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H Witschi

Publications and source records attributed to H Witschi.

At least 55 records · Page 3Linked to original sources
PubMed1994

Ozone, NO, and NO2: oxidant air pollutants and more.

This article reviews the acute and chronic toxicity of the three oxidant air pollutants ozone, nitric oxide (NO), and nitrogen dioxide (NO2). The toxicity of binary mixtures of NO2 with other inhaled agents is also discussed. Newer studies are emphasized, especially those published in the last 5 years or still in press. Very recent data from our laboratory that suggest a new cellular mechanism of importance in lung injury in animals exposed to mixtures of ozone and NO2 that may have general relevance with regard to the effects of oxidant air pollutants on the lung are also presented.

Air Pollutants↗
PubMed1993

Airway epithelial labeling index as an indicator of ozone induced lung injury.

Rats were implanted subcutaneously with a bromodeoxyuridine-filled minipump and then were exposed to ozone delivered at a low dose rate (0.4 ppm during 12 h per night) or at a high dose rate (0.8 ppm during 6 h per night). Three and 7 days after pump implantation the cumulative labeling indices were measured in the alveolar zone and in the airways. Greater alveolar labeling indices were observed 7 days after implantation of the minipumps than after 3 days in all groups, but no ozone-related changes were found in the alveoli of rats in either experimental group at either time. After 3 or 7 days, the labeling index in the large intrapulmonary airways and in the terminal bronchioli of the rats exposed to the higher dose rate (0.8 ppm) was increased. In rats exposed to the lower dose rate (0.4 ppm) the labeling index was significantly elevated in the terminal bronchioli after 3 days and in both the terminal bronchioli and large intrapulmonary airways after 7 days. In the terminal bronchioli the extent of cell proliferation appeared to be defined by dose rate rather than by cumulative exposure. It is concluded that measurement of the airway labeling index is a sensitive indicator of the response of the rat lung to acute exposure to ozone.

Animals↗
PubMed1993

Modulation of N-nitrosodiethylamine-induced hamster lung tumors by ozone.

Male Syrian Golden hamsters were treated with subcutaneous injections of N-nitrosodiethylamine (DEN), 20 mg/kg, twice a week for 24 weeks. Half the animals were kept in filtered air and the other half was exposed continuously to an atmosphere of 0.8 ppm of ozone. After 6 months, no more DEN injections were given and all animals were kept in air until termination of the experiment at 7 months. It was found that the animals kept in ozone developed half as many peripheral lung tumors as did the animals kept in air; however, the difference was not statistically significant. Tumors of the trachea, bronchi, nasal cavity and liver developed with the same incidence whether the animals were exposed to ozone or not. It was concluded that ozone, an agent known to produce cell proliferation in the respiratory tract, does not enhance the development of tumors in the peripheral lung or in the nasal cavity of hamsters.

Administration, Inhalation↗
PubMed1993

Alveolar and airway cell kinetics in the lungs of rats exposed to nitrogen dioxide, ozone, and a combination of the two gases.

Rats carrying minipumps filled with 5-bromo-2'deoxyuridine were exposed to ozone, NO2, or a mixture of the two gases using four different protocols: (A) ozone 0.2 ppm, NO2 3.6 ppm, or their mixture for 24 hr a day; (B) ozone 0.2 ppm, NO2 7.2 ppm, or their mixture for 12 hr per night; (C) ozone 0.6 ppm, NO2 10.8 ppm, or their mixture for 8 hr per night; and (D) ozone 0.8 ppm, NO2 14.4 ppm, or their mixture for 6 hr per night. After three consecutive daily exposures, the animals were returned to filtered air and killed 7 days after implantation of the minipump. Alveolar labeling indices were comparable to control values except in the group of animals exposed for 6 hr nightly to a combination of 0.8 ppm of ozone and 14.4 ppm of NO2. Labeling indices in the peripheral airways were the most sensitive exposure index since they were significantly increased over control values in all animals exposed to ozone, NO2, or a mixture of the two gases, regardless of concentration or exposure duration. Labeling indices increased with elevated dose rate, i.e., concentration of the gases in the inspired air. The response to the combined gases was greater than the calculated sum of the responses to the two individual gases for the three higher dose rates in the large airways and for the highest dose rate in the peripheral airways. The results led to the following conclusions: (1) By the criterion of analysis of cell kinetics in rat large and peripheral airways, neither ozone, NO2, nor their mixture follows Haber's law (c x t = k) over the concentration ranges studied; and (2) at the higher dose rates studied, there is a more than additive (synergistic) airway response to the combination of ozone and NO2.

Animals↗
PubMed1993

K-ras and p53 point mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced hamster lung tumors.

Lung tumors were induced in Syrian golden hamsters by s.c. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). After 40 weeks lung tumor tissue was isolated. Administration of the NNK and exposure of the animals to an atmosphere of 65% oxygen resulted in a statistically significant reduction in tumor size but did not alter the histological tumor type or tumor incidence when compared with carcinogen treated animals maintained under ambient air. Histologically, lung tumors had the morphologic features of adenomas and adenocarcinomas with approximately 15% being squamous cell carcinomas. Lung tumors were examined for mutations in the Ki-ras oncogene and the p53 tumor suppressor gene by direct sequencing. The Ki-ras mutation frequency in RNA isolated from pooled tumors and in DNA isolated from individual tumors were found to be identical. Activated Ki-ras alleles were detected in 77-94% of tumors. All mutations observed (from a total of 65) except one were GC-AT. The Ki-ras mutations resulted in amino acid substitutions at either codons 12 or 13. No mutations were detected at the 61st codon. Examination of the same tumors for p53 mutations showed only one point mutation. We conclude that the NNK treatment in Syrian golden hamsters results in a distinctive mutation pattern in the Ki-ras gene whereas p53 gene mutations may not play a major role at this stage in hamster lung tumorigenesis.

Animals↗
PubMed1993

A new model of progressive pulmonary fibrosis in rats.

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

Administration, Inhalation↗
PubMed1993

Cationized Bowman-Birk protease inhibitor as a targeted cancer chemopreventive agent.

The conjugate of the Bowman-Birk inhibitor (BBI) with poly(D-lysine) (PDL-ss-BBI) has been suggested as a lung-targeted anti-carcinogenic agent. The authors demonstrate that PDL-ss-BBI, given i.p., reduces the tumor number in the lungs of 3-methylcholanthrene treated mice (61-71% compared to control group) in a dose-dependent manner, but is toxic to the treated animals at a high dosage. In order to develop a better lung-targeted anti-carcinogenic agent, spermine-conjugated BBI (spermine-BBI) was synthesized by coupling BBI to spermine through amide bonds using a carbodiimide-mediated reaction. Results from in vitro transformation assays demonstrated that spermine-BBI was at least as effective as BBI in reducing the transformation yield in C3H10T1/2 cells. When injected intravenously into mice [125I]spermine-BBI accumulated to a greater extent in the lungs and the liver compared to BBI. The in vitro cytotoxicity of spermine-BBI in C3H10T1/2 cells was 30-fold less than that of PDL-ss-BBI. These results suggest that spermine-BBI is likely to be an improved cancer chemopreventive agent compared to BBI or PDL-ss-BBI.

Animals↗
PubMed1993

Failure of ozone and nitrogen dioxide to enhance lung tumor development in hamsters.

We tested the hypothesis that the two common oxidant air pollutants, ozone and nitrogen dioxide, modulate the development of respiratory tract tumors in Syrian golden hamsters. The animals received subcutaneous injections of the carcinogen diethylnitrosamine (20 mg/kg) twice a week while being exposed continuously to an atmosphere of 0.8 parts per million (ppm)* of ozone or 15 ppm of nitrogen dioxide. Animals were killed 16 weeks or 24 to 32 weeks after the beginning of the treatment. Ozone delayed the appearance of tracheal tumors and reduced the incidence of tumors in the lung periphery. A suspected neuroendocrine differentiation of those lung tumors could not be established by immunocytochemistry due to overfixation of tissues. On the other hand, ozone seemed to mitigate development of hepatotoxic lesions mediated by diethylnitrosamine. In animals treated with diethylnitrosamine and exposed to nitrogen dioxide, fewer tracheal tumors and no lung tumors were found. Only a few lung tumors were produced in animals treated with diethylnitrosamine and kept in an atmosphere of 65% oxygen. The previously observed neuroendocrine nature of tumors induced by simultaneous exposure to diethylnitrosamine and hyperoxia could not be established because the long fixation of tissues precluded immunocytochemical stains. Animals treated with diethylnitrosamine and kept in filtered air while being housed in wire-mesh cages developed fewer lung tumors than animals given the same treatment and kept on conventional bedding in shoebox cages. Although all inhalants tested are known to produce substantial cell proliferation in the respiratory tract, it was not possible to document whether this would enhance lung tumor development. The role of the two common air pollutants, ozone and nitrogen dioxide, as possible additional risks in the pathogenesis of lung cancer in animals continues to remain uncertain.

Animals↗
PubMed1992

Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis.

In human lung cancers, alterations of both a dominant oncogene (ras) and a tumor suppressor gene (p53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki-ras-2 and p53 genes from Syrian golden hamsters. The PCR products were confirmed by predicted-size analysis, probing with nonradioactive (biotin-labeled) oligonucleotides, and direct sequencing. Lung tumors were produced in hamsters by repeated injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Of six tumors examined, three (50%) had mutations in codon 12 of Ki-ras. Examination of the conserved regions of p53 revealed no mutations. We conclude that NNK-induced carcinogenesis in the hamster results in characteristic alterations of Ki-ras but may not necessarily involve the p53 gene.

Animals↗
PubMed1992

Synergistic interaction of nitrogen dioxide and ozone on rat lungs: acute responses.

Rats were exposed for 6 hr per day to either ozone alone (0.2-0.8 ppm), nitrogen dioxide (NO2) alone (3.6-14.4 ppm), or to combinations of these two oxidant air pollutants. Their response was quantified by changes in the total protein content of lung lavage supernatants or by changes in the content of specific cell types in the lung lavage pellets. A concentration-dependent synergistic response was observed when rats were exposed to the combination of ozone and NO2. Apparent threshold concentrations for the observation of synergistic interaction between ozone and NO2 were assay specific, with epithelial cell content of lung lavage fluid being the most sensitive parameter evaluated, showing positive interaction (greater than additive response) at the lowest concentrations tested. Concurrent exposure to ozone and NO2 was necessary to elicit greater than additive responses; no such interactions were seen upon sequential exposure to ozone or NO2 in either order of presentation. Based upon apparent disappearance rates of ozone in the chambers during exposure of rats to ozone and NO2, we modelled the predicted outcomes based upon the assumption that the two oxidant gases were reacting to form nitrogen pentoxide (N2O5) in the chambers. Agreement between predicted concentrations of ozone and NO2 and those actually observed was excellent. Based upon such modelling estimates and our acute toxicological data, we conclude that synergistic toxicologic interactions between ozone and NO2 are found only at concentrations very much higher than would be encountered in environmental or occupational settings. It remains to be determined whether there are any chronic toxicological responses to exposure to combinations of ozone and NO2 at concentrations below the thresholds for observing acute responses.

Administration, Inhalation↗
PubMed1992

Concentration-response relationships of rat lungs to exposure to oxidant air pollutants: a critical test of Haber's Law for ozone and nitrogen dioxide.

Exposure protocols were designed to ask whether lung damage in rats exposed to either ozone or nitrogen dioxide is proportional to dose rate or to cumulative dose. Thus, the response of rats to a constant product of concentration of oxidant air pollutant and time of exposure (C x T) was evaluated for 3-day exposures over a fourfold range of concentrations of ozone (0.2-0.8 ppm) or of nitrogen dioxide (3.6-14.4 ppm) for exposure durations of 6-24 hr per day. The response of rat lungs was quantified by changes in total protein content of lung lavage supernatants or by changes in content of specific cell types in lung lavage pellets. The results of these experiments clearly demonstrate that acute lung damage is a function of cumulative dose (that is, C x T product) for the three highest dose rates tested. However, when exposure duration is extended to include the entire 24-hr period (the lowest dose rate tested), there is a marked attenuation of pulmonary response. Rats were also exposed to mixtures of ozone and nitrogen dioxide with the C x T product held constant. Our results clearly demonstrate that when rats are exposed to combinations of ozone and nitrogen dioxide, lung damage is a function of peak concentration rather than a function of cumulative dose. This deviation from Haber's Law is attributed to a concentration-dependent, synergistic (greater than additive) response to this specific mixture of oxidant air pollutants.

Administration, Inhalation↗
PubMed1991

Diffuse and continuous cell proliferation enhances radiation-induced tumorigenesis in hamster lung.

Syrian Golden hamsters received 8 weekly intratracheal instillations of 0.2 microCi of the alpha-emitting isotope Po210 while being exposed to an atmosphere of 65% oxygen in the inspired air. Three months later, 42% of the animals had poorly differentiated lung carcinomas. On the other hand, no lung tumors were found in hamsters that received intratracheal instillations of Po210 and were kept in air. It is concluded that diffuse cell hyperplasia in the lung, caused by an inhalant, may constitute an additional risk factor in the pathogenesis of alpha-radiation induced lung cancer.

Animals↗
PubMed1991

Increased c-Ki-ras expression in hamster lung exposed to N-nitrosodiethylamine and hyperoxia as detected by the polymerase chain reaction.

Neuroendocrine lung cancers can be induced in hamsters within 8-12 weeks by combined exposure to N-nitrosodiethylamine (DEN) and hyperoxia. The expression of the c-Ki-ras gene in this lung cancer model was studied using polymerase chain reaction analysis of mRNA (RNA/PCR). We used four different groups of hamsters, exposed for 6 weeks to DEN with hyperoxia (60% oxygen), DEN, hyperoxia, or ambient air, respectively. Total RNA was isolated from lung tissues and cDNA made prior to PCR amplification. A 234-bp product was amplified from c-Ki-ras cDNA and quantitated using scanning laser densitometry. The data obtained were normalized to the expression of the house keeping gene B-actin. The c-Ki-ras products were present after amplification of all hamster lung RNA samples. The hamster lungs exposed to DEN with hyperoxia displayed higher c-Ki-ras protooncogene expression than hamsters exposed to DEN, hyperoxia, or ambient air alone. Since the animals studied were sacrificed at 6 weeks, prior to the appearance of tumors, we conclude that this increased expression may indicate a role for c-Ki-ras in the initial steps in malignant transformation of neuroendocrine cells.

Animals↗
PubMed1991

Acute effects of the Bowman-Birk protease inhibitor in mice.

The soybean-derived Bowman-Birk inhibitor (BBI) has been shown to inhibit carcinogenesis in both in vitro and in vivo model systems. In the present study, protease enzyme activity in selected tissues of male strain A mice was measured by hydrolysis of the synthetic substrate Boc-Val-Pro-Arg-MCA (t-butoxycarbornylvalylprolylarginine 7-amido-4-methylcoumarin). When added to homogenates of lung, liver and kidney in vitro, purified BBI inhibited hydrolytic activity at concentrations ranging from 10-100 microM. In vivo, hydrolytic activity was found to be significantly and in a dose-dependent manner, decreased in the lung as early as 2 h after i.p. injection of purified BBI. Less inhibition was found in the liver and kidney after in vivo administration of purified BBI. A crude preparation of BBI, given at 100 mg/kg, had no influence on the overall disposition of radiolabeled benzo[alpha]pyrene in mice although it decreased the hepatic activities of cytochrome P-450, 7-ethoxycoumarin-O-deethylase and ethoxy resorufin-O-deethylase. It is concluded that the chemopreventive effects of BBI on mouse lung tumor development are most likely mediated through its protease-inhibitory properties in the target organ rather than by a non-specific effect on metabolism and disposition of carcinogens.

Amino Acid Sequence↗
PubMed1990

Responses of the lung to toxic injury.

Analysis of toxic lung damage may focus on the offending agent and define patterns of bioactivation and interactions with the target tissues. It may also focus on a study of the biological response. While it was originally thought that cell proliferation, particularly Type II epithelial cell proliferation following lung injury, was a common event, it now has become obvious that on occasion proliferation occurs only late after the initial lung damage. Also Type II cell proliferation can occur in the absence of alveolar Type I cell damage. Delayed reepithelialization of the alveolar surface may lead to pulmonary fibrosis. Toxicological interactions often can be best recognized and defined by the extensive lesions that result from concomitant or sequential exposure to such toxic agents as ozone and acidic aerosols or anticancer drugs and oxygen. A correlation of cell proliferation and tumor development in mouse lung has shown that target cell hyperplasia is not a necessary prerequisite for enhanced tumor development. On the other hand, oxygen-induced proliferation of the neuroendocrine cell population results in the short-term development of neuroendocrine lung cell cancer in hamsters. While it is possible to draw some conclusions from an analysis of the lung response to toxic injury, predictions made from such knowledge are sometimes, but not necessarily always, correct.

Animals↗