P. Nettesheim

Effect of Nitrogen Dioxide on Pulmonary Bacterial Defense Mechanisms

Effect of nitrogen dioxide on antibacterial activity in vivo was investigated by simultaneously determining physical removal and bactericidal activity rates of murine lung. Mice were exposed to various concentrations of nitrogen dioxide for 17 hours prior to or 4 hours after infection with aerosols of Staphylococcus aureus labeled with radioactive phosphorus (32P). Animals infected and then exposed to levels of nitrogen dioxide above 7.0 ppm showed a progressive decrease in percent pulmonary bactericidal activity which could not be accounted for by physical removal of bacteria. Exposure to levels of nitrogen dioxide of 2.3 ppm or greater for 17 hours prior to staphylococcal infection caused decreases in bactericidal activity. The finding that murine resistance to infection is diminished at exposure levels only slightly above ambient (2.3 ppm) suggests that human populations may incur a similar risk.

Tobacco smoke inhalation studies in rats

Abstract The feasibility of using rats in a bioassay for the effects of fresh tobacco smoke was investigated by a series of acute and long-term inhalation studies. Female SPF rats were exposed to 10% smoke from standard test cigarettes on an intermittent smoke machine. [ 14 C]dotriacontane was used as label for the smoke particles, and it was calculated that under the described exposure conditions 0.3-0.4 mg of total particulate matter was retained in the rats from exposure to the smoke of one cigarette. This is similar to the dose sustained by hamsters under identical conditions. It was found that respiratory minute volume is decreased to 25% of normal during smoke exposure. The great sensitivity of rats to smoke toxicity could be overcome by gradual adaptation. This made it possible to chonically expose rats to 7 and 10 cigarettes per day with a death rate of 10 and 20%, respectively, at 12 months, and of 18 and 53%, respectively, at 18 months of exposure. This represents a far better survival rate at high smoke exposure levels for rats (or hamsters) than has ever been reported in the literature. Smoke-induced pathological changes were observed in the respiratory tract only. These included mild focal hyperplasia of the upper airways, bronchiolitis of the terminal bronchioles, and severe focal alveolitis.

Reduced Immune Potential of Aged Mice Significance of Morphologic Changes in Lymphatic Tissue.

Summary Hemagglutinin responding capacity to sheep erythrocyte antigen in 3-year-old BC3F1 mice was approximately 10% of the response in normal young adult mice. The reduction in primary antibody-forming capacity was determined in aged animals that had no specific lesion of lymphatic tissue such as lymphoma, lymphosarcoma, suggesting that the reduction was primarily due to unspecific atrophy or degenerative changes. Results of splenectomy in the aged mice suggest that the spleen is the major source of immunological competence in the aged animals and that the reduced immune capacity in these mice is not due simply to failing spleen function.

Respiratory Cocarcinogenesis Studies with Ferric Oxide: A Test Case of Current Experimental Models

Laboratory studies conducted to date strongly suggest that ferric oxide dust can act as a cofactor in respiratory tract carcinogenesis. The available data indicate at least 2 different mechanisms by which these otherwise fairly innocuous particles might exert their effect: 1. by retarding carcinogen clearance (this applies to conditions in which the carcinogen is adsorbed to the particle surface) and 2. by causing cytopathological effects (irritation?, enhanced cell proliferation?) at the site of deposition.

Impairment of Deep Lung Clearance by Influenza Virus Infection

This paper reports experimentally observed effects of influenza virus infection on pulmonary clearance of chromic oxide dust tagged with chromium 51 (51Cr2O3). The usual course of this viral infection produces a stage of acute pneumonitis at 10 to 14 days after exposure, with subsequent, and often permanent, fibrotic scarring of the lung tissue. When 51Cr2O3 was administered simultaneously with, or at 1, 3, 5, 9, or 56 weeks after, virus inoculation, a marked deficiency in pulmonary clearance of the dust was noted. The distribution of retained chromium in the lungs of infected animals was found to depend on the relation between time of infection and time of 51Cr2O3 administration, a relationship which suggests that individuals with respiratory infections are at increased risk from exposure to toxic and radioactive particles.

Separation of multiple forms of protein-bound metabolites of the carcinogenic hydrocarbons 3-methylcholanthrene and 7,12-dimethylbenz- (a)anthracene from several rodent species.

Abstract Our findings demonstrate that the carcinogenic hydrocarbons 7,12-dimethylbenz[a] anthracene (DMBA) and 3-methylcholanthrene (3-MCA) bind in multiple forms to the proteins of skin and lung tissue. These metabolites are freed from the proteins by treatment with Raney nickel, thus, the metabolites are most likely bound through cysteine or homocysteine. The numbers and the relative quantities of the bound metabolites vary greatly among the Fischer rat, the Syrian golden hamster, and 3 mouse strains. It is possible that the metabolites (which indicate a particular pathway of metabolic activation) correlate with species susceptibility to hydrocarbon carcinogenesis.

Effect of immunosuppressive agents on retention of antigen in the mouse spleen.

Summary The effects of four immunosuppressive agents (X-ray, actinomycin D, cyclophosphamide, and cortisone acetate) on localization and retention of radioactive antigen in liver and spleen were studied. All four agents interfered with antigen retention by spleen and spleen germinal centers but not with that by the liver; this damage of splenic antigen retention was more easily induced when the insult was given before the test antigen. At the dose applied (500 mg/kg) cortisone acetate did not interfere with immune elimination—a sign of early antibody production—but most severely damaged retention of antigen in spleen germinal centers. The data are consistent with the hypothesis that the antigen depots in germinal centers are of functional significance for the late (particularly 7S) antibody production. Our experiments also emphasize the dual effect of immunosuppressive agents on lymphatic organs: (i) reduction of their immunologically responsive cell population, and (ii) impairment of their capacity to capture and retain antigen.

Mouse leukocytes in culture.

Summary Efforts to establish a routine method for in vitro culture of mouse peripheral blood leukocytes are described. These cells generally failed to respond mitotically to PHA under a wide variety of culture conditions, In diffusion chambers placed in the peritoneal cavity of mice, however, proliferative activity of leukocytes was observed. Failure to obtain successful in vitro cultures therefore is probably attributable to culture conditions unfavorable for support of mouse leukocytes.

In Vitro and in Vivo Culture of Mouse Peripheral Blood for Chromosome Preparations

Summary The in vitro and in vivo culture methods for consistently obtaining mitotic divisions suitable for chromosome analysis from peripheral blood of various mouse strains have been described. In the in vitro culture system pokeweed was used as the mitogenic agent. The DNA-synthesis and mitotic activity commenced much earlier than in the diffusion chamber cultures in which the allogeneic or heterologous environment provided the mitogenic stimulus. In the latter system cells could be maintained for at least 7 days. Mitoses were still frequent at this time.

Respiratory Tract Deposition of Smoke Particles Using a Nasal Bypass Device

In order to avoid nasal absorption, an intralaryngeal cannula was tested as a device for bypassing the nose in delivering smoke into the lungs of hamsters. The intralaryngeal cannula increased lung deposition of radiolabeled smoke particles twofold to threefold over that in nose-breathing controls. Stabilization of respiration (absence of avoidance reaction), rather than prevention of nasal absorption of smoke, was demonstrated to be the cannulas major mechanism of action. Although suitable for acute exposures, the device is of limited use for chronic exposures that require daily insertion of the cannula during an extended period of time.