Drummond H. Bowden

Dose response of the pulmonary macrophagic system to various particulates and its relationship to transepithelial passage of free particles.

Alveolar macrophages are thought to arise from both marrow-derived monocytes and pulmonary interstitial cells. Macrophage kinetics are now studied under various conditions of alveolar loading using several doses of carbon (0.03 micrometers diameter), polystyrene latex (0.1 and 1.0 micrometers), and heat-killed bacteria. In serial studies we examined the number of macrophages recovered by lavage, DNA synthesis by lung cells on autoradiographs, and the passage of free particles into lung tissues by electron microscopy. The dual origin of the alveolar macrophage was confirmed for each particulate. The observed peak in macrophagic output at 1 day may be explained by monocytic egress. With greater loads, the peak value did not increase, but the continuing macrophagic production correlated with a period of interstitial cell proliferation. For all particles used, the number of new macrophages was related more closely to number of particles instilled than to the total dose by weight delivered to the lungs. With increasing number, more free particles of carbon and latex crossed the Type 1 epithelium to be phagocytized by interstitial macrophages. The results suggest that the adaptive outpouring of alveolar macrophages occurs by an acceleration of the normal biphasic pathway; when the adaptive response is prolonged, the interstitial compartment appears to be the predominant source of new cells.

The intracellular site of surfactant synthesis: Autoradiographic studies on murine and avian lung explants

Abstract In murine and avian lungs maintained in organ culture, the Type II epithelial cells selectively incorporate labelled precursors of lecithin; the Clara cells, alveolar macrophages and other pulmonary cells show a low isotopic uptake. Within Type II cells, the silver grains, though associated with the lamellar bodies, are predominantly located at the periphery of these structures; saturated phospholipids are also concentrated at these sites. It is concluded that the perilamellar membrane of the Type II cell is the active site of surfactant synthesis.

The “Emphysema Profile” in Two Midwestern Cities in North America

A comparison of St. Louis and Winnipeg was made. St. Louis put out 13 times greater SO/sub x/, 7 times greater NO/sub x/, 6 times greater hydrocarbons, and twice the particulate (dustfall). Also, the St. Louis climate favors inversion and discourages dispersion. A study of 300 lungs by autopsy was performed. St. Louis had more emphysema cases: 7 times as many among 20- to 49-yr-olds, 2 times as many among 50- to 69-yr-olds, and 1.5 times as many in over-70 age group. Also a difference in severity was noted. Severe emphysema is uncommon in Winnipeg, whereas severe cases were encountered in every age group in St. Louis. No severe emphysema in non-smokers was found in either city. A synergistic effect between smoking and pollution is suggested.

The Alveolar Macrophage and its Role in Toxicology

As a pulmonary cell and as a member of a multisystemic family of mononuclear phagocytes, the alveolar macrophage contributes not only to the maintenance of pulmonary homeostasis but also constitutes a vital link in the general systemic defensive chain. In this review, the role of the macrophage as the ultimate scavenger of the respiratory tree is explored in the context of the variety of environmental and other agents that may disturb this function and thereby injure the host. Analysis of these factors suggests that under conditions of increased inhalant load the macrophagic response is, in most instances, completely adequate to keep the air sacs free from injurious particles and microorganisms. Disturbances of the clearance mechanism induced by toxic injury or overloading of the macrophage may, by permitting the accumulation of harmful chemicals and microorganisms in the lung, contribute to the development of several chronic pulmonary diseases that are associated with our urban-industrial society.

Fibroblast inhibition does not promote normal lung repair after hyperoxia.

Severe alveolar epithelial injury disrupts the normal epithelial cell-fibroblast relationship, leading to abnormal repair and the uncontrolled growth of fibroblasts. It is postulated that selective inhibition of fibroblasts growth after injury may allow epithelial regeneration to occur, reestablish fibroblast control, and reduce fibrosis. This hypothesis was studied using organ cultures after lung injury was induced in vivo by exposing mice to 90% oxygen for 6 days to produce necrosis of Type 1 epithelium. When explants of this lung tissue were cultured, proliferation of cuboidal epithelial cells was reduced, whereas fibroblast growth and hydroxyproline (HYP) levels were significantly higher than in controls. In attempts to inhibit fibrosis, explants were also cultured in the presence of a proline analog, L-azetidine carboxylic acid (LACA). At concentrations that reduced fibroblast proliferation, epithelial repair was also inhibited. The explants appeared fibrotic, and reduced HYP/DNA was due to lower DNA synthesis. Using pure cell cultures, LACA reduced fibroblast but not epithelial growth, and also abolished the usual increase in epithelial cell proliferation that control cells show when exposed to fibroblast supernatants. These results provide further evidence of interdependence between epithelial cells and fibroblasts such that agents that inhibit fibroblast growth after lung injury either directly or indirectly retard regeneration of the overlying epithelium, and so fail to produce normal repair.

The Acute Toxicity of Reactor Polyphenyls on the Lung

Mice were exposed to an aerosol of a polyphenyl reactor coolant for several hours daily up to eight days. The oil concentration was comparable to that measured in the atmosphere at the reactor site. No evidence of lung injury was detected by light microscopy. At the ultrastructural level, many type 2 alveolar epithelial cells showed central vacuolation of mitochondria. These ceils exhibited the normal turnover time of around 35 days. Following the cessation of aerosol exposure, the succeeding generation of epithelial cells showed no abnormality.

Proliferation of Pulmonary Macrophages during the Early Phase of an Acute Graft-Versus-Host Reaction in Mice

The pulmonary response was investigated during the early lymphoproliferative phase of an acute graft-versus-host (GVH) reaction induced in (C57BL/6 x A/J)F1 hybrid mice by iv injection of 50 x 10(6) A/J spleen and lymph node cells. The GVH reaction was monitored by measuring splenomegaly and immunosuppression. Animals were sacrificed after 5, 7, 11, and 16 d and bronchoalveolar lavage was performed; on each day a significant increase in the number of alveolar macrophages (AM) was seen, whereas no increase was found in other inflammatory cells. In lung sections, interstitial mononuclear cell infiltrates were seen around airways and pulmonary veins on d 11 and in alveolar septae on d 16. The kinetics of cell proliferation was evaluated in lung, liver, and peritoneum of mice with GVHR reactions by injecting [3H] thymidine 1 h before sacrifice. Autoradiographs revealed a marked increase in the number of labeled AM, pulmonary interstitial cells, Kuppfer cells, peritoneal macrophages, and intravascular monocytes. The results indicate that the GVH reaction causes a proliferative response of pulmonary macrophages early in its course. This stimulus appears to by systemic, since resident macrophages in other organs show a similar response. It is possible that local macrophage proliferation and the subsequent activation of these cells may play a role in the cellular mechanism of tissue injury seen during later stages of the reaction.

RADIATION SURVIVAL: IMPROVED RATES FOLLOWING CHLORTETRACYCLINE ADMINISTRATION.

Oral administration of chlortetracycline to mice before and after 1100 rads whole body x-irradiation resulted in a substantially enhanced survival rate (88%) over nontreated animals. This occurred in spite of severe pancytopenia as illustrated by the depression of marrow DNA and leukocyte values. Antibiotic administration solely in the preirradiation or postirradiation periods produced a smaller increase in survival (56%). The results are attributed to the control of endogenous and exogenous bacterial infection before and after irradiation rather than a radioprotective effect.

Fibroblast Interactions with Epithelial Cells in Lung Injury and Repair

Acute Hyperoxia. If adult mice are exposed to 90% oxygen for 6 days, either they die or, on return to air, they make a complete recovery with no sequelae. In those that die the lungs are hemorrhagic, solid, and airless (Adamson and Bowden 1974).