urocortin gene expression in the pituitary may help explain why proopiomelanocortin (POMC) mRNA levels are not decreased during hypothalamo-pituitary disconnection, and also describes a new level of complexity in the regulation of hypothalamo-pituitary function. Future studies should consider the possibility that pituitary function might be regulated at the local level by urocortin.