Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2013
Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine.
The nucleus accumbens (NAc) regulates motivated behavior by, in part, processing excitatory synaptic projections from several brain regions. Among these regions, the prefrontal cortex (PFC) and basolateral amygdala, convey executive control and affective states, respectively. Whereas glutamatergic synaptic transmission within the NAc has been recognized as a primary cellular target for cocaine and other drugs of abuse to induce addiction-related pathophysiological motivational states, the understanding has been thus far limited to drug-induced postsynaptic alterations. ⋯ Thus, cocaine-induced procedure- and pathway-specific presynaptic enhancement of excitatory synaptic transmission in the NAc. These results, together with previous findings of cocaine-induced postsynaptic enhancement, suggest an increased PFC-to-NAc shell glutamatergic synaptic transmission after withdrawal from exposure to cocaine. This presynaptic alteration may interact with other cocaine-induced cellular adaptations to shift the functional output of NAc neurons, contributing to the addictive emotional and motivational state.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2013
Endothelial glucocorticoid receptor is required for protection against sepsis.
The glucocorticoid receptor (GR) is ubiquitously expressed on nearly all cell types, but tissue-specific deletion of this receptor can produce dramatic whole organism phenotypes. In this study we investigated the role of the endothelial GR in sepsis in vivo and in vitro. Mice with an endothelial-specific GR deletion and controls were treated with 12.5 mg/kg LPS and phenotyped. ⋯ Both eNOS and iNOS mRNA was increased by qPCR. In HUVECs lacking GR, NF-κB levels and NF-κB-dependent genes tissue factor and IL-6 were increased compared with controls. Thus, endothelial GR is a critical regulator of NF-κB activation and nitric oxide synthesis in sepsis.
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Proc. Natl. Acad. Sci. U.S.A. · Jan 2013
Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2.
In healthy adults, activation of γ-aminobutyric acid (GABA)(A) and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl(-)](i)), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). ⋯ Up-regulation of KCC2 function by targeting 5-HT(2A) receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT(2A)R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2012
Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion.
Mutations in the genes encoding the lung surfactant proteins are found in patients with interstitial lung disease and lung cancer, but their pathologic mechanism is poorly understood. Here we show that bronchoalveolar lavage fluid from humans heterozygous for a missense mutation in the gene encoding surfactant protein (SP)-A2 (SFTPA2) contains more TGF-β1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-β1, which is capable of autocrine and paracrine signaling. ⋯ Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-β1 and two TGF-β1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-β autocrine positive feedback loop by a pan-TGF-β-neutralizing antibody, a TGF-β receptor antagonist, or LTBP gene silencing results in the reversal of TGF-β-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-β1 is induced specifically by mutant SP-A2 proteins, therapeutics targeted to block this pathway may be especially beneficial for this molecularly defined subgroup of patients.
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2012
Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model.
Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsis-induced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ(-/-) mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. ⋯ In contrast, NOD/SCID/IL2Rγ(-/-) mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.