Epithelium Smooth Muscle Regulation and Interactions

Spina, Dom

doi:10.1164/ajrccm.158.supplement_2.13tac100a

Cited by 49 publications

(41 citation statements)

References 63 publications

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“…Total leukocyte counts have not been demonstrated to correlate with clinical indicators of illness in human infants (13). It is possible that the severity of RSV infection is not the result of the number or activity of a single cell type or cytokine, but the end effects of either airway obstruction, or else sloughing of the bronchiolar epithelium, with the loss of homeostatic factors normally produced by airway epithelial cells (12,32). These abnormalities may increase the work of breathing necessary for the animal to maintain adequate ventilation.…”

Section: Discussionmentioning

confidence: 99%

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Papin

Wolf

Kosanke

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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infection of the lower respiratory tract is the leading cause of respiratory failure among infants in the United States of America and annually results in Ͼ300,000 deaths worldwide. Despite the importance of RSV, there is no licensed vaccine, and no specific form of therapy. This is largely due to the absence of an appropriate animal model for the evaluation of vaccines and therapeutic agents. We inoculated anesthetized infant (4 wk) baboons (Papio anubis) with a human strain of RSV intranasally or intratracheally. Baboons were monitored daily for clinical changes. Anesthetized baboons were intubated at various intervals, and bronchoalveolar lavage (BAL) was performed for viral culture and determination of leukocyte counts. Sham-infected baboons served as controls. Necropsies were performed on infected baboons on days 1, 3, 5, 8, or 13 after inoculation, with pathological analysis and immunohistochemical staining of lung tissues to detect RSV antigen. Infected baboons developed tachypnea and reduced oxygenation peaking from 4 to 8 days after infection and persisting for Ն14 days. Virus was recoverable in BAL fluid up to 8 days following infection. Necropsy revealed intense interstitial pneumonia, sloughing of the bronchiolar epithelium, and obstruction of the bronchiolar lumen with inflammatory cells and sloughed epithelial cells. RSV antigen was identified in bronchiolar and alveolar epithelium. We conclude that RSV-infected infant baboons develop clinical and pathological changes that parallel those observed in human infants with RSV infection. The infant baboon represents a muchneeded model for studying the pathogenesis of RSV infection and evaluating antivirals and vaccines. interstitial pneumonia; bronchiolitis; baboon model; animal models; respiratory syncytial virus vaccine RESPIRATORY SYNCYTIAL VIRUS (RSV) is the most important respiratory pathogen of early life. RSV infection, in the form of interstitial pneumonia and bronchiolitis, annually results in Ͼ120,000 hospitalizations in the United States of America and Ͼ300,000 deaths worldwide (21, 24). RSV lower respiratory tract infection (LRTI) in infancy also may predispose to the development of childhood asthma (33). Despite the considerable impact of RSV infection, there is no approved vaccine and no effective specific form of therapy. The lack of an appropriate animal model has resulted in an incomplete understanding of the pathophysiology of the disease and an inability to evaluate the safety and efficacy of vaccines and pharmacological agents. An animal model developing clinical and pathological manifestations similar to those of human infants with RSV infection would provide a significant step toward overcoming these problems. To reflect human disease, an appropriate animal model should develop tachypnea, reduced oxygenation, and interstitial and peribronchiolar inflammation with obstruction of the bronchiolar lumen by invading leukocytes and exfoliated epithelial cells following infection. These manifestations should be most prominent in an infant...

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Section: Discussionmentioning

confidence: 99%

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Papin

Wolf

Kosanke

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Many studies demonstrated increased responsiveness of airway smooth muscle in vitro to contractile agonists such as acetylcholine (ACh) and 5-hydroxytryptamine (5-HT), as well as sensory neuropeptides, including substance P and neurokinin A, following removal of the epithelium (Aarhus et al, 1984;Hay et al, 1986;Spina, 1998). Therefore, damage to the epithelium by flavorings would be expected to increase reactivity to contractile agonists in vivo and in vitro, especially after contractile agonists are applied to the mucosal surface.…”

mentioning

confidence: 99%

Popcorn Flavoring Effects on Reactivity of Rat Airways in Vivo and in Vitro

Zaccone

Thompson

Ponnoth

et al. 2013

Journal of Toxicology and Environmental Health, Part A

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Abstract"Popcorn workers' lung" is an obstructive pulmonary disease produced by inhalation of volatile artificial butter flavorings. In rats, inhalation of diacetyl, a major component of butter flavoring, and inhalation of a diacetyl substitute, 2,3-pentanedione, produce similar damage to airway epithelium. The effects of diacetyl and 2,3-pentanedione and mixtures of diacetyl, acetic acid, and acetoin, all components of butter flavoring, on pulmonary function and airway reactivity to methacholine (MCh) were investigated. Lung resistance (R L ) and dynamic compliance (C dyn ) were negligibly changed 18 h after a 6-h inhalation exposure to diacetyl or 2,3-pentanedione (100-360 ppm). Reactivity to MCh was not markedly changed after diacetyl, but was modestly decreased after 2,3-pentanedione inhalation. Inhaled diacetyl exerted essentially no effect on reactivity to mucosally applied MCh, but 2,3-pentanedione (320 and 360 ppm) increased reactivity to MCh in the isolated, perfused trachea preparation (IPT). In IPT, diacetyl and 2,3-pentanedione (≥3 mM) applied to the serosal and mucosal surfaces of intact and epithelium-denuded tracheas initiated transient contractions followed by relaxations. Inhaled acetoin (150 ppm) exerted no effect on pulmonary function and airway reactivity in vivo; acetic acid (27 ppm) produced hyperreactivity to MCh; and exposure to diacetyl + acetoin + acetic acid (250 + 150 + 27 ppm) led to a diacetyl-like reduction in reactivity. Data suggest that the effects of 2,3-pentanedione on airway reactivity are greater than those of diacetyl, and that flavorings are airway smooth muscle relaxants and constrictors, thus indicating a complex mechanism.Employees at microwave popcorn manufacturing factories have developed "popcorn workers' lung" (Department

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“…5 The HBE plays an important physiological role in innate immunity by providing a physical barrier to environmental insults and, if breached, initiating a defense response via an array of receptor-mediated events. 6 Barrier function of the HBE is maintained through the cooperation of two mutually exclusive structural units: trans-membrane mucins on the apical cell surface of ciliated cells (mucociliary barrier) 7 and subapical junctional complexes consisting of tight junctions (TJs) and adherens junctions (AJs) on the lateral membranes.…”

mentioning

confidence: 99%

Cigarette Smoke Induces Epidermal Growth Factor Receptor-Dependent Redistribution of Apical MUC1 and Junctional β-Catenin in Polarized Human Airway Epithelial Cells

Chen

Gallup

Nikulina

et al. 2010

The American Journal of Pathology

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Cigarette smoke (CS) accounts for nearly 90% of lung cancer deaths worldwide; however, an incomplete understanding of how CS initiates preneoplastic changes in the normal airway hinders early diagnosis. Short-term exposure to CS causes aberrant activation of epidermal growth factor receptor (EGFR) and canonical Wnt/␤-catenin signaling pathways in human bronchial epithelial (HBE) cells. We hypothesize that this response is elicited through the disruption of spatially segregated cell membrane proteins in the polarized airway epithelium. Using an in vitro model of highly differentiated HBE cells, we observed membrane characteristics consistent with the native airway, including the presence of a membrane mucin, MUC1, at the apical cell pole, ␤-catenin at the apicallateral membrane, and EGFR at the basolateral membrane. Following exposure to smoke, intercellular spaces enlarge and cilia disappear. This histopathology is accompanied by molecular events that include perinuclear trafficking of basolateral EGFR, EGFR phosphorylation, pEGFR-mediated phosphorylation of MUC1's cytoplasmic tail (CT), loss of E-cadherin/␤-catenin complexes at the adherens junctions (AJs), intracellular formation and nuclear shuffling of ␤-catenin/MUC1-CT complexes, and, ultimately, upregulation and nuclear localization of Wnt nuclear effector, Lef-1. In the presence of EGFR inhibitor, AG1478, CS-induced histopathology and molecular events were inhibited. These data point to EGFR as a portal through which CS mediates its damaging effects on AJ-mediated cell polarity and activation of canonical Wnt/␤-catenin signaling.

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Epithelium Smooth Muscle Regulation and Interactions

Cited by 49 publications

References 63 publications

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

Popcorn Flavoring Effects on Reactivity of Rat Airways in Vivo and in Vitro

Cigarette Smoke Induces Epidermal Growth Factor Receptor-Dependent Redistribution of Apical MUC1 and Junctional β-Catenin in Polarized Human Airway Epithelial Cells

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