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Changes are noted in the bronchial epithelium of dogs subjected to 44 and more than 420 days of experimental cigarette smoke inhalation. At the early time point goblet cells are more numerous and the surface lining cells possess fewer cilia. By 420 days the apparent number of cell layers in the epithelium is double that of the controls. The luminal surface is devoid of ciliated columnar cells and goblet cells, these being replaced by columnar and cuboidal cells whose free surface is covered by stubby projections. Basal cells are frequently columnar-shaped and mitotic figures are common. Most cells contain a profusion of cytoplasmic filaments which often appear to displace cell organelles. A “special type cell” with cell-specific granules, first described in the control, is found in great abundance in the intermediate region between the basal cells and the surface lining cells. In both osmium- and acrolein-fixed tissue the two special migratory cell types, which are so common in the controls, are rarely seen. The basement membrane is frequently interrupted by gaps through which cytoplasmic processes of basal cells protrude; a thickened zone underlying the basement membrane contains an increase in fibrillar components and multiple layers of basement membrane material.

Evaginations or blebs involving both layers of the nuclear envelope were observed in ciliated columnar cells of the bronchial epithelium obtained from four patients during lobectomies. These are visible with the light microscope as supranuclear vacuoles. In adjacent sections electron micrographs showed the “vacules” to be bounded by “double membranes” identical in appearance to, and in some instances continuous, with the nuclear envelope. Nuclear components extend from the nucleus into the evagination. In some cells multiple evaginations extend in a row. These may be interconnected, or only the most proximal one may be continuous with the nucleus. In some evaginations, appearing at a distance from the nucleus and with no apparent attachment to it, breakdown of the enclosing envelope suggests the possible dissolution of the entire structure into the cytoplasm thus providing a means of transfer of nuclear material.

Moderately electron-dense bodies without a limiting membrane and having a diameter of approximately 700A were observed in the cytoplasm of ciliated columnar cells in the bronchial epithelium of man. They seem to consist of aggregates of coiled filaments about 25A thick and have been termed “filosomes.” Filosomes, singly, in small groups, or in larger clusters, were found randomly distributed throughout the cytoplasm between the nucleus and the cell apex and were sometimes associated with structures resembling components of cilia. By site, the filosomes were associated with many cell organelles, especially the nucleus, and their consistont occurrence with annulate lamellae was specifically noted. The similarity of the material of the filosomes to that of structures which have been shown by others to be involved in ciliogenesis suggests a similar role for filosomes.

Electron microscopic observations in areas of fibrosis and emphysema of the lungs of dogs subjected to experimental cigarette smoking show that alterations occur both in the pleura and the lung parenchyma. In the pleura the major alteration is the increased thickness of the stroma due to large amounts of collagen present. In the lung parenchyma two major alterations appear in the interstitium of the alveolar septa where there is a complete loss or a great reduction in the number of capillaries and a marked thickening of the septa due to the increased amounts of collagen. Changes in the alveolar epithelium are slight; changes in capillary endothelium, such as rarefication of cytoplasm and blebbing of the plasmalemma, are found. More frequently noted are the changes involving the basement membrane of the alveolar epithelium which in some places appear to be greatly thickened and in others to be exceptionally thin or missing entirely. Another of the most striking alterations noted in both the pleura and parenchyma is the presence of large numbers of macrophages occurring singly, in clumps, and in granulomas. Although macrophages are found in the lungs of nonsmoking dogs they are not found in such numbers nor with the unique content observed in the lungs of smoking dogs. Crystalline-like structures are found in membrane-bound inclusions and ferritin-like particles occur both in large membrane-bound aggre-gates and lying free in the cytoplasm. Conclusive identification of these structures and their relationship to inhalation of cigarette smoke requires further study.

Hyperplasia of bronchiolar epithelium was observed in the lung parenchyma of 14 smoking dogs. Besides the increased number of cell layers in the bronchiolar epithelium, there was a virtual absence of glycogen in the cell cytoplasm. Sheetlike arrangements of squamous cells containing an abundance of tonofilament bundles were found lining alveoli. Type II cells were found adjacent to, and sometimes extending over the squamous cells. In all cases, a proliferation of type II cells was found in the alveolar epithelium, almost completely lining some alveoli. Acinarlike structures also lined by many type II cells were sometimes found near the pleura. Microinvasions of cytoplasmic processes into the underlying connective tissue often occurred through defects in the basal lamina. In some type II cells an unusual content of RER was observed. It possessed electron dense banding ≈ 180 A wide with a repeat at intervals of ≈ 540 A and was found in narrow cisternae and in bulbous dilatations of the cisternae of the RER. Fibrogranular material of the same appearance and periodicity was also found in the perinuclear space in some cells. Type II cells are further implicated as a reserve cell or stem cell in metaplastic alterations.