Browsing by Subject "Epithelium"

Now showing 1 - 9 of 9
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    A beta-adrenergic receptor kinase-like enzyme is involved in olfactory signal termination.
    (Proc Natl Acad Sci U S A, 1993-02-15) Schleicher, S; Boekhoff, I; Arriza, J; Lefkowitz, RJ; Breer, H
    We have previously shown that second-messenger-dependent kinases (cAMP-dependent kinase, protein kinase C) in the olfactory system are essential in terminating second-messenger signaling in response to odorants. We now document that subtype 2 of the beta-adrenergic receptor kinase (beta ARK) is also involved in this process. By using subtype-specific antibodies to beta ARK-1 and beta ARK-2, we show that beta ARK-2 is preferentially expressed in the olfactory epithelium in contrast to findings in most other tissues. Heparin, an inhibitor of beta ARK, as well as anti-beta ARK-2 antibodies, (i) completely prevents the rapid decline of second-messenger signals (desensitization) that follows odorant stimulation and (ii) strongly inhibits odorant-induced phosphorylation of olfactory ciliary proteins. In contrast, beta ARK-1 antibodies are without effect. Inhibitors of protein kinase A and protein kinase C also block odorant-induced desensitization and phosphorylation. These data suggest that a sequential interplay of second-messenger-dependent and receptor-specific kinases is functionally involved in olfactory desensitization.
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    Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling.
    (Dis Model Mech, 2010-09) Rock, Jason R; Randell, Scott H; Hogan, Brigid LM
    The small airways of the human lung undergo pathological changes in pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), asthma, bronchiolitis obliterans and cystic fibrosis. These clinical problems impose huge personal and societal healthcare burdens. The changes, termed 'pathological airway remodeling', affect the epithelium, the underlying mesenchyme and the reciprocal trophic interactions that occur between these tissues. Most of the normal human airway is lined by a pseudostratified epithelium of ciliated cells, secretory cells and 6-30% basal cells, the proportion of which varies along the proximal-distal axis. Epithelial abnormalities range from hypoplasia (failure to differentiate) to basal- and goblet-cell hyperplasia, squamous- and goblet-cell metaplasia, dysplasia and malignant transformation. Mesenchymal alterations include thickening of the basal lamina, smooth muscle hyperplasia, fibrosis and inflammatory cell accumulation. Paradoxically, given the prevalence and importance of airway remodeling in lung disease, its etiology is poorly understood. This is due, in part, to a lack of basic knowledge of the mechanisms that regulate the differentiation, maintenance and repair of the airway epithelium. Specifically, little is known about the proliferation and differentiation of basal cells, a multipotent stem cell population of the pseudostratified airway epithelium. This Perspective summarizes what we know, and what we need to know, about airway basal cells to evaluate their contributions to normal and abnormal airway remodeling. We contend that exploiting well-described model systems using both human airway epithelial cells and the pseudostratified epithelium of the genetically tractable mouse trachea will enable crucial discoveries regarding the pathogenesis of airway disease.
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    BMP signaling in the development of the mouse esophagus and forestomach.
    (Development, 2010-12) Rodriguez, Pavel; Da Silva, Susana; Oxburgh, Leif; Wang, Fan; Hogan, Brigid LM; Que, Jianwen
    The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function (Shh-Cre;Rosa26(CAG-loxpstoploxp-caBmprIa)) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function experiments, conditional deletion of the BMP receptor in Shh-Cre;Bmpr1a(flox/flox) embryos allows the formation of a multilayered squamous epithelium but this fails to differentiate, as shown by the absence of expression of the suprabasal markers loricrin and involucrin. Together, these findings suggest multiple roles for BMP signaling in the developing esophagus and forestomach.
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    Epithelial injury and interstitial fibrosis in the proximal alveolar regions of rats chronically exposed to a simulated pattern of urban ambient ozone.
    (Toxicology and applied pharmacology, 1992-08) Chang, LY; Huang, Y; Stockstill, BL; Graham, JA; Grose, EC; Menache, MG; Miller, FJ; Costa, DL; Crapo, JD
    Electron microscopic morphometry was used to study the development of lung injury during and after chronic (78 weeks) exposure to a pattern of ozone (O3) designed to simulate high urban ambient concentrations that occur in some environments. The daily exposure regimen consisted of a 13-hr background of 0.06 ppm, an exposure peak that rose from 0.06 to 0.25 ppm, and returned to the background level over a 9-hr period, and 2-hr downtime for maintenance. Rats were exposed for 1, 3, 13, and 78 weeks. Additional groups of rats exposed for 13 or 78 weeks were allowed to recover in filtered clean air for 6 or 17 weeks, respectively. Rats exposed to filtered air for the same lengths of time were used as controls. Samples from proximal alveolar regions and terminal bronchioles were obtained by microdissection. Analysis of the proximal alveolar region revealed a biphasic response. Acute tissue reactions after 1 week of exposure included epithelial inflammation, interstitial edema, interstitial cell hypertrophy, and influx of macrophages. These responses subsided after 3 weeks of exposure. Progressive epithelial and interstitial tissue responses developed with prolonged exposure and included epithelial hyperplasia, fibroblast proliferation, and interstitial matrix accumulation. The epithelial responses involved both type I and type II epithelial cells. Alveolar type I cells increased in number, became thicker, and covered a smaller average surface area. These changes persisted throughout the entire exposure and did not change during the recovery period, indicating the sensitivity of these cells to injury. The main response of type II epithelial cells was cell proliferation. The accumulation of interstitial matrix after chronic exposure consisted of deposition of both increased amounts of basement membrane and collagen fibers. Interstitial matrix accumulation underwent partial recovery during follow-up periods in air; however, the thickening of the basement membrane did not resolve. Analysis of terminal bronchioles showed that short-term exposure to O3 caused a loss of ciliated cells and differentiation of preciliated and Clara cells. The bronchiolar cell population stabilized on continued exposure; however, chronic exposure resulted in structural changes, suggesting injury to both ciliated and Clara cells. We conclude that chronic exposure to low levels of O3 causes epithelial inflammation and interstitial fibrosis in the proximal alveolar region and bronchiolar epithelial cell injury.
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    HPV clearance and the neglected role of stochasticity.
    (PLoS Comput Biol, 2015-03) Ryser, MD; Myers, ER; Durrett, R
    Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response. To date, little attention has been paid to the potential role of stochastic cell dynamics in the time it takes to clear an HPV infection. In this study, we combine mechanistic mathematical models at the cellular level with epidemiological data at the population level to disentangle the respective roles of immune capacity and cell dynamics in the clearing mechanism. Our results suggest that chance-in form of the stochastic dynamics of basal stem cells-plays a critical role in the elimination of HPV-infected cell clones. In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance-the rest is taken care of by the stochastic proliferation dynamics in the basal layer. In HIV-negative individuals, the contribution of the immune response may be negligible.
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    Interactions of oxygen radicals with airway epithelium.
    (Environ Health Perspect, 1994-12) Wright, DT; Cohn, LA; Li, H; Fischer, B; Li, CM; Adler, KB
    Reactive oxygen species (ROS) have been implicated in the pathogenesis of numerous disease processes. Epithelial cells lining the respiratory airways are uniquely vulnerable regarding potential for oxidative damage due to their potential for exposure to both endogenous (e.g., mitochondrial respiration, phagocytic respiratory burst, cellular oxidases) and exogenous (e.g., air pollutants, xenobiotics, catalase negative organisms) oxidants. Airway epithelial cells use several nonenzymatic and enzymatic antioxidant mechanisms to protect against oxidative insult. Nonenzymatic defenses include certain vitamins and low molecular weight compounds such as thiols. The enzymes superoxide dismutase, catalase, and glutatione peroxidase are major sources of antioxidant protection. Other materials associated with airway epithelium such as mucus, epithelial lining fluid, and even the basement membrane/extracellular matrix may have protective actions as well. When the normal balance between oxidants and antioxidants is upset, oxidant stress ensues and subsequent epithelial cell alterations or damage may be a critical component in the pathogenesis of several respiratory diseases. Oxidant stress may profoundly alter lung physiology including pulmonary function (e.g., forced expiratory volumes, flow rates, and maximal inspiratory capacity), mucociliary activity, and airway reactivity. ROS may induce airway inflammation; the inflammatory process may serve as an additional source of ROS in airways and provoke the pathophysiologic responses described. On a more fundamental level, cellular mechanisms in the pathogenesis of ROS may involve activation of intracellular signaling enzymes including phospholipases and protein kinases stimulating the release of inflammatory lipids and cytokines. Respiratory epithelium may be intimately involved in defense against, and pathophysiologic changes invoked by, ROS.
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    Loss of epithelial oestrogen receptor α inhibits oestrogen-stimulated prostate proliferation and squamous metaplasia via in vivo tissue selective knockout models.
    (The Journal of pathology, 2012-01) Chen, Ming; Yeh, Chiuan-Ren; Chang, Hong-Chiang; Vitkus, Spencer; Wen, Xing-Qiao; Bhowmick, Neil A; Wolfe, Andrew; Yeh, Shuyuan
    Squamous metaplasia (SQM) is a specific phenotype in response to oestrogen in the prostate and oestrogen receptor (ER) α is required to mediate this response. Previous studies utilizing tissue recombination with seminal vesicle (SV) mesenchyme and prostatic ductal tips from wild type and ERαKO mice suggested that both epithelial and stromal ERα are necessary for SQM. However, tissue recombination is conducted in the renal capsule of immune-deficient mice, in which the microenvironment is different from normal prostate microenvironment in the intact mice. Furthermore, whether the requirement of stromal ERα in the SV for developing SQM is the same as in the prostate is unknown. Therefore, there is a clear need to evaluate the respective roles of ERα in prostate epithelial versus stromal compartments in the intact mouse. Here we generated a mouse model that has selectively lost ERα in either stromal (FSP-ERαKO) or epithelial prostate cells (pes-ERαKO) to determine the requirements of ERα for oestrogen-stimulated prostate proliferation and SQM. Our results indicated that FSP-ERαKO prostates develop full and uniform SQM, which suggests that loss of the majority (~65%) of stromal ERα will not influence oestrogen-mediated SQM. In contrast, loss of epithelial ERα inhibits oestrogen-mediated prostate growth and SQM evidenced by decreasing cytokertin 10 positive squamous cell stratification and differentiation, by reduced ERα protein expression in SQM compared to wild type mice ERα, and by the presence of normal proliferative activities in the oestrogen-treated pes-ERαKO prostates. These in vivo results suggest that epithelial ERα is required for oestrogen-mediated proliferative response and could be an appropriate target for preventing aberrant oestrogen signalling in the prostate.
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    Lung Regeneration: Cells, Models, and Mechanisms.
    (Cold Spring Harbor perspectives in biology, 2022-10) Konkimalla, Arvind; Tata, Aleksandra; Tata, Purushothama Rao
    Lung epithelium, the lining that covers the inner surface of the respiratory tract, is directly exposed to the environment and thus susceptible to airborne toxins, irritants, and pathogen-induced damages. In adult mammalian lungs, epithelial cells are generally quiescent but can respond rapidly to repair of damaged tissues. Evidence from experimental injury models in rodents and human clinical samples has led to the identification of these regenerative cells, as well as pathological metaplastic states specifically associated with different forms of damages. Here, we provide a compendium of cells and cell states that exist during homeostasis in normal lungs and the lineage relationships between them. Additionally, we discuss various experimental injury models currently being used to probe the cellular sources-both resident and recruited-that contribute to repair, regeneration, and remodeling following acute and chronic injuries. Finally, we discuss certain maladaptive regeneration-associated cell states and their role in disease pathogenesis.
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    The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates.
    (Environ Health Perspect, 1997-09) Martin, LD; Krunkosky, TM; Dye, JA; Fischer, BM; Jiang, NF; Rochelle, LG; Akley, NJ; Dreher, KL; Adler, KB
    Epidemiologic and occupational studies indicate adverse health effects due to inhalation of particulate air pollutants, but precise biologic mechanisms responsible have yet to be fully established. The tracheobronchial epithelium forms the body's first physiologic barrier to such airborne pollutants, where ciliary movement functions to remove the offending substances caught in the overlying mucus layer. Resident and infiltrating phagocytic cells also function in this removal process. In this paper, we examine the role of reactive oxygen and nitrogen species (ROS/RNS) in the response of airway epithelium to particulates. Some particulates themselves can generate ROS, as can the epithelial cells, in response to appropriate stimulation. In addition, resident macrophages in the airways and the alveolar spaces can release ROS/RNS after phagocytosis of inhaled particles. These macrophages also release large amounts of tumor necrosis factor alpha (TNF-alpha), a cytokine that can generate responses within the airway epithelium dependent upon intracellular generation of ROS/RNS. As a result, signal transduction pathways are set in motion that may contribute to inflammation and other pathobiology in the airway. Such effects include increased expression of intercellular adhesion molecule 1, interleukin-6, cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase, cytosolic phospholipase A2, and hypersecretion of mucus. Ultimately, ROS/RNS may play a role in the global response of the airway epithelium to particulate pollutants via activation of kinases and transcription factors common to many response genes. Thus, defense mechanisms involved in responding to offending particulates may result in a complex cascade of events that can contribute to airway pathology.