Proliferative and Metaplastic Lesions in Nonolfactory Nasal Epithelia Induced by Inhaled Chemicals (original) (raw)
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Factors modulating the epithelial response to toxicants in tracheobronchial airways
Toxicology, 2001
As one of the principal interfaces between the organism and the environment, the respiratory system is a target for a wide variety of toxicants and carcinogens. The cellular and architectural complexity of the respiratory system appears to play a major role in defining the focal nature of the pulmonary response to environmental stressors. This review will address the biological factors that modulate the response of one of the major target compartments within the respiratory system, the tracheobronchial airway tree. Individual airway segments respond uniquely to toxic stress and this response involves not only the target cell population, e.g. epithelium, but also other components of the airway wall suggesting a trophic interaction within all components of the airway wall in maintaining steady state and responding to injury. A number of biological factors modulate the nature of the response, including: (1) metabolic potential at specific sites for activation and detoxification; (2) the nature of the local inflammatory response; (3) age of the organism at the time of exposure; (4) gender of the exposed organism; (5) history of previous exposure; and (6) species and strain of the organism exposed.
Chest, 1996
contact or for short half-life soluble intermediates in the obseiVed response. These results demonstrate that exposure of type II pulmonary epithelial cells in primary culture to anthracite coal dust alters cell function by both direct and indirect pathways. Evidence that fl.bronectin modulates type II cell differentiation, 6 combined with obseiVations that extracellular matrix assembled by dust-exposed cells exhibits elevated fi.bronectin content and altered biological activity, suggests that coal dust also may have indirect effects on type II cell differentiation. The results thus indicate that the sequelae of dust-induced lung damage at the alveolar surface may be determined by cell-dust, cell-cell, and cell-extracellular matrix interactions.
Inhalation Toxicology, 2017
Objective-Mucociliary clearance sustains a baseline functionality and an "on demand" capability to upregulate clearance upon irritant exposure involving mucus hypersecretion and accelerated ciliary beat frequency (CBF) modulated by nitric oxide (NO). This study characterized these elements as well as cellular and exogenous NO concentrations subsequent to a single exposure to tobacco smoke (TS) or e-cigarette vapor (EV) on cultured human airway epithelium. Materials and methods-Air-liquid interface (ALI) airway epithelial cultures per nonsmoking human subjects were subjected to single TS or EV exposures. Measures of ciliary function and secretion were performed and cellular and exogenous NO concentrations under control and experimental conditions were assessed. Results-Both TS and EV exposures resulted similar patterns of decline in CBF within 1 min of the completion of exposure followed by a gradual return often exceeding baseline within 1 h. Postexposure examination of exposed cultures suggested morphologic differences in secretory function relative to controls. The relative NO concentrations of TS and EV chamber air were sharply different with EV NO being only slightly elevated relative to cellular NO production. Discussion and conclusions-Epithelial remodeling and mucociliary dysfunction have been clearly associated with TS exposure. However, information contrasting epithelial structure/ function following a single acute TS or EV exposure is limited. This study demonstrates a similar pattern of epithelial response to acute TS or EV exposure. Inasmuch as NO may contribute to an Contact: Johnny L. Carson
Toxicology letters, 1993
of airway mucus are important characteristics of human respiratory disorders, especially chronic bronchitis and cystic fibrosis. These changes in secretory patterns also occur in animals experimentally exposed to chemical irritants such as ozone (0,), sulfur dioxide (SO& and cigarette smoke. The cellular and molecular mechanisms involved in irritant-induced mucous cell metaplasia (MCM; transformation of airway epithelium, normally devoid of mucous cells, to a secretory epithelium containing numerous mucous cells) are still unclear. We used two experimental models of toxicant-induced MCM in rat airways to study the cellular and molecular changes that occur during the development of this respiratory tract lesion. MCM can be induced in the nasal transitional epithelium of rats by repeated exposure to ambient levels of ozone. In addition, MCM can be induced in the tracheobronchial airways of rats repeatedly exposed to endotoxin, a lipopolysaccharide-protein molecule found in the outer walls of Gram-negative bacteria. The pathogenesis of ozone-or endotoxin-induced MCM has been partially characterized using a variety of morphometric and histochemical techniques. Toxicant-induced changes in the numbers and types of airway epithelial cells have been estimated using morphomet~c methods designed for estimating the abundance of cell populations. Nasal pulmona~ airway tissues are also processed for light microscopy and stained with Alcian Blue (pH 2SYPeriodic Acid Schiff (ABIPAS) for detection of acidic and neutral mucosubstances (the specific glycoprotein product of mucous cells), respectively, within the tissue. Computerized image analysis is used to quantitate the amount of the stained mucous product within the airway epithelium. To better characterize the molecular and cellular events in the pathogenesis of ozone-or endotoxin-induced MCM in the rat airway epithelium, we are conducting studies to determine when, and in which epithelial cells, the mucin gene is expressed after exposure to the toxicant. In these studies, rats undergo single or repeated exposures to ozone or endotoxin and are then sacrificed immediately or a few days after the end of the exposures. Airway tissues are microdissected from specific regions of the exposed respiratory tract, and changes in mucin core polypeptide mRNA are evaluated by Northern analysis using human and rat mucin cDNA. In future studies using
Toxicology, 2000
An in vitro model of the rat nasal cavity has been used to compare the responses of nasal tissues in vitro, using loss of intracellular ATP and potassium as indices of toxicity, with the pathological changes occurring following in vivo exposure to four test compounds. Turbinates were incubated in vitro with the test compounds for 4 h, for 24 h or for 4 h followed by 20 h in fresh medium. Titanium dioxide caused little or no loss of ATP in either olfactory epithelium (OE) or respiratory epithelium (RE). Sodium carbonate decreased olfactory, but not respiratory ATP, while acetic acid and 3-methylindole markedly decreased ATP in both tissues. Intracellular potassium concentrations were generally affected to a lesser degree. In vivo, no morphological changes were observed in the nasal cavity following inhalation exposure to either titanium dioxide or sodium carbonate. Inhalation of acetic acid resulted in a very focal lesion in the RE of the dorsal meatus of level 1, while administration of 3-methylindole by intraperitoneal injection caused severe degeneration of OE. In further experiments olfactory turbinates were exposed to a range of concentrations (0-100 mM) of sodium carbonate, acetic acid and 3-methylindole for 4 h and ATP concentrations determined. Concentration-dependent decreases in ATP were observed for sodium carbonate and 3-methylindole, with EC 50 values estimated as 2.57 and 0.91 mM, respectively. Acetic acid only decreased ATP significantly at the 100-mM concentration. In summary, this in vitro model has predicted the nasal toxicity of several compounds, including both direct-acting agents (sodium carbonate, acetic acid) and one requiring metabolic activation (3methylindole). However, the lack of airflow-dependent dosimetry, results in some lack of discrimination between the different regions of the nasal cavity and may make this model overly sensitive.
Experimental and Toxicologic Pathology, 2005
People are often concurrently exposed to more than one air pollutant whether they are in outdoor or indoor environments. Therefore, inhalation studies that are designed to examine the toxicity of coexposures to two or more airborne toxicants may be more relevant for assessing human health risks than those studies that investigate the toxic effects of only one airborne toxicant at a time. Furthermore, airborne biogenic substances such as pollens, bacteria, fungi, and microbial toxins often coexist with common air pollutants in the ambient air, and when inhaled may also cause specific adverse effects on the respiratory tract. One such biogenic substance, bacterial endotoxin, is a potent stimulus of airway inflammation and is commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and common air pollutants, such as ozone or airborne particulate matter. In the last few years, we have performed a series of in vivo studies using laboratory rodents that examined how airway surface epithelial cells are altered by coexposure to ozone and a biogenic substance, either bacterial endotoxin or a commonly used experimental aeroallergen (ovalbumin). Results from these studies indicate that the ozone-induced epithelial and inflammatory responses in laboratory rodents may be markedly enhanced by coexposure to an inhaled biogenic substance. Conversely, the adverse airway alterations caused by exposure to biogenic substances may be enhanced by coexposure to ozone. The results from these initial studies have also suggested some of the cellular and molecular mechanisms underlying the phenotypic epithelial alterations induced by these coexposures. Many more studies are needed to fully elucidate the potential risk to human health from coexposure to air pollutants and airborne biogenic substances.
Toxicologic Pathology, 2006
The nose is a very complex organ with multiple functions that include not only olfaction, but also the conditioning (e.g., humidifying, warming, and filtering) of inhaled air. The nose is also a "scrubbing tower" that removes inhaled chemicals that may be harmful to the more sensitive tissues in the lower tracheobronchial airways and pulmonary parenchyma. Because the nasal airway may also be a prime target for many inhaled toxicants, it is important to understand the comparative aspects of nasal structure and function among laboratory animals commonly used in inhalation toxicology studies, and how nasal tissues and cells in these mammalian species may respond to inhaled toxicants. The surface epithelium lining the nasal passages is often the first tissue in the nose to be directly injured by inhaled toxicants. Five morphologically and functionally distinct epithelia line the mammalian nasal passages-olfactory, respiratory, squamous, transitional, and lymphoepithelial-and each nasal epithelium may be injured by an inhaled toxicant. Toxicant-induced epithelial lesions in the nasal passages of laboratory animals (and humans) are often site-specific and dependent on the intranasal regional dose of the inhaled chemical and the sensitivity of the nasal epithelial tissue to the specific chemical. In this brief review, we present examples of nonneoplastic epithelial lesions (e.g., cell death, hyperplasia, metaplasia) caused by single or repeated exposure to various inhaled chemical toxicants. In addition, we provide examples of how nasal maps may be used to record the character, magnitude and distribution of toxicant-induced epithelial injury in the nasal airways of laboratory animals. Intranasal mapping of nasal histopathology (or molecular and biochemical alterations to the nasal mucosa) may be used along with innovative dosimetric models to determine dose/response relationships and to understand if site-specific lesions are driven primarily by airflow, by tissue sensitivity, or by another mechanism of toxicity. The present review provides a brief overview of comparative nasal structure, function and toxicologic pathology of the mammalian nasal epithelium and a brief discussion on how data from animal toxicology studies have been used to estimate the risk of inhaled chemicals to human health.
An ex vivo model of the rat trachea to study the effect of inhalable toxic compounds
Research in experimental medicine. Zeitschrift für die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie, 1996
Different cell culture and organ systems are used to evaluate the physiological responses of the airways to the effects of carcinogenic [e.g., benzo(a)pyrene] and anticarcinogenic (e.g., retinoids) compounds on cellular growth and differentiation. However, in contrast to in vivo conditions dissociated epithelial cells or tracheal ring cultures are covered with medium. Therefore, we developed an ex vivo perfusion model enabling evaluation of morphology and metabolism of different compounds under near-physiological conditions. The trachea was surrounded with culture medium and perfused with air by means of a small animal respirator. To test the viability of the system under various experimental conditions tracheal probes were incubated with either retinoids (retinol 10(-5) mol/l; retinyl palmitate 10(-5) mol/l) or benzo(a)pyrene (10(-7) mol/l) for up to 7 days. At the end of the incubation period metabolites in the trachea and in the medium were measured by means of high-performance l...
Comparative Pathology of the Nasal Mucosa in Laboratory Animals Exposed to Inhaled Irritants
Environmental Health Perspectives, 1990
The nasal cavity is susceptible to chemically induced iinjury as a result of exposure to inhaled irritants. Some responses of the nasal mucosa to inhaled toxicants are species specific. These species-related differences in response may be due to variations in structural, physiologic, and biochemical factors, such as gross nasal cavity structure, distribution of luminal epithelial cell populations along the nasal airway, intranasal airflow patterns, nasal mucociliary apparatus, and nasal xenobiotic metabolism among animal species. This paper reviews the comparative anatomy and irritant-induced pathology of the nasal cavity in laboratory animals. The toxicologist, pathologist, and environmental risk assessor must have a good working knowledge of the similarities and differences in normal nasal structure and response to injury among species before they can select animal models for nasal toxicity studies, recognize toxicantinduced lesions in the nasal airway, and extrapolate experimental results to estimate the possible effects of an inhaled toxicant on the human nasal airway.