Analysis of mechanical stresses within the alveolar septa leading to pulmonary edema.

Mechanical ventilation has been associated with pulmonary edema in the clinical setting, but the pathophysiological mechanisms of this process have not been clearly defined. Experimental studies have shown that high transpulmonary pressures resulting from ventilation may damage the capillary walls, thereby leading to edema. Knowledge of the stress distribution within the alveolar septa would be an important step in understanding this phenomenon. A newly developed saline-filled alveolar sac model was utilized for analysis of septal stresses in young and aging healthy lungs, in order to examine their vulnerability to pulmonary edema during ventilation. Significant stress concentrations were shown to develop near highly curved regions (small local radii of less than 4 mum in a lung inflated to 80% could be as high as 25 times that of average septal stresses. The combination of elevated stress sites that are formed in the stiffer parenchyma of the aging lung, together with the cyclic loading of ventilation, may explain the gaps and breaks previously observed in pulmonary edema.     

The development of alveolar septa in fetal sheep lung. An ultrastructural and immunohistochemical study

The morphogenesis of pulmonary alveolar septa in the sheep was studied by light microscopy, transmission electron microscopy and light microscopic immunohistochemistry for the detection of elastin. The primordia of alveolar septa developed in the glandular stage in areas subjacent to the epithelium, and formed alveolar septa by protruding into the glandular lumina. In their earliest stage, the primordia consisted of groups of fibroblasts, which were associated with elastic fibers and unit collagen fibrils and were surrounded by epithelial basement membrane and by more immature fibroblasts. The fibroblasts in the primordia subsequently became myofibroblasts or smooth muscle cells. In the alveolar zone of the glands, elastic fibers were exclusively found in the primordia of alveolar septa in early developing lung. In early developing lung, wavy, thickened epithelial basement membranes were found in the regions of the glands, which eventually underwent considerable expansion of their surface areas, especially in the primordia of alveolar septa and the bifurcations in the alveolar zones. Areas of fusion of the basement membranes of capillary endothelial cells and epithelial cells in the alveolar zone were found after the formation of the primordia of alveolar septa was accomplished. These areas of fusion were not found in the primordia themselves, but in regions between the primordia. Epithelial cell flattening and differentiation occurred after the formation of the primordia of alveolar septa, and flattening was first observed in the areas of the primordia and the bifurcations of the alveolar zones.     

Vesicle numerical densities and cellular attenuation: comparisons between endothelium and epithelium of the alveolar septa in normal dog lungs

The alveolar septa are divided into two anatomically distinct portions: The thin sides consist of capillary endothelium, alveolar epithelium, and their closely apposed (often fused) basal laminae; the thick sides are characterized by prominent interstitial spaces, containing fibrils and cells, which separate the respective basal laminae. Vesicle numerical densities are comparable (approximately 400 vesicles/ micron3 cytoplasm) in the endothelial and epithelial cells on both sides of the septa. Mean vesicle diameters, however, are substantially less in the epithelial cells on both the thin and thick sides. The extent of both endothelial and epithelial attenuation is significantly greater on the thin sides of the septa. Further, epithelial attenuation is more marked than endothelial attenuation on both sides of the septa. The attenuated cellular portions, possibly because of their extreme thinness, are void of vesicles but provide relatively short diffusion distances (20-30 nm) from vessel or alveolar lumen to the basal lamina. Whether these structural differences between endothelial and epithelial cells contribute to physiologic evidence that describes the endothelium as more permeable than the epithelium remains to be established.     

Flow-cytometric and ultrastructural analysis of alveolar macrophage maturation

Alveolar macrophages (AM) from adult and newborn rats were studied by flow cytometry and ultrastructural morphometry. We observed that the laser scatter and autofluorescent properties of newborn macrophages were different from those of adult cells. Relative to the adult AM, the forward-angle laser scatter obtained with the newborn AM was reduced; this optical measurement appeared to correlate with the smaller mean size, as determined by ultrastructural and electronic volume measurements. The diminished right-angle laser scatter (90 degrees angle) correlated with the presence of fewer small, irregularly shaped lysosomal structures in the newborn AM, compared with AM from adult animals. AM from 1-2-day-old rats displayed large vacuoles containing multilamellar structures, which proved to be less effective at scattering light. Cells from newborn rats were less autofluorescent, a finding that appeared to correlate best with the numbers of secondary lysosomes. Flow cytometry may be used to discern structural alterations that occur during the maturation of AM. These changes correlate well with quantitative ultrastructural analyses of these cells.     

Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung.

Metaplastic epithelial cells are often observed lining alveoli in bleomycin-induced pulmonary fibrosis. The hypothesis that these cellular changes are induced by the direct action of the drug on differentiating Type 2 cells is now examined in a sequential study to correlate the presence of 3H bleomycin in the lung with the pattern of injury and repair of the alveolar epithelium. A single intravenous dose or multiple small intraperitoneal doses induce focal necrosis of Type 1 epithelial cells followed by Type 2 cell regeneration. At the time of maximal deoxyribonucleic acid (DNA) synthesis in these cells, significant amounts of 3H bleomycin are demonstrable in the lung by scintillation counting; and in autoradiographs, the drug appears to concentrate in epithelial cells. Subsequently many abnormal Type 2 cells are seen. Some are binucleate, and others show nuclear disruption. The usual process of differentiation to Type 1 cells does not occur; instead, a variety of epithelial forms are found, including fetal-like tubular structures and ciliated and squamous metaplastic cells. The correlation of epithelial injury and repair with the direct demonstration of bleomycin in the lung indicates that Type 2 cells are susceptible to injury in the division and differentiation phases of the cell cycle and may then produce a variety of inappropriate alveolar lining cells.     

Growth and activity but not maturation are affected by perinatal diet

Growth, maturation and activity in Sprague-Dawley rat offspring were studied as a function of two diets which were offered both pre- and postnatally. Day 1 gravid rats were placed ad lib on either Purina chow or Ensure, a total liquid diet. Half of each group was switched to the other diet on day 21 of gestation and maintained on it through weaning. Offspring remained on the same diet until sacrificed on postnatal day 60. Seven developmental measures were assessed daily until all of the animals reached criterion. The type of diet significantly affected maternal weight gain during the second third of gestation, and neonatal weight gain as measured on days 7, 14, 21, 28 and 45. Females were affected more than were male littermates. Males were significantly heavier than female littermates at all postnatal weighings. Diet had little or no effect on the developmental measures. Male/female differences were found for voluntary activity in the wheel which was measured on day 45. The use of liquid diets in behavioral teratology studies and the wisdom of using pellet diets as a control are discussed. The possibility of substituting careful measures of growth as an alternative to developmental testing is discussed.     

Primary alveolar soft part sarcoma of the lung

Alveolar soft part sarcoma (ASPS) is a rare epithelial-like soft tissue sarcoma. The two main sites of its occurrence are the lower extremities in adults and the head and neck in children. Primary pulmonary involvement of this sarcoma, without evidence of soft tissue tumor elsewhere, is very exceptional. We present a case of primary ASPS of the lung in a 42-yr-old woman. A computed tomographic scan of the thorax demonstrated a well-circumscribed, solid tumor located in the right upper lobe. The mass was resected by right upper lobectomy. After 5 months, three metastatic lesions, involving lumbar vertebrae and occipital scalp, were found. Histologically, the tumor consisted of alveolar nests of large polygonal tumor cells, the cytoplasm of which frequently revealed periodic acid-Schiff-positive, diastase-resistant intracytoplasmic rod-like structures. On immunohistochemical staining, the tumor cells were positive only for vimentin and alpha-smooth muscle actin. Ultrastructural study using electron microscopy revealed characteristic electron-dense, rhomboid intracytoplasmic crystals.     

Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network.

Postnatal glucocorticoid treatment of preterm infants was mimicked by treating newborn rats with dexamethasone (0.1-0.01 microg/g, days 1-4). This regimen has been shown to cause delayed alveolarization. Knowing that microvascular maturation (transformation of double- to single-layered capillary networks in alveolar septa) and septal thinning prevent further alveolarization, we measured septal maturation on electron photomicrographs in treated and control animals. In treated rats and before day 10, we observed a premature nonreversing microvascular maturation and a transient septal thinning, which both appeared focally. In vascular casts of both groups, we observed contacts between the two capillary layers of immature alveolar septa, which were predictive for capillary fusions. Studying serial electron microscopic sections of human lungs, we were able to confirm the postulated fusion process for the first time. We conclude that alveolar microvascular maturation indeed occurs by capillary fusion and that the dexamethasone-induced impairment of alveolarization is associated with focal premature capillary fusion.     

Non-uniform lung elastic properties and the slope of the alveolar plateau

Dispersion of elastic properties within the lungs may contribute to the creation of a sloping alveolar plateau of the single-breath N2 washout curve. In this study we have systematically explored the behaviour of a simple two-compartment lung model with non-uniform pressure-volume characteristics. The inhomogeneity was expressed in terms of the ratio between the shape constants (k1/k2) of the compartmental pressure-volume curves and the ratio between compartmental RV/TLC (R-RV/TLC). The model simulations indicate that normal slope magnitudes can be achieved with a moderate degree of inhomogeneity (k1/k2 and R-RV/TLV = 2). The model simulations also show that a phase II-like shape of the curve--of non dead space origin--may occur and furthermore that single-breath TLC determinations increasingly underestimate true TLC as the R-RV/TLC deviates from unity. For a given degree of inhomogeneity, the model predicts the slope to increase with overall RV/TLC and k but decrease with TLC. The relations between these overall factors and the slope of phase III are also found in a patient group, where these factors explain approximately 61% of the slope variance.     

Classification of the lung conditions in cases of perinatal death

Comparability of morphological lung findings depends on the greatest possible consistency in assessment and verbal definition. It is for that purpose that a classification of perinatal pulmonary morphology is proposed, based on latest knowledge in foetal and paediatric pathology and established with due consideration of findings from clinical and physiological research as well as of the author's own experience. The findings have been subdivided into five main groups, each of them with several sub-groups, and have been pathomorphologically so characterised that the new classification can be easily used in prosector practice.