Joseph H Sisson

University of Nebraska Medical Center, Omaha, Nebraska, United States

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Publications (113)441.61 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol abuse results in an increased incidence of pulmonary infection, in part, due to impaired mucociliary clearance. Analysis of motility in mammalian airway cilia has revealed that alcohol impacts the ciliary dynein motors by a mechanism involving altered axonemal protein phosphorylation. Given the highly conserved nature of cilia, we hypothesize that the mechanisms for alcohol-induced ciliary dysfunction (AICD) are conserved. Thus, we utilized the experimental advantages offered by the model organism, Chlamydomonas, to determine the precise effects of alcohol on ciliary dynein activity and identify axonemal phosphoproteins that are altered by alcohol exposure. Analysis of live cells or reactivated cell models showed that alcohol significantly inhibits ciliary motility in Chlamydomonas via a mechanism that is part of the axonemal structure. Taking advantage of informative mutant cells, we found that alcohol impacts the activity of the outer dynein arm. Consistent with this finding, alcohol exposure results in a significant reduction in ciliary beat frequency, a parameter of ciliary movement that requires normal outer dynein arm function. Using mutants that lack specific HC motor domains, we have determined that ethanol impacts the β- and γ-heavy chains of the outer dynein arm. Furthermore, using a phospho-threonine specific antibody, we determined that the phosphorylation state of DCC1 of the Outer Dynein Arm-Docking Complex is altered in the presence of alcohol and its phosphorylation correlates with AICD. These results demonstrate that ethanol targets specific ODA components and suggest that DCC1 is part of an alcohol-sensitive mechanism that controls outer dynein arm activity. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 01/2015; 308(6):ajplung.00257.2014. DOI:10.1152/ajplung.00257.2014 · 4.04 Impact Factor
  • Alcohol 11/2014; 48(7). DOI:10.1016/j.alcohol.2014.09.012 · 2.04 Impact Factor
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    ABSTRACT: Introduction: Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. Hypothesis: We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. Methods: To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat & kinase responsiveness and cilia-associated phosphorylation targets when stimulated by beta-agonist or cAMP. Results: Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat & Protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, I-2, restoring cAMP-stimulated cilia beat & PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Conclusion: Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    Alcohol 11/2014; 48(7). DOI:10.1016/j.alcohol.2014.09.024 · 2.04 Impact Factor
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    ABSTRACT: Co-exposure to cigarette smoke and ethanol generates malondialdehyde and acetaldehyde, which can subsequently lead to the formation of aldehyde-adducted proteins. We have previously shown that exposure of bronchial epithelial cells to malondialdehyde-acetaldehyde (MAA) adducted protein increases protein kinase C (PKC) activity and proinflammatory cytokine release. A specific ligand to scavenger receptor A (SRA), fucoidan, blocks this effect. We hypothesized that MAA-adducted protein binds to bronchial epithelial cells via SRA. Human bronchial epithelial cells (BEAS-2B) were exposed to MAA-adducted protein (either bovine serum albumin [BSA-MAA] or surfactant protein D [SPD-MAA]) and SRA examined using confocal microscopy, fluorescent activated cell sorting (FACS), and immunoprecipitation. Differentiated mouse tracheal epithelial cells (MTEC) cultured by air-liquid interface were assayed for MAA-stimulated PKC activity and keratinocyte-derived chemokine (KC) release. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for 3–7 min and subsided by 20 min. Likewise, MAA-adducted protein co-localized to SRA from 3–7 min with a subsequent internalization of MAA by 10 min. These results were confirmed using FACS analysis and revealed a reduced mean fluorescence of SRA after 3 min. Furthermore, increased amounts of MAA-adducted protein could be detected by Western blot in immunoprecipitated SRA samples after 3 min treatment with MAA. MAA stimulated PKCε-mediated KC release in wild type, but not SRA knockout mice. These data demonstrate that aldehyde-adducted proteins in the lungs rapidly bind to SRA and internalize this receptor prior to the MAA-adducted protein stimulation of PKC-dependent inflammatory cytokine release in airway epithelium.
    Alcohol 08/2014; 48(5). DOI:10.1016/j.alcohol.2014.02.005 · 2.04 Impact Factor
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    ABSTRACT: When Paramecium encounter positive stimuli, the membrane hyperpolarizes and ciliary beat frequency increases. We adapted an established immobilization protocol using a biological adhesive and a novel digital analysis system to quantify beat frequency in immobilized Paramecium. Cells showed low mortality and demonstrated beat frequencies consistent with previous studies. Chemoattractant molecules, reduction of external potassium, and posterior stimulation all increased somatic beat frequency. In all cases, the oral groove cilia maintained a higher beat frequency than mid-body cilia, but only oral cilia from cells stimulated with chemoattactants showed an increase from basal levels.This article is protected by copyright. All rights reserved.
    Journal of Eukaryotic Microbiology 07/2014; 62(1). DOI:10.1111/jeu.12153 · 2.91 Impact Factor
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    ABSTRACT: Non-motile primary cilia are recognized as important sensory organelles during development and normal biological functioning. For example, recent work demonstrates that transcriptional regulators of the sonic hedgehog signaling pathway localize to primary cilia and participate in sensing and transducing signals regarding the cellular environment. In contrast, motile cilia are traditionally viewed as mechanical machinery, vital for the movement of solutes and clearance of bacteria and debris, but not participants in cellular sensing and signaling mechanisms. Recently, motile cilia were found to harbor receptors responsible for sensing and responding to environmental stimuli. However, no transcription factors are known to be regulated by cilia localization as a sensing mechanism in vertebrates. Using a mouse model of organic dust-induced airway inflammation, we found that the transcription factor serum response factor (SRF) localizes to motile cilia of airway epithelial cells and alters its localization in response to inflammatory stimuli. Furthermore, inhibition of SRF signaling using the small molecule CCG-1423 reduces organic dust-induced IL-8 release from bronchial epithelial cells, and stimulates cilia beat frequency in ciliated mouse tracheal epithelial cells. Immunohistochemical analyses reveal SRF localizes to the cilia of mouse brain ependymal and ovarian epithelial cells as well. These data reveal a novel mechanism by which a transcription factor localizes to motile cilia and modulates cell activities including cilia motility and inflammation response. These data challenge current dogma regarding motile cilia functioning, and may lead to significant contributions in understanding motile ciliary signaling dynamics, as well as mechanisms involving SRF-mediated responses to inflammation and injury.
    AJP Lung Cellular and Molecular Physiology 03/2014; 306(9). DOI:10.1152/ajplung.00364.2013 · 4.04 Impact Factor
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    ABSTRACT: The elderly are at much higher risk for developing pneumonia than younger individuals. Pneumonia is a leading cause of death and the third most common reason for hospitalization in the elderly. One reason that the elderly may be more susceptible to pneumonia is a breakdown in the lung's first line of defense, mucociliary clearance. Cilia beat in a coordinated manner to propel out invading microorganisms and particles. Ciliary beat frequency (CBF) is known to slow with aging, however little is known about the mechanism(s). We compared the CBF in BALB/c and C57BL/6 mice aged 2 months, 12 months and 24 months and found that CBF diminishes with age. Both the 12 and 24-month cilia retained their ability to be stimulated by the β2 agonist, procaterol. To help determine the mechanism of ciliary slowing, we measured PKCα and PKCε activity. There were no activity differences in PKCα; however, we demonstrate a significantly higher PKCε activity in the 12- and 24-month mice than the 2-month mice. The increase in activity is likely due to a nearly 3-fold increase in PKCε protein in the lung during aging. To strengthen the connection between PKCε activation and ciliary slowing, we treated 2-month tracheas with the PKCε agonist, 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA). We noted a similar decrease in baseline CBF, and the cilia remained sensitive to stimulation with β2 agonists. Conclusions: In this mouse model of aging, we show that the decreases in CBF are related to an increase in PKCε activity.
    AJP Lung Cellular and Molecular Physiology 01/2014; 306(6). DOI:10.1152/ajplung.00175.2013 · 4.04 Impact Factor
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    ABSTRACT: The debilitating and persistent effects of ICU-acquired delirium and weakness warrant testing of prevention strategies. The purpose of this study was to evaluate the effectiveness and safety of implementing the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility bundle into everyday practice. Eighteen-month, prospective, cohort, before-after study conducted between November 2010 and May 2012. Five adult ICUs, one step-down unit, and one oncology/hematology special care unit located in a 624-bed tertiary medical center. Two hundred ninety-six patients (146 prebundle and 150 postbundle implementation), who are 19 years old or older, managed by the institutions' medical or surgical critical care service. Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility bundle. For mechanically ventilated patients (n = 187), we examined the association between bundle implementation and ventilator-free days. For all patients, we used regression models to quantify the relationship between Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility bundle implementation and the prevalence/duration of delirium and coma, early mobilization, mortality, time to discharge, and change in residence. Safety outcomes and bundle adherence were monitored. Patients in the postimplementation period spent three more days breathing without mechanical assistance than did those in the preimplementation period (median [interquartile range], 24 [7-26] vs 21 [0-25]; p = 0.04). After adjusting for age, sex, severity of illness, comorbidity, and mechanical ventilation status, patients managed with the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility bundle experienced a near halving of the odds of delirium (odds ratio, 0.55; 95% CI, 0.33-0.93; p = 0.03) and increased odds of mobilizing out of bed at least once during an ICU stay (odds ratio, 2.11; 95% CI, 1.29-3.45; p = 0.003). No significant differences were noted in self-extubation or reintubation rates. Critically ill patients managed with the Awakening and Breathing Coordination, Delirium monitoring/management, and Early exercise/mobility bundle spent three more days breathing without assistance, experienced less delirium, and were more likely to be mobilized during their ICU stay than patients treated with usual care.
    Critical care medicine 01/2014; DOI:10.1097/CCM.0000000000000129 · 6.15 Impact Factor
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    ABSTRACT: Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
    Nature 12/2013; DOI:10.1038/nature12807 · 42.35 Impact Factor
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    ABSTRACT: Background. Vest chest physiotherapy (VCPT) enhances airway clearance in cystic fibrosis (CF) by an unknown mechanism. Because cilia are sensitive to nitric oxide (NO), we hypothesized that VCPT enhances clearance by changing NO metabolism. Methods. Both normal subjects and stable CF subjects had pre- and post-VCPT airway clearance assessed using nasal saccharin transit time (NSTT) followed by a collection of exhaled breath condensate (EBC) analyzed for NO metabolites (NO x ). Results. VCPT shorted NSTT by 35% in normal and stable CF subjects with no difference observed between the groups. EBC NO x concentrations decreased 68% in control subjects after VCPT (before = 115 ± 32 μ M versus after = 37 ± 17 μ M; P < 0.002). CF subjects had a trend toward lower EBC NO x . Conclusion. We found an association between VCPT-stimulated clearance and exhaled NO x levels in human subjects. We speculate that VCPT stimulates clearance via increased NO metabolism.
    11/2013; 2013:291375. DOI:10.1155/2013/291375
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    ABSTRACT: The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases, and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88 and airway remodeling and pulmonary function were evaluated. In IFT88(-) mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88(-) mice exhibited increased airway reactivity to a methacholine challenge, and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of Clara cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of Clara cells, since these cells are involved in airway repair. Clara cells may be prevented from differentiating into respiratory epithelial cells due to a lack of IFT88 protein that is necessary to form a single non-motile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function.
    AJP Lung Cellular and Molecular Physiology 11/2013; 306(2). DOI:10.1152/ajplung.00095.2013 · 4.04 Impact Factor
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    ABSTRACT: The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase by ADMA blocks alcohol-stimulated increases in CBF. To test this hypothesis, ciliated primary bovine bronchial epithelial cells (BBEC) were preincubated with ADMA (100 µ M) and stimulated with 100 mM ethanol. CBF was measured and PKA assayed. By 1 hr, ethanol activated PKA, resulting in elevated CBF. Both alcohol-induced PKA activation and CBF were inhibited in the presence of ADMA. ADMA alone had no effect on PKA activity or CBF. Using a mouse model overexpressing the ADMA-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), we examined PKA and CBF in precision-cut mouse lung slices. Alcohol-stimulated increases in lung slice PKA and CBF were temporally enhanced in the DDAH mice versus control mice.
    Mediators of Inflammation 11/2013; 2013:592892. DOI:10.1155/2013/592892 · 2.42 Impact Factor
  • Alcohol 11/2013; 47(7):576. DOI:10.1016/j.alcohol.2013.09.038 · 2.04 Impact Factor
  • Alcohol 11/2013; 47(7):575. DOI:10.1016/j.alcohol.2013.09.033 · 2.04 Impact Factor
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    ABSTRACT: Previously we have shown that chronic alcohol intake causes alcohol-induced ciliary dysfunction (AICD), leading to non-responsive airway cilia. AICD likely occurs through the downregulation of nitric oxide (NO) and cyclic nucleotide-dependent kinases, protein kinase G (PKG) and protein kinase A (PKA). Studies by others have shown that dietary supplementation with the antioxidants N-acetylcysteine (NAC) and procysteine prevent other alcohol-induced lung complications. This led us to hypothesize that dietary supplementation with NAC or procysteine prevents AICD. To test this hypothesis, C57BL/6 mice drank an alcohol/water solution (20% w/v) ad libitum for 6 weeks and were concurrently fed dietary supplements of either NAC or procysteine. Ciliary beat frequency (CBF) was measured in mice tracheas, and PKG/PKA responsiveness to β-agonists and NOx levels were measured from bronchoalveolar lavage (BAL) fluid. Long-term alcohol drinking reduced CBF, PKG and PKA responsiveness to β-agonists, and lung NOx levels in BAL fluid. In contrast, alcohol-drinking mice fed NAC or procysteine sustained ciliary function and PKG and PKA responsiveness to β-agonists. However, BAL NO levels remained low despite antioxidant supplementation. We also determined that removal of alcohol from the drinking water for as little as 1 week restored ciliary function, but not PKG and PKA responsiveness to β-agonists. We conclude that dietary supplementation with NAC or procysteine protects against AICD. In addition, alcohol removal for 1 week restores cilia function independent of PKG and PKA activity. Our findings provide a rationale for the use of antioxidants to prevent damage to airway mucociliary functions in chronic alcohol-drinking individuals.
    Alcohol (Fayetteville, N.Y.) 10/2013; DOI:10.1016/j.alcohol.2013.09.004 · 2.04 Impact Factor
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    ABSTRACT: The purpose of this descriptive study was to determine if older patients discharged from intensive care units (ICU) would be willing to use mobile phone and sensor technology (aka "mobile monitoring") to measure their functional recovery in the posthospitalization period. Semistructured interviews were conducted with 22 older ICU patients and/or their surrogates 24 to 48 hr prior to hospital discharge. While 11 respondents reported they would agree to participate in a future study involving mobile monitoring, an equal number reported they would not participate. Numerous contextual factors were found to affect older adults' willingness to participate including the belief the research would ultimately benefit themselves or other older adults, concerns about loss of privacy, perception that the research is feasible and valuable, and lack of skills using the technology. Future studies using the mobile monitoring technique with older survivors of a serious illness will require substantial recruitment and educational efforts.
    05/2013; 34(3). DOI:10.1177/0733464813480267
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    ABSTRACT: Adenosine levels are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease (COPD), where it balances between tissue repair and excessive airway remodeling. We previously demonstrated activation of adenosine A2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The current study investigates if cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/antioxidant balance. Utilizing an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract (smoke extract), wounded and stimulated with either 10 μM adenosine or the specific A2A receptor agonist, 5'-(N-Cyclopropyl)-carboxamido-adenosine (CPCA; 10 μM) and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, there was significant delay in both adenosine- and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a non-specific antioxidant, reversed smoke extract-mediated inhibition. We found cells overexpressing mitochondrial catalase repealed smoke extract inhibition of CPCA-stimulated wound closure while superoxide dismutase overexpression had no effect. Kinase studies revealed smoke extract significantly reduced A2A-mediated activation of cAMP-dependent protein kinase (PKA); however, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A2A-stimulated wound repair via a reactive oxygen species-dependent mechanism and provides a better understanding of adenosine signaling that may direct the development of pharmacological tools for treatment of chronic inflammatory lung disorders.
    American Journal of Respiratory Cell and Molecular Biology 01/2013; DOI:10.1165/rcmb.2011-0273OC · 4.11 Impact Factor
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    ABSTRACT: BACKGROUND: Cilia are finger-like motor-driven organelles, which propel inhaled particles and mucus from the lung and airways. We have previously shown that brief alcohol exposure stimulates ciliary motility through an endothelial nitric oxide synthase (eNOS)-dependent pathway localized in the ciliary metabolon. However, the signaling molecules of the ciliary metabolon involved in alcohol-triggered ciliary beat frequency (CBF) stimulation upstream of eNOS activation remain unknown. METHODS: We hypothesized that brief alcohol exposure alters threonine and serine phosphorylation of proteins involved in stimulating CBF. Two-dimensional electrophoresis indicated both increases and decreases in the serine and threonine phosphorylation states of several proteins. One of the proteins identified was heat shock protein 90 (HSP90), which undergoes increased threonine phosphorylation after brief alcohol exposure. Because HSP90 has been shown to associate with eNOS in lung tissue, we hypothesized that HSP90 is a key component in alcohol-triggered eNOS activation and that these 2 proteins co-localize within the ciliary metabolon. RESULTS: Immunofluorescence experiments demonstrate that eNOS and HSP90 co-localize within basal bodies of the ciliary metabolon and partially translocate to the axoneme upon brief alcohol exposure. Pretreatment with geldanamycin, which disrupts HSP90 chaperone functions, prevented eNOS-HSP90 association and prevented the translocation of eNOS from the ciliary metabolon to the axoneme. Functional cilia motility studies revealed that geldanamycin blocked alcohol-stimulated ciliary motility in bovine bronchial epithelial cells and mouse tracheal rings. CONCLUSIONS: On the basis of the HSP90 localization with eNOS, alcohol activation of HSP90 phosphorylation, and geldanamycin's ability to inhibit HSP90-eNOS association, prevent eNOS translocation to the axoneme, and block alcohol-stimulated ciliary motility, we conclude that alcohol-induced cilia stimulation occurs through the increased association of HSP90 with eNOS. These data help further elucidate the mechanism through which brief alcohol exposure stimulates CBF.
    Alcoholism Clinical and Experimental Research 10/2012; DOI:10.1111/acer.12014 · 3.31 Impact Factor
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    ABSTRACT: ABSTRACT Organic dust samples from swine confinement facilities elicit pro-inflammatory cytokine/chemokine release from bronchial epithelial cells and monocytes, dependent, in part, upon dust-induced activation of the protein kinase C (PKC) isoform, PKCε. PKCε is also rapidly activated in murine tracheal epithelial cells following in vivo organic dust challenges, yet the functional role of PKCε in modulating dust-induced airway inflammatory outcomes is not defined. Utilizing an established intranasal inhalation animal model, experiments investigated the biologic and physiologic responses following organic dust extract (ODE) treatments in wild-type (WT) and PKCε knock-out (KO) mice. We found that neutrophil influx increased more than twofold in PKCε KO mice following both a one-time challenge and 3 weeks of daily challenges with ODE as compared with WT mice. Lung pathology revealed increased bronchiolar and alveolar inflammation, lymphoid aggregates, and T cell influx in ODE-treated PKCε KO mice. Airway hyperresponsiveness to methacholine increased in PKCε KO + ODE to a greater magnitude than WT + ODE animals. There were no significant differences in cytokine/chemokine release elicited by ODE treatment between groups. However, ODE-induced nitric oxide (NO) production differed in that ODE exposure increased nitrate levels in WT mice but not in PKCε KO mice. Moreover, ODE failed to upregulate NO from ex vivo stimulated PKCε KO lung macrophages. Collectively, these studies demonstrate that PKCε-deficient mice were hypersensitive to organic dust exposure and suggest that PKCε is important in the normative lung inflammatory response to ODE. Dampening of ODE-induced NO may contribute to these enhanced inflammatory findings.
    Experimental Lung Research 08/2012; 38(8):383-95. DOI:10.3109/01902148.2012.714841 · 1.75 Impact Factor

Publication Stats

2k Citations
441.61 Total Impact Points

Institutions

  • 1992–2015
    • University of Nebraska Medical Center
      • • Department of Internal Medicine
      • • Division of Pulmonary, Critical Care, Sleep and Allergy
      Omaha, Nebraska, United States
  • 2007–2014
    • University of Nebraska at Omaha
      • Department of Internal Medicine
      Omaha, Nebraska, United States
  • 2003–2014
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2006
    • Emory University
      Atlanta, Georgia, United States
  • 1995
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States