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    Open AccessPublished:June 21, 2012DOI:https://doi.org/10.1016/j.ajpath.2012.06.001

        Cigarette Smoke and Alcohol Co-Exposure Decreases Airway Epithelial Cell Cilia Beating

        Alcohol abuse disorders are associated with increased lung infections and exacerbations of chronic lung diseases. Although the effects of cigarette smoke are well recognized, the interplay of smoke and alcohol in modulating lung diseases is not clear. Because innate lung defense is mechanically maintained by airway cilia action and hindered by protein kinase C (PKC), Wyatt et al (Am J Pathol 2012, 181:431–440) examined the effects of combined exposure to smoke and alcohol on ciliary beat frequency (CBF) in vitro. Smoke and alcohol co-exposure activated PKCε and slowed both CBF and cilia beating, whereas a specific activator of PKCε, DCP-LA, slowed CBF following maximal PKCε activation. Further, PKCε activation by smoke and alcohol was only observed in ciliated cells, not basal bronchial epithelium. In vivo, no decreases in CBF were observed in PKCε knockout mice co-exposed to smoke and alcohol. These data identify PKCε as a key regulator of cilia slowing in response to combined smoke- and alcohol-induced lung injury.

        α-7 nAchR Prevents Gut Barrier Failure after Severe Injury

        Vagal nerve stimulation prevents intestinal barrier loss in a model of severe burn injury, which dysregulates intestinal tight junction proteins. The α-7 nicotinic acetylcholine receptor (α-7 nAchR) is necessary for the vagus nerve to modulate the systemic inflammatory response; however, the role of α-7 nAchR in mediating gut protection is unknown. Constantini et al (Am J Pathol 2012, 181:478–486) used in vivo mouse models as well as an in vitro model of intestinal epithelial cell and enteric glial cell (EGC) co-culture to define the ability of nicotine to improve barrier function. Nicotine injection following injury prevented burn-induced intestinal permeability and limited histological gut injury. Treatment also prevented the decreased expression and altered localization of tight junction proteins occludin and ZO-1. The barrier-protective effects of nicotine were lost in cytokine-stimulated intestinal epithelial cells when EGCs were removed from culture. Future studies of the interaction between the vagus nerve, EGCs, and the intestinal epithelium may lead to targeted therapeutics aimed at reducing gut barrier failure after severe injury.

        Activated B Cells Found in Mycobacterium tuberculosis Granulomas

        Host immune cells form a granuloma as a physical and immunological barrier that contains Mycobacterium tuberculosis. To understand the importance of humoral immunity in controlling M. tuberculosis infection, Phuah et al (Am J Pathol 2012, 181:508–514) characterized the B cell and plasma cell populations in infected animals. B cells were primarily present in clusters within the granuloma. These B cell clusters were found in close proximity to peripheral node addressin (PNAd)+ cells, contained cells positive for the proliferation marker Ki-67, expressed CXCR5, and had elevated HLA-DR expression. Tissues containing M. tuberculosis bacilli had higher levels of M. tuberculosis-specific IgG, and plasma cells detected within the granuloma produced mycobacteria-specific antibodies. Thus, activated B cells, plasma cells, and antibodies are enriched within M. tuberculosis granulomas, having some characteristics of germinal centers and possibly the capacity to modulate local control of infection in tissues.

        Classical BSE Prions Spread from the Gut to the Brain

        Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disease in cattle with similarities to Creutzfeldt-Jakob disease (CJD) in humans. Kaatz et al (Am J Pathol 2012, 181:515–524) examined the pathogenesis of BSE in the natural host on oral infection from early preclinical to terminal disease. Tissue samples collected from the gut, the central and the autonomic nervous system over the entire incubation period were examined for the presence of pathological prion protein PrPSc, followed by bioassay in cellular PrPC-overexpressing transgenic mice (Tgbov XV), which lack the species barrier for bovine prions. PrPSc accumulated in the distal ileum in almost all animals, while PrPSc was found in the sympathetic nervous system starting at 16 months postinfection (mpi), and in the parasympathetic nervous system at 20 mpi. These findings decipher the centripetal spread of BSE prions along the autonomic to the central nervous system starting midway in the incubation time.

        NANOG-Positive Stromal Cells Promote Human Cervical Cancer Progression

        The embryonic stem cell gene NANOG, a divergent homeodomain transcription factor, is expressed in germ cells and several tumor types. Gu et al (Am J Pathol 2012, 181:652–661) examined the role of NANOG and its pseudogenes in cervical cancer. NANOG was expressed from the NANOG gene but was frequently localized to the cytoplasm, rather than the nucleus, in cervical cancer. Mesenchymal stem cells were identified as cytoplasmic NANOG-positive cells in cervical cancer stroma. Co-culture of cervical cancer-derived mesenchymal stem cells with SiHa human cervical cancer cells demonstrated increased proliferation characteristics in vitro as well as enhanced tumor growth in vivo. These findings provide evidence that NANOG is a cervical cancer progression marker, suggesting a starting point for a more extensive exploration of the cellular translocation of NANOG and the multifunctionality of the stromal microenvironment.

        Linked Article

        • Cytoplasmic NANOG-Positive Stromal Cells Promote Human Cervical Cancer Progression
          The American Journal of PathologyVol. 181Issue 2
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            Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell gene NANOG, a divergent homeodomain transcription factor that is independent of leukemia inhibitory factor, has been reported to be expressed in germ cells and in several tumor types. However, the short-term expression and role of NANOG in cervical cancer remain unclear. In the present study, we demonstrate that NANOG exhibits cellular shuttling behavior and increasing stromal distribution during the progression of cervical cancer.
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        • Co-Exposure to Cigarette Smoke and Alcohol Decreases Airway Epithelial Cell Cilia Beating in a Protein Kinase Cε-Dependent Manner
          The American Journal of PathologyVol. 181Issue 2
          • Preview
            Alcohol use disorders are associated with increased lung infections and exacerbations of chronic lung diseases. Whereas the effects of cigarette smoke are well recognized, the interplay of smoke and alcohol in modulating lung diseases is not clear. Because innate lung defense is mechanically maintained by airway cilia action and protein kinase C (PKC)-activating agents slow ciliary beat frequency (CBF), we hypothesized that the combination of smoke and alcohol would decrease CBF in a PKC-dependent manner.
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          Open Access
        • Spread of Classic BSE Prions from the Gut via the Peripheral Nervous System to the Brain
          The American Journal of PathologyVol. 181Issue 2
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            An experimental oral bovine spongiform encephalopathy (BSE) challenge study was performed to elucidate the route of infectious prions from the gut to the central nervous system in preclinical and clinical infected animals. Tissue samples collected from the gut and the central and autonomic nervous system from animals sacrificed between 16 and 44 months post infection (mpi) were examined for the presence of the pathological prion protein (PrPSc) by IHC. Moreover, parts of these samples were also bioassayed using bovine cellular prion protein (PrPC) overexpressing transgenic mice (Tgbov XV) that lack the species barrier for bovine prions.
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        • Activated B Cells in the Granulomas of Nonhuman Primates Infected with Mycobacterium tuberculosis
          The American Journal of PathologyVol. 181Issue 2
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            In an attempt to contain Mycobacterium tuberculosis, host immune cells form a granuloma as a physical and immunological barrier. To date, the contribution of humoral immunity, including antibodies and specific functions of B cells, to M. tuberculosis infection in humans remains largely unknown. Recent studies in mice show that humoral immunity can alter M. tuberculosis infection outcomes. M. tuberculosis infection in cynomolgus macaques recapitulates essentially all aspects of human tuberculosis.
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          Open Access
        • Targeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System: A Cholinergic Agonist Prevents Gut Barrier Failure after Severe Burn Injury
          The American Journal of PathologyVol. 181Issue 2
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            We have previously shown that vagal nerve stimulation prevents intestinal barrier loss in a model of severe burn injury in which injury was associated with decreased expression and altered localization of intestinal tight junction proteins. α-7 Nicotinic acetylcholine receptor (α-7 nAchR) has been shown to be necessary for the vagus nerve to modulate the systemic inflammatory response, but the role of α-7 nAchR in mediating gut protection remained unknown. We hypothesized that α-7 nAchR would be present in the gastrointestinal tract and that treatment with a pharmacological agonist of α-7 nAchR would protect against burn-induced gut barrier injury.
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