The Respiratory Epithelium

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Seeretory leukocyte protease inhibitor Elafin Colony-stimulating factors G-CSF 

Eosinophil peroxidase Neutrophil elastase Mast eell tryptase Cytokines Nitrie oxide 

Bordetella pertussus (e.g., tracheal toxin) Haemophilus influenzae (e.g., endotoxin) Pseudomonas aeruginosa (e.g., nitrite reductase) 

Influenza virus A Respiratory syncytial virus Adenovirus Fungi 

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ENaC is located in the apical membrane of polarized epithelial cells where it mediates Na+ transport across tight epithelia [3], The most important tight epithelia expressing ENaC include the distal nephron of the kidney, the respiratory epithelium, and the distal colon. The basic function of ENaC in polarized epithelial cells is to allow vectorial transcellular transport of Na+ ions. This transepithelial Na+ transport through a cell involves... 

W. Schurch, H.C. Kaiser and C.C. Harris, The Respiratory Epithelium IV. Histogenesis of Epidermoid Metaplasia and Carcinoma in Situ in the Human, J. Nat 1. Cancer Inst. 61 563-575 (1978). 

Exposure to hexachloroethane vapors can cause irritation to the respiratory system. Acute exposure to 260 ppm hexachloroethane had no apparent effect on the lungs and air passages in rats, but acute exposure to a concentration where particulate hexachloroethane was present in the atmosphere caused lung irritation (Weeks et al. 1979). On the other hand, intermediate-duration exposure to 260 ppm hexachloroethane appeared to cause some irritation of the respiratory epithelium, which may have increased susceptibility to respiratory infection. When exposure ceased, the animals recovered, so there were no histopathological indications of tissue damage after a 12-week recovery period. Lesions of the nasal passages, trachea, and bronchi increased mycoplasma infections mucus in the nasal cavities and decreased oxygen consumption were indicators of respiratory tract irritation from repeated episodes of hexachloroethane exposure. 

There was an increased incidence of a mycoplasma respiratory tract infection in rats exposed to 260 ppm hexachloroethane for 6 weeks but not in rats exposed to lower doses or in other species. This could indicate compromised immune function or a weakened mucosal barrier along the respiratory epithelium. There were no studies identified that evaluated a wide range of immunological parameters. Therefore, there are no reliable LOAELs or NOAELs for this end point. Increases in spleen weights are not classified as LOAELs since they were not accompanied by histopathological changes. 

Excess mucus in the nasal turbinates, irritation of the epithelium, and increased incidence of a mycoplasma respiratory infection were seen in rats with inhalation exposure to 260 ppm for 6 weeks and in pregnant rats with inhalation exposure to 48 ppm for 11 days. Pulmonary irritation was also present in pregnant rats treated with an oral dose of 500 mg/kg/day for 11 days (Weeks et al. 1979). Effects on the respiratory epithelium were not apparent in the tissue of the lungs, nasal cavity, nasal turbinates, larynx, trachea, or bronchi based on histopathological examination (NTP 1977, 1989 Weeks et al. 1979). Exposure to... 

An advantage of using the fluid-filled lung is the accuracy of dosimetry and the even distribution of solute throughout the lung. This ensures that permeability is measured across the entire area of the respiratory epithelium. A concern, however, is that the IPL in which the airspaces are flooded with the donor solution may suffer distension of the epithelium leading to increased permeability. 

McDowell EM, Barrett LA, Glavin F, Harris CC, Trump BF (1978) The respiratory epithelium. I. Human bronchus. J Natl Cancer Inst 61(2) 539-549. 

Radioactivity from " C-labeled chloroform was detected in the placenta and fetuses of mice shortly after inhalation exposure (Danielsson et al. 1986). In early gestation, accumulation of radioactivity was observed in the embryonic neural tissues, while the respiratory epithelium was more involved in chloroform metabolism in the late fetal period. 

In experimental animals the respiratory system is a primary target of acrolein exposure after inhalation, and there is an inverse relationship between the exposure concentration and the time it takes for death to occur." Inhalation LCso values of 327ppm for 10 minutes and 130ppm for 30 minutes have been reported in rats." Of 57 male rats, 32 died after exposure to 4 ppm for 6 hours/day for up to 62 days. Desquamation of the respiratory epithelium followed by airway occlusion and asphyxiation is the primary mechanism for acrolein-induced mortality in animals." Sublethal acrolein exposure in mice at 3 and 6 ppm suppressed pulmonary antibacterial defense mechanisms. A combination of epithelial cell injury and inhibition of macrophage function may be responsible for acrolein-induced suppression of pulmonary host defense. ... 

Inhalation of 7 ppm for 6 hours/day caused necrosis and complete erosion of nasal mucosa after 4 days squamous metaplasia of the respiratory epithelium and focal erosion of the olfactory epithelium with evidence of regeneration of some epithelial surface occurred in mice after 9-14 days at this exposure level." Rats and mice exposed to concentrations as low as 4 ppm for 13 weeks had squamous metaplasia, hyperplasia, and inflammation of the nasal mucosa. ... 

In mice exposure to 9 ppm caused a 50% decrease in respiratory rate. Lesions included ulceration and necrosis of the respiratory epithelium and moderate damage to lung tissue. Rats administered, via oral gavage, 10, 20, 40, or 80mg/kg for 10 consecutive days or 32 mg/kg for 90 consecutive days had inflammation, necrosis, acantholysis, hyperkeratosis, and epithelial hyperplasia of the forestomach. Chloropicrin was genotoxic in bacterial test systems."... 

Sneezing, tearing, reddened nose, and lesions of the nasal mucosa were observed in rats exposed at 200ppm for 6.5 hours/day, 5 days/week for 24 weeks. Histopathologic examinations showed squamous metaplasia, suppurative rhinitis, and lymphoid hyperplasia of the respiratory epithelium. 

Oronasal exposure of mice to 2.6ppm led to a 50% decrease in respiratory rate. Mice exposed at 0.3, 1.0, and 2.6ppm 6 hour/day for 4, 9, and 14 days had lesions of the respiratory epithelium including squamous metaplasia, focal necrosis, and keratin exudate that were dose dependent at the lower exposure levels. Lesions persisted 2 weeks after exposure but were decreasing 4 weeks after the end of exposure. No exposure-related lesions were observed in the lungs of exposed mice. 

There was no evidence of carcinogenicity in rats or mice exposed to 0.01, 0.05, or 0.2 ppm for 6 hours/day for 2 years. Pigmentation of the respiratory epithelium occurred in both species, and squamous metaplasia of the laryngeal epithelium occurred in female rats. Geno-toxic assays have been uniformly negative. 

Nasal tumors were induced in rats by inhalation exposure to HMPA for 6-24 months at levels of 50, 100, 400, and 4000 ppb, 6 hours/ day, 5 days week, but not in rats exposed to 10 ppb for 24 months. Most nasal mmors were epidermoid carcinomas and developed from the respiratory epithelium or subepithelial nasal glands, both of which revealed squamous metaplasia or dysplasia in the anterior nasal cavity. 

Two-year inhalation studies (6 hours/day, 5 days/week for 103 weeks) in rodents showed clear evidence of carcinogenicity. Mice exposed at 375 and 750ppm had increased incidences of harderian gland adenomas and carcinomas female mice exposed at 188 and 750 ppm had increased liver neoplasms female rats in the 188 and 375ppm-exposed groups had increased incidences of mammary gland fibroadenomas and carcinomas. Other treatment-related effects were an increase in nasal lesions and degeneration of the respiratory epithelium in mice. 

Vitamin A is essential for growth and development of cells and tissues. In its active form, retinoic acid (RA), it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Biesalski, 1996 Biesalski et al, 1999). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin A deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin A supplementation (Biesalski et ah, 2001 Greenberg et ah, 1997 John et ah, 1997). 

On the basis of a few reports, it is assumed that a "local vitamin A deficiency exists in meta- and dysplastic areas. Measurements of vitamin A concentrations in metaplastic areas of the respiratory epithelium and the cervix epithelium actually proved that vitamin A in comparison to the surrounding tissues was not found (Biesalski, 1996). Clearly one cannot say what is cause and effect. Studies carried out by Edes et al. (1991) confirm an induction of a vitamin A deficit. These studies showed that a depletion of vitamin A ester stores is caused by toxins, present in cigarette smoke (predominantly polyhalogenated compounds), in different tissues. 

By inhalative application of vitamin A, an accumulation of peripheral vifamin A stores is achieved. For the Irmg and the respiratory epithelium, concentrations in the range of 1-20 (ig/g were obtained (Biesalski, 1990). Looking at quantitative concentrations in the respiratory epithelium and in the mixed epithelium of the nasal mucosa yielded an accumulation of vifamin A — after topical administration in different animal species — in the epithelium of the nose increased by factor 10-100 (in human of factor 5-20) compared to the concentrations of the respiratory mucosa (Lewis, 1973). 

It should be elucidated to what extent the "topical" application of retinyl esters on the respiratory epithelium, especially with BDP, can contribute to the replenishment of the lung stores and thus leading to the improvement of the clinical outcome. 

Vitamin A deficiency is worldwide one of the most prevalent nutrition-dependent deficiency diseases. It leads to changes of the respiratory epithelium, which result in repeated infections of the respiratory tract, the main cause of death in vitamin A-deficient children. The difficulty in supplying the respiratory epithelium with vitamin A is that the affected children frequently suffer as well from infections of the gastrointestinal tract with subsequent reduction of the absorption of fat-soluble vitamins. Nutritargeting can in these cases avoid the problems of malabsorption and ensure the micronutrient supply. 

Data are insufficient for derivation of an acute inhalation MRL for nickel because a less-serious LOAEL was not identified for the most toxic nickel compound, nickel sulfate. In an acute study (exposure 12/16 days), the lowest concentration of nickel sulfate studied (0.8 mg nickel/m ) resulted in labored breathing, pneumonia, degeneration of the respiratory epithelium, atrophy of the olfactory epithelium, and a 28% decrease in body weight gain (Benson et al. 1988 Durmick et al. 1988 NTP 1996c). 

Kotin, P., H. L. Falk, and G. J. McCammon, The Experimental Induction of Pulmonary Tumors and Changes in the Respiratory Epithelium in C57B1 Mice Following Their Exposure to an Atmosphere of Ozonized Gasoline, Cancer, 11, 473-481 (1958). 

In a two-year inhalation study, male and female Fischer 344/N rats and B6C3Fi mice (six weeks of age) were exposed to 0, 94, 188 or 375 ppm [0, 235, 470 or 938 mg/m ] and 0, 188, 375 or 750 ppm [0, 470, 938 or 1875 mg/m ] nitromethane, respectively, for 6 h per day on five days per week for 103 weeks. Non-neoplastic lesions that developed with increased incidence included nasal lesions with degeneration and metaplasia of the olfactory epithelium and degeneration of the respiratory epithelium in male and female mice (National Toxicology Program, 1997). 

Male and female Fischer 344 rats and B6C3Fi mice were exposed to 0, 10,30,90 or 150 ppm [0, 45, 136, 409 or 681 mg/m ] technical grade 1,3-dichloropropene (cis, 48.6% trans, 42.3%) vapours for 6 h per day on five days per week for 13 weeks (Stott et al., 1988). At the end of the exposure, slight degeneration of the nasal olfactory epithelium and mild hyperplasia of the nasal respiratory epithelium were observed in rats exposed to 150 ppm 1,3-dichloropropene. All male and female Fischer 344 rats exposed to 90 or 150 ppm and two of the 10 rats exposed to 30 ppm 1,3-dichloropropene exhibited minimally detectable hyperplasia of the respiratory epithelium. Exposure to 90 or 150 ppm 1,3-dichloropropene also produced diffuse, moderate hyperplasia of the olfactory epithelium in female B6C3Fi mice. 

Biomarkers of Disease. No biomarkers are known that are specific for BCME-induced lung injury. Standard chemical examination of nose and throat can provide an index of local irritation, and examination of sputum for abnormal cell types can provide information on the state of the respiratory epithelium. However, these tests cannot distinguish BCME-induced effects from effects caused by smoking or exposure to other chemicals, and can only discover changes after damage to the tissue has already occurred. Continued efforts to devise more sensitive and more specific early biomarkers of disease (especially lung cancer) would be valuable. 

Hillery, E., Cheng, S.H., Geddes, D.M. and Alton, E. (1999) Effects of altering dosing on cationic hposome-mediated gene transfer to the respiratory epithelium. Gene Ther., 6, 1313-1316. 

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