In Vivo Effects of Endotoxin on Nasal Epithelial Mucosubstances: Quantitative Histochemistry

Harkema, Jack R.; Hotchkiss, Jon A.

doi:10.3109/01902149109062876

Cited by 105 publications

(128 citation statements)

References 19 publications

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“…The number of airway mucous cells and the volume of intraepithelial stored mucosubstances were quantified as described (18). In all cases, both methods of quantification for MCH showed similar results, indicating that increases were due to MCH and not only enlargement of existing mucous cells.…”

Section: Histopathological Evaluationmentioning

confidence: 99%

STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-γ

Stout

Melendez

Seagrave

et al. 2007

The Journal of Immunology

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Disruption of the normal resolution process of inflammation-induced mucous cell hyperplasia may lead to sustained mucous hypersecretion in chronic diseases. During prolonged exposure of mice to allergen, IFN-γ reduces mucous cell hyperplasia, but the signaling responsible for the cell death is largely unknown. A brief phosphorylation of STAT1 by IFN-γ was required for cell death in airway epithelial cells (AEC), and during prolonged exposure to allergen, mucous cell hyperplasia remained elevated in STAT1−/− but was resolved in STAT1+/+ mice. Although IFN-γ treatment of primary human AECs and other airway cell lines left Bax protein levels unchanged, it caused translocation of Bax from the cytosol to the endoplasmic reticulum (ER) but not to the mitochondria. Localization of Bax to the ER was observed in IFN-γ-treated primary AECs isolated from STAT1+/+ mice but not in cells from STAT1−/− mice. In addition, ER Bax was detected in mucous cells of STAT1+/+ but not STAT1−/− airways of mice exposed to allergen for prolonged periods. IFN-γ did not release cytochrome c from mitochondria but reduced ER calcium stores and dilated the ER, confirming that the IFN-γ-induced cell death is mediated through changes localized in the ER. Collectively, these observations suggest that STAT1-dependent translocation of Bax to the ER is crucial for IFN-γ-induced cell death of AECs and the resolution of allergen-induced mucous cell hyperplasia.

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Section: Histopathological Evaluationmentioning

confidence: 99%

STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-γ

Stout

Melendez

Seagrave

et al. 2007

The Journal of Immunology

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“…Ozone exposure (0.8 ppm, 6 hr/day for 7 days), for example, induced hyperplastic lesions in TE of rats on the lateral wall and turbinates, but the RE along the adjacent septum had no lesions (19). Although only a few nasal irritant studies using nonhuman primates have been reported (1,2,36), results from these experiments indicate that irritant lesions are also common in the anterior aspects of the nasal cavity covered by TE, but are usually distributed on both the septal and lateral walls. they did have deciliation along the walls of the more distal nasopharynx (19).…”

Section: Nasal Epithelial Populationsmentioning

confidence: 99%

Comparative Pathology of the Nasal Mucosa in Laboratory Animals Exposed to Inhaled Irritants

Harkema¹

1990

Environmental Health Perspectives

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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.

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“…In 1992 we demonstrated that intranasal instillation of endotoxin causes significant alterations in the mucous apparatus lining axial pulmonary airways of rats (37). Specifically, increases in stored mucosubstances, secretory cell hyperplasia, and secretory cell metaplasia occurred in the respiratory epithelium of airways that normally consist of ciliated and secretory cells.…”

Section: Ozone Enhancement Of Endotoxininduced Mucous Cell Metaplasiamentioning

confidence: 99%

“…Instillation of endotoxin into the airways of laboratory rodents causes a similar inflammatory response to that observed in humans, including neutrophil infiltration and cytokine production. We have further documented some structural and cellular changes in the airways of laboratory rodents elicited by intranasal instillation (36)(37)(38) and aerosolized endotoxin (39). Among these are epithelial cytotoxicity, hyperplasia, and increased synthesis, storage, and secretion of products by airway secretory cells.…”

Section: Airborne Bacterial Endotoxinmentioning

confidence: 99%

“…A robust migration of neutrophils is an early response elicited by instilled and aerosolized endotoxin, and the oxidant and proteolytic potential of activated neutrophils have been implicated in epithelial cell alterations in endotoxin-treated airways (63,64). Furthermore, we have used endotoxin-instilled animals to document epithelial cell changes such as hyperplasia and metaplasia in the respiratory epithelium, which normally consists of some secretory cells (36,37). As mentioned previously, endotoxin does not cause mucous cell metaplasia in rat NTE.…”

Section: Endotoxin Enhancement Of Ozoneinduced Mucous Cell Metaplasiamentioning

confidence: 99%

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Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

Wagner

Hotchkiss

Harkema

2001

Environ Health Perspect

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Tropospheric ozone is the major oxidizing component in photochemical smog and is one of the most pervasive problems to human health of the criteria air pollutants for which the National Ambient Air Quality Standards have been designated by the Clean Air Act. Although many adverse health effects of ozone exposure have been documented in both humans and laboratory animals, controversy surrounds the establishment and implementation of ozone standards set forth by the U.S. Environmental Protection Agency. Because people are commonly exposed to more than one air pollutant at a time, studies that examine coexposures to airborne materials may be more relevant for assessing their risks to human health. Airborne biogenic substances such as pollens, spores, and bacterial products are ubiquitous in the environment, and when inhaled can cause adverse respiratory symptoms. One such biogenic agent, bacterial endotoxin, is a potent stimulus of airway inflammation and is a ubiquitous airborne contaminant commonly found in domestic, agricultural, and industrial settings. Little is known about the interaction of exposures to biogenic substances and criteria air pollutants such as ozone. In the last few years we have performed a series of studies in rodents that examined the biologic responses of the respiratory epithelium after airway exposures to both endotoxin and ozone. When exposed to ozone (0.5 ppm 8 hr/day for 3 days), Fischer rats develop lesions in the nasal transitional epithelium, whereas intranasal instillation of endotoxin (20 microg) elicits epithelial lesions in the respiratory epithelium of the nose and conducting airways. Our studies were designed to examine how exposure to one toxicant may affect the airway epithelial lesions induced by the other toxicant. We investigated the potential role of acute inflammation in the enhancement of airway epithelial lesions after exposure of these two toxicants in neutrophil-sufficient and neutrophil-deficient rodents. A summary of these results indicates that epithelial and inflammatory responses to coexposure of these two pollutants are greater than those elicited by either agent alone. Interestingly, each toxicant enhances the epithelial alterations induced by the other. Furthermore, the synergistic effects elicited by coexposure to ozone and endotoxin are mediated partly by neutrophils. These studies provided some new insights into how inhaled co-pollutants interact to initiate and promote alterations of airway epithelium. Further studies with these and other air pollutants will help define their true risk to human health.

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In Vivo Effects of Endotoxin on Nasal Epithelial Mucosubstances: Quantitative Histochemistry

Cited by 105 publications

References 19 publications

STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-γ

STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-γ

Comparative Pathology of the Nasal Mucosa in Laboratory Animals Exposed to Inhaled Irritants

Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

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