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Death after burn injury is usually due to complications, of which bacterial causes are dominant. We treated a patient with a burn injury who had the unusual complication of multiple brain abscesses, which were caused by methicillin-resistant Staphylococcus aureus (MRSA). The patient, a 27-year-old man, had MRSA septicemia on day 9 and pneumonia on day 18. Hemiparesis, which was the first manifestation of brain abscesses, occurred on day 27. Although antibiotics were administered aggressively, the infection was never resolved, and the patient died on day 50. Brain abscesses and MRSA infection are still major problems in the treatment of burns. This is the first report of (metastatic) multiple brain abscesses complicating treatment of a burn injury. (J BURN CARE REHABIL 1992;13:446–50)

The ABCA3 gene, of the ABCA subclass of ATP-binding cassette (ABC) transporters, is expressed exclusively in lung. We report here the cloning, molecular characterization, and distribution of human ABCA3 in the lung. Immunoblot analysis using the specific antibody reveals a 150-kDa protein in the crude membrane fraction of human lung. Immunohistochemical analyses of alveoli show that ABCA3 is expressed only in the type II cells expressing surfactant protein A. At the ultrastructural level, ABCA3 immunoreactivity was detected mostly at the limiting membrane of the lamellar bodies. Since members of the ABCA transporter family are known to be involved in transmembrane transport of endogenous lipids, our findings suggest that ABCA3 plays an important role in the formation of pulmonary surfactant in type II cells.

We studied 5 patients with acute eosinophilic pneumonia. Radiologic findings were Kerley's lines and pleural effusion on chest X-ray films, and interlobular septa on chest CT scans. Examination of transbronchial lung biopsy specimens revealed infiltration of eosinophils and lymphocytes into alveolar walls and edema of alveolar walls, interlobular septa, and perivascular connective tissue. The findings of interstitial edema were consistent with the radiological findings. Epithelial damage and bud-type intraluminal fibrosis were also seen, but residual alveolar structure was maintained. Bronchoalveolar lavage fluid contained abnormally high percentages of eosinophils and lympocytes. It also contained basophils and mast cells, which were not seen in fluid from normal subjects. Fluid from patients with chronic eosinophilic pneumonia had significantly fewer basophils than did fluid from those with acute eosinophilic pneumonia (p0.01). These findings suggest that release of chemical mediators from basophils plays a key role in interstitial edema in acute eosinophilic pneumonia.

We studied, by immunohistochemical and ultrastructural observations, the basic mechanism of interstitial fibrosis and endothelial metaplasia of alveolar capillaries in the lungs of Sprague-Dawley rats that received a single intratracheal infusion of silica particles. Immediately after silica administration, alveolar capillaries collapsed and their endothelial cells became necrotic over wide ranges. Alveolar myofibroblasts migrated into luminal silicaladen granulomas through defects in the alveolar linings. They proliferated and produced collagenous matrices that were incorporated into adjacent walls by coverage of regenerating epithelial cells. By day 4, endothelial cells of peribronchiolar small vessels had become positive for proliferating cell nuclear antigen. These endothelial cells apparently migrated along alveolar capillary tubes to replace injured endothelial cells through the processes of interdigitation of their cytoplasms. After one month, these alveolar endothelial cells, which were originally negative for factor VIII-related antigen (F-VIII) had become positive, especially in those segments in fibrotic scars. These endothelial cells developed numerous Weibel-Palade bodies containing F-VIII. Some endothelial cells formed specific ultrastructural fenestrations, which are unique to capillary endothelial cells that originated from bronchial arteries. The mechanism of endothelial metaplasia might consist of the following processes in endothelial cells that originated from broncho-pulmonary anastomoses: proliferation, migration, replacement, and differentiation of endothelial cells of bronchial arteries in the chronic fibrotic stages.

Experimental silicosis was induced by intratracheal infusions of 1 ml saline containing 50 mg standard silica (less than 5 microns diameter) in Sprague-Dawley rats. The lung tissues were observed histologically and ultrastructurally from half an hour up to 4 months. Macrophages, neutrophils, desquamated cells and their debris piled up around the alveolar ducts where the central cores of silicotic granuloma appeared. The granuloma became apparent by day 4 after the infusion and were covered by type II alveolar epithelial cells and bronchiolar cuboidal epithelial cells. Macrophages, fibroblasts and epithelial cells began to react to the antibody against proliferating cell nuclear antigen (PCNA) indicating self-replication on day 1. Macrophages in the granuloma made a close interdigitation with adjacent macrophages, and they gradually formed subplasmalemmal linear densities (SPLD) as paired forms between adjacent plasma membranes, and unpaired forms facing the interstitial matrix. SPLD were composed of linear densities with actin-like microfilaments along the leaflets of plasma membrane and were associated with extracellular dense bands which resembled a limited length of basement membrane. Interdigitation and SPLD structures were quite rare on day 1, but the number of macrophages with both structures increasingly appeared. The frequency of SPLD in macrophages also increased on a time course of granuloma maturation up to 4 months. Thus SPLD, which were originally found in the mononuclear phagocytes including macrophages, epithelioid cells and multi-nucleated giant cells, particularly in immune granuloma of man, also played a basic role in immobilizing macrophages in lesions of silica-induced granulomas.

Sprague-Dawley rats received intratracheal instillation of 50 mg silica dissolved in 1 ml saline. Animals were killed by intraperitoneal injection of nembutal at periods between 0.5 hour and 4 months. Analysis of bronchoalveolar lavage (BAL) cells and histological and ultrastructural studies were performed on the right and left lungs, respectively. A large number of neutrophils was recovered in BAL fluid from 3 hours after silica infusion, and was maintained until 4 months as the silica stimulus remained in the lung tissues. The absolute number of lymphocytes gradually increased in BAL fluid from day 2. The recovery of macrophages was quite low 24 hours after silica instillation. In contrast, massive aggregates of macrophages were forming silica granulomata in the lung tissues. This discrepancy of results between cells obtained from BAL and those in the lung tissues was caused by an impaired capacity of migration of alveolar macrophages by the development of a junctional apparatus, the "subplasmalemmal linear densities (SPLD)". These structures consisting of hemidesmosome-like unpaired and desmosome-like paired ones infrequently appeared in the acute stages of granuloma formation and were quite common in macrophages and epithelioid-like cells in granulomata 2 weeks after instillation and thereafter. Silicotic granulomata grew in the alveolar ducts from the aggregates of macrophages superimposed on a various number of alveolar sacs. Regeneration of type II alveolar epithelial cells and bronchiolar cuboidal cells usually covered the outer border of the granuloma. Endothelial cells of alveolar capillaries regenerated following recurrent injuries, and only occasionally formed a fenestration structure in their cytoplasm.(ABSTRACT TRUNCATED AT 250 WORDS)

We made histochemical and ultrastructural studies of mast cells of the skin and airways in human fetuses (7 to 40 weeks' gestation) and newborn infants. Epithelial differentiation of the skin and bronchial airways was assessed of immunohistochemical characteristics, especially on their basal cells. Histological phenotype and the characteristics to anti-total keratin antibody became identical with the phenotype in the adult by the 11th and 36th week of gestation, respectively. Interstitial fibroblastoid cells appeared oval in shape and remained relatively immature to the termination. Mast cells were first recognized by electron microscopy in the fetal skin of 18-week-old fetuses and histochemically detected in both skin and airways of 24-week-old fetuses. Mast cell counts under high power magnification (40X optical lens) light microscopy gradually increased and made a relatively dramatic rise in the early postnatal periods. The cytoplasm of mast cells showed irregular pseudopod-like elongations which gradually developed microvillous protrusions. It contained immature granules composed of varieties of morphology such as amorphous dense bodies, vesicles with dense cores, particulates and their compound forms. They were located in a corner of the cytoplasm surrounded by lamellated rough-surfaced endoplasmic reticulum. These granules became scattered widely in the cytoplasm showing distinct particulate type. Granules typical of the scroll type became dominant in the process of maturation, and the transformation of crystal-substructures occasionally took place. Prior to birth, mast cell granules fully developed as mature as those in the adult. This process of granule maturation is indicative of a reversed proceeding of slow degranulation, which is commonly seen in the so-called mucosal mast cells.

Aim: Keloid lesions develope as a result of abnormal growth of dermal fibroblasts after the injury. On the other hand, cell division cycle (Cdc) 25 is a family of phosphatases that activate the cell cycle regulating cyclin-dependent kinases. The three members of this family, Cdc25A, Cdc25B, and Cdc25C act in different phases of the cell cycle. In this study, we examined the dgree of expression of these phosphatases in keloid fibroblasts. Methods: Primary cultures of keloid and adjacent normal dermal fibroblasts (n = 4) as well as frozen and paraffin-embedded keloid and normal dermal tissues (n = 12 and n = 17 respectively) were examined by Western blot and immunohistochemical analyses for the expressions of Cdc25A, Cdc25B, Cdc25C and phosphorylated Cdk2. Results: Cdc25A protein levels were frequently increased in keloid fibroblasts as compared to the adjacent normal-appearing fibroblasts or different normal dermal fibroblasts. In contrast, Cdc25B and Cdc25C were none or rarely expressed. The incrased levels of Cdc25A were associated with lower levels of its substrate, Cdk2, in a phosphorylated or inactive form. Conclusions: Taken together, our data show that Cdc25A protein levels increase in keloid fibroblasts and this increase may be sufficient to activate its substrate, Cdk2, and accelerate the cell cycling. These results may have implication for the development of strategies to silence Cdc25A activity after the wound healing as a therapeutic modality for the keloid lesions.

Aim: When surgery with postoperative superficial electron irradiation is applied, the recurrence rate of keloid lesion has been found to be

Morphologic studies of normal anterior parietal pericardium from seven patients revealed this tissue to be composed of three layers: (1) the serosa, consisting of a surface layer of mesothelial cells and a narrow submesothellal space, (2) the fibrosa, containing variously oriented layers of collagen fibrils and small elastic fibers, and (3) the epipericardial connective tissue layer, containing mainly large coarse bundles of collagen and forming part of the pericardiosternal ligament. Scanning electron microscopic examination is most useful for study of the surface features of pericardial mesothelial cells, which have single cilia and are covered with microvilli. The latter bear friction and increase the surface area for fluid transport. Junctional complexes between adjacent mesothelial cells consist of desmosomes, which reinforce intercellular adhesion and zonulae occludentes, which form permeability barriers. Actin-like filaments (50 A in diameter) are present in microvilli and in immediately subjacent regions of the cells; these filaments mediate changes in cell shape. Intermediate filaments (100 A in diameter) are associated with desmosomes and form bundles in the perinuclear regions; these filaments provide structural support to the cytoplasm.

SERS has been used to study adsorption of adenine, adenosine, adenosine 5'-monophosphate, cytidine, and cytidylyl(3' → 5')adenosine on an Ag electrode. Cytidine adsorption is promoted or suppressed by equimolarly coexisting adenosine at lower or higher bulk concentration, respectively. This would reflect the limited number of SERS-active sites on the electrode surface. Investigation of the potential-induced change in the SERS spectra of adenosine derivatives provides a clear picture for the orientational change of the adsorbed molecules.

Evidence is given that SERS-active sites at Ag electrodes are associated with Ag + ions, forming sparingly soluble surface complexes with ligands such as pyridine molecules and halide ions. Such surface Ag + complexes contribute a factor of >800 to the overall (10 7 -fold) enhancement, possibly via a resonance Raman effect.

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.

Idiopathic pulmonary fibrosis (IPF) is a usually fatal disorder of lung with clearly defined clinical, roentgenographic, physiologic, morphologic, scintigraphic and bronchoalveolar lavage features. Current concepts of the pathogenesis of this disorder suggest a central role for a chronic alveolitis in causing changes in parenchymal cell populations and derangements in interstitial collagen. Of the many inflammatory and immune effector cells comprising the alveolitis of IPF, it is likely that the neutrophil is the most important mediator of parenchymal damage. To follow the status of lung neutrophils in patients with this disease, two methods have been utilized. Both gallium-67 scanning and bronchoalveolar lavage quantitate the extent of the alveolitis and can be used to stage and follow these patients. The treatment of IPF remains controversial, but it is likely that corticosteroids reduce the alveolitis and prolong the lifespan of these patients.

After intratracheal injection of short chrysotile asbestos fibres in guinea-pigs an intense neutrophil alveolitis was observed within three days. Evaluation by bronchoalveolar lavage of the inflammatory and immune effector cells producing the alveolitis by three days showed an increased proportion of polymorphonuclear leucocytes, which comprised 21% +/- 3% of the total leucocytes compared with 9% +/- 2% for the controls (p less than 0.05), persisting for at least six weeks (after which time the polymorphonuclear leucocytes comprised 28% +/- 2% compared with 7% +/- 1% for the controls: p less than 0.05). One mechanism by which asbestos fibres may cause polymorphonuclear leucocytes to be attracted to the alveolar structures is by induced release of neutrophil chemotactic factor by alveolar macrophages. When exposed in vitro to short or intermediate chrysotile fibres or amosite or crocidolite fibres guinea-pig alveolar macrophages released appreciable amounts of neutrophil chemotactic factor. The release of this chemotactic factor was augmented when the asbestos fibres had been previously exposed to normal serum. The chemotactic factor was lipid soluble, and was similar to the neutrophil chemotactic factor spontaneously released by alveolar macrophages recovered from guinea-pigs exposed in vivo to short chrysotile fibres. These observations suggest that alveolar macrophages may play an important part in the early stages of asbestosis by modulating the migration of neutrophils to the lung.

Langerhans' cells were found in lung biopsies in one of nine control patients and in 20 of 160 patients with fibrotic lung disorders, including 13 of 56 patients with idiopathic pulmonary fibrosis, two of nine patients with collagen vascular diseases, two of seven patients with hypersensitivity pneumonitis, and each of three patients with end stage fibrosis of uncertain cause. Langerhans' cells were not found in any of the 41 patients with sarcoidosis, the 35 patients with interstitial lung diseases associated with inhalation of inorganic dusts, the seven patients with pulmonary lymphangioleiomyomatosis, or the two patients with chronic eosinophilic pneumonia. In the control patient, Langerhans' cells were found between epithelial cells in bronchioles. In patients with fibrotic lung disorders, Langerhans' cells were found in the epithelial layer of bronchioles and alveoli containing proliferating epithelial cells, i.e., either cuboidal epithelial cells of bronchiolar origin or type II alveolar epithelial cells. Severe fibrosis or squamous metaplasia were not prerequisites for the presence of Langerhans' cells. The motility of Langerhans' cells apparently was restricted, as they were not found in the air spaces in any of the biopsies, and they were not recovered from bronchoalveolar lavage fluid of any of the 97 patients studied, even though some of these patients had relatively numerous Langerhans' cells in lung biopsies. These observations are in sharp contrast to those in pulmonary histiocytosis X, in which histiocytosis X cells (HX cells) occur in granulomas, in alveolar interstitium, and between epithelial cells of the lower respiratory system. HX cells also migrate into air spaces, as shown by their occurrence in bronchoalveolar lavage fluid. The HX bodies in HX cells are morphologically similar to Langerhans' cell granules, but are more numerous and pleomorphic. HX cells are considered to be reactive or activated Langerhans' cells.

Publisher Summary This chapter discusses the different aspects of human alveolar macrophage. Alveolar macrophages are part of a family of mononuclear phagocytic cells that are widely scattered throughout the body. A primary function of alveolar macrophages is to keep the alveolar surfaces of the lung sterile and free of debris. Alveolar macrophages and lung lymphocytes can be obtained directly from lung biopsy specimens by placing the specimens immediately in sterile heparinized saline at 4°C at the time of thorocotomy. One of the critical determinants of the ability of alveolar macrophages to function and/or survive is whether they are attached to a surface or are suspended in a fluid. Macrophages attached to a surface synthesize greater amounts of protein for longer periods of time and are more efficient at phagocytosis than suspended cells. The ability of the alveolar macrophage to ingest and kill microorganisms has been demonstrated in vivo and in vitro in many types of animal models. The alveolar macrophage may also function to remove various abnormal cells in its environment.

The tight-skin (Tsk/+) mouse is a genetically determined model characterized by alveolar enlargement and physiologic evidence of emphysema. Morphologic evaluation of the lungs of these animals demonstrated increased numbers of potential protease-secreting cells (alveolar macrophages and neutrophils) in the lower respiratory tract prior to development of the emphysematous lesions. Quantitation of the neutrophils in the lungs of these animals was carried out by bronchoalveolar lavage. In the Tsk/+ mice, neutrophils constituted 3.5 +/- 2% of all inflammatory and immune effector cells present compared with 0.4 +/- 0.1% in control (+/+) mice (p less than 0.01). The Tsk/+ animals had no evidence of infection to explain the presence of the neutrophils and had normal proportions of lung T- and B-lymphocytes, suggesting that their lungs were immunologically normal. There was no evidence that the Tsk/+ mice have an antiprotease deficit; the capacity of serum of Tsk/+ mice to inhibit neutrophil elastase was no different from that of control +/+ animals. However, the fact that these animals have a persistent low level macrophage-neutrophil alveolitis prior to the development of the emphysematous lesion implies that the lung destruction may be associated, in part, with a chronic protease-antiprotease imbalance, similar to that hypothesized for human emphysema.

The topographic distribution, population density, and ultrastructural features of metachromatic cells (mast cells and basophilic leukocytes) were studied in lung biopsies from five control patients and 17 patients with fibrotic lung disorders. The great majority of metachromatic cells were mast cells. The average number of metachromatic cells per square millimeter of tissue section was much larger in patients with fibrotic lung disorders (45.8 +/- 6.5) than in control patients (2.6 +/- 1.6). In control patients, mast cells were most frequently seen in subpleural and perivascular connective tissue. In contrast, the vast majority of mast cells in patients with fibrotic lung disorders was present in thickened, fibrous alveolar septa; mast cells also were found within the alveolar epithelial layer and alveolar lumina. The quantitative distribution of different types of mast cell granules differed in the two groups of patients: granules composed of scrolls were more frequent in control patients, and granules of the combined type (containing mixtures of different components within the same granule) were more frequent in patients with fibrotic lung disorders. Mast cells in the latter patients appeared to migrate through defects in the basement membrane into the epithelial layer and alveolar lumina; mast cells in these areas often showed reduced numbers of granules and disorganized granule content. These changes suggest that pulmonary parenchymal mast cells in fibrotic lung disorders undergo a chronic process of partial degranulation which differs from that found in anaphylaxis; this chronic release of mast cell products may contribute to the continuing alveolar injury and the ventilation-perfusion inequalities observed in the fibrotic lung disorders.

Ultrastructural studies were made of the types of alveolar epithelial cells in fibrotic lungs from 34 patients, including 20 with idiopathic pulmonary fibrosis, five with collagen-vascular diseases, six with sarcoidosis, one with lymphangioleiomyomatosis, one with histiocytosis X, and one with chronic eosinophilic pneumonia. In 28 patients, proliferation of type II alveolar epithelial cells was recognized on the basis of lamellar bodies in the cytoplasm, microvilli in the luminal surface, focal microfoldings of the basal plasma membrane, close interaction with underlying mesenchymal cells, and unilayered arrangement. Two types of cuboidal epithelial cells were recognized and were considered to be derived from bronchiolar basal cells (type A cuboidal cells) and from cuboidal cells in respiratory bronchioles (type B cuboidal cells). Type A cuboidal cells frequently contained large numbers of cytoskeletal filaments, and their basal plasma membranes possessed hemidesmosomes in close association with anchoring fibrils. Type B cells lacked hemidesmosomes and anchoring fibrils, Proliferation of either or both types of cuboidal cells was found in 30 patients. In 10 patients (average degree of fibrosis = 3.5 on a scale of 0 to +4), the proliferation involved type A cells; in 10 other patients (average degree of fibrosis = 2.5), type B cells in nine patients (average degree of fibrosis = 3.4), both type A and type B cells; in one patient cuboidal cells were identified only by light microscopy. In 17 patients, proliferating cuboidal cells formed foci of epithelial pseudostratification. Type II alveolar epithelial cells did not participate in the process of multilayering. Thus, type II alveolar epithelial cells and two types of cuboidal epithelial cells are sources of epithelial renewal in damaged alveoli in fibrotic lungs. Type II cells proliferate mainly in areas of less severe degrees of fibrosis; cuboidal cells become the main source of epithelial renewal in areas of very severe lung damage.

The tight-skin (Tsk/+) mouse represents an autosomal dominant mutation characterized by increased thoracic size, large lungs, and a variety of abnormalities of loose subcutaneous connective tissue, cartilage, tendon, and bone. Because an increase in the size of the lung and thorax may result from destruction of alveolar walls and a loss of elastic recoil of the lung, the present study was undertaken to determine if the Tsk/+ mouse exhibits morphologic and physiologic characteristics of emphysema. In contrast to the lungs of normal mice, examination of the lungs of Tsk/+ mice by light and scanning electron microscopy revealed generalized enlargement of air spaces with numerous subpleural cysts and scattered bullae. In addition, many alveolar walls were either markedly thinned or broken and there was an increase in the number and size of the pores of Kohn. Consistent with these morphologic observations, the lungs of the Tsk/+ mice also exhibited physiologic characteristics consistent with emphysema. Compared to the lungs of normal mice, the lungs of Tsk/+ mice had a markedly increased total lung capacity of (1.8 +/- 0.1 ml versus 3.3 +/- 0.1 ml, p less than 0.001); compliance (0.077 +/- 0.006 ml/cm H2O versus 0.345 +/- 0.025 ml/cm H2O, p less than 0.001), and specific compliance (4.23 +/- 0.34% TLC/cm H2O versus 10.64 +/- 1.01% TLC/cm H2O, p less than 0.001). These findings suggested that the Tsk/+ mouse is a genetically determined model of emphysema that may be useful in determining the pathogenesis of destructive lung disease.

Ultrastructural study of pulmonary biopsy specimens from patients with fibrotic lung disease disclosed the presence of nuclear inclusions in 1% or less of cuboidal alveolar epithelial cells in 9 of 19 patients, including 6 of 12 patients with idiopathic pulmonary fibrosis, 2 of 3 patients with collagen-vascular disease, and 1 of 3 patients with sarcoidosis. Nuclear inclusions were not observed by ultrastructural study in 5 control patients. The inclusions consisted of masses or aggregates of tubules which probably were derived from the inner nuclear membranes. These tubules were smooth-walled, showed branchings and bifurcations, were composed of single trilaminar membranes, usually had a clear content, and ranged from 500 to 1000 Å in diameter. They resembled nuclear tubules which occur in other cell types under conditions of rapid growth or specific hormonal stimulation. Statistically significant differences between the groups of patients with and without nuclear inclusions in cuboidal alveolar epithelial cells were not found with respect to smoking history, degree of fibrosis in the lung biopsy specimen, or the degree of pulmonary physiologic impairment. However, the average age of the patients having nuclear inclusions was significantly greater than that of patients not having nuclear inclusions. In addition, the frequency of indentations in the nuclei of cuboidal alveolar epithelial cells was greater in patients with nuclear inclusions than in patients without nuclear inclusions. Highly significant correlations were observed between the presence of nuclear inclusions and the presence of a) anchoring fibrils and hemidesmosomes along the basal surfaces of alveolar epithelial cells and b) multilayering of the alveolar epithelium.

A 35-year-old primigravida was admitted to the Department of obstetrics complaining of dyspnea and left back pain at 21 weeks' gestation. Chest roentgenogram revealed diffuse reticulonodular shadows predominantly in both lower lung fields and arterial hypoxemia was present. Pulmonary function tests showed restrictive impairment and decreased carbon monoxide diffuse capacity. From these results, interstitial pneumonia was suspected and she was first treated with prednisolone. However during her pregnancy, spontaneous pneumothorax occurred. Following spontaneous delivery of healthy infant at 37 weeks, left chylothorax occurred, and pleurodesis was performed with OK432. Thereafter the histological diagnosis of pulmonary lymphangiomyomatosis was made by transbronchial lung biopsy and treatment of prednisolone was stopped. She was treated with tamoxifen. In addition, progesterone-receptor was detected in the pulmonary tissue obtained at open lung biopsy. She was treated with cyclophosphamide in addition to tamoxifen. At present, shortness of breath has decreased slightly in comparison with one year previously, but no improvement has been seen in lung function tests or chest roentgenogram.

Electron microscopic study of the normal canine respiratory tree disclosed the presence of anchoring fibrils, a distinct class of fibrils of extracellular connective tissue, in association with the following types of cells: (1) basal cells and special type cells of trachea and bronchi; (2) ciliated cells and basal cells of bronchioles; (3) ductal cells, secretory cells, and myoepithelial cells of tracheobronchial glands. Anchoring fibrils in the normal respiratory system measured up to 6,000 A in length and from 170 to 400 A in thickness, and had a banding pattern that differed from that of collagen fibrils and connective tissue microfibrils. They formed arcs, the ends of which inserted into the basal lamina underlying the basal portions of the cells, often in the vicinity of hemidesmosomes. Anchoring fibrils decreased in number and size in the more distal portions of the respiratory tree, and were not found in alveolar septums. Anchoring fibrils in lung appeared similar to those described in other organs, but were often small and inconspicuous. The function of these structures is to reinforce the attachment of the epithelial basal lamina to the underlying connective tissues.

The tight-skin mouse is a newly described mutant characterized in heterozygotes (Tsk/ +) by generalized connective tissue defects. Since the Tsk/ + mouse also has an enlarged thorax with enlarged lungs, features often found in people with destructive lung diseases, this animal was evaluated as a possible model of pulmonary emphysema. Morphologically, Tsk/ + mouse lungs are characterized by enlarged airspaces, distention of alveoli, and destruction of alveolar septa. In addition, there are increased numbers of pores of Kohn which appear irregular in size. Physiologically, Tsk/ + lungs have an increased total lung capacity and an increased lung compliance compared to normal mice. The destructive lung disease in the Tsk/ + mice is associated with increased numbers of alveolar macrophages and neutrophils at sites of disease activity. The presence of neutrophils in the lungs of Tsk/ + mice was confirmed by bronchoalveolar lavage. The proportion of lung T- and B-lymphocyte sub-populations in Tsk/ + mice was similar to that present in normal animals. The antiprotease screen of the Tsk/ + mice seems to be normal since the ability of their serum to inhibit neutrophil elastase is similar to that of control mice. Thus, the Tsk/ + mouse is a genetically determined model of pulmonary emphysema associated with increased numbers of protease secreting cells in the alveolar structures and a generalized connective tissue abnormality. This model may be useful to understand the interaction between connective tissue defects, increased protease activity in the lung, and destruction of alveolar capillary units.

Electron microscopic studies of lung were made and compared in 17 patients with lung disease (10 with idiopathic pulmonary fibrosis, 3 with collagen--vascular diseases, 3 with sarcoidosis, and 1 with chronic eosinophilic pneumonia) and in 5 control patients. In control patients, the alveolar epithelial cells were normal, and no hemidesmosomes were present between the plasma membranes and the basal laminae. In comparison, cuboidal alveolar epithelial cells were present in 15 of the patients with fibrotic lung disease; in 9 of these the alveolar epithelial cells were multilayered. In 7 of the latter 9 patients (5 with idiopathic pulmonary fibrosis and 2 with collagen-vascular diseases), the basal laminae of the alveolar epithelial cells were attached to the plasma membranes by hemidesmosomes and to the underlying interstitial connective tissue by "anchoring fibrils." These fibrils measured from 4000 to 6000 A in length and from 200 to 600 A in width. One or both ends of the anchoring fibrils inserted into thebasal lamina, often forming arcs through which collagen fibrils and connective tissue microfibrils penetrated. Anchoring fibrils showed a complex pattern of transverse banding, which differed from that of collagen and appeared to be symmetric about the center of the fibril. These anchoring fibrils, which resemble those in normal skin and other tissues, were not found in lungs of control patients. In addition, there was a significant correlation between the severity of the pulmonary fibrosis and the presence of anchoring fibrils. These observations suggest that in severe fibrotic lung disease, anchoring fibrils reinforce the attachment of the basal lamina of multilayered alveolar epithelial cells to interstitial connective tissue.

Endotoxin shock was made in guinea pigs to understand the initial pathogenesis in connection with the oxygen radicals from leukocytes. The intraperitoneal injection of LD50 E. coli endotoxin induced rapid leukopenia, and leukocytosis appeared at 24 hours of injection. The cell differential counts of bronchoalveolar lavage fluid revealed a significant increase in eosinophil at 10 and 30 minutes. There was also a significant increase in neutrophil at 24 hours. The activity of superoxide dismutase in the lung tissue decreased at 10 minutes of injection and remained low for 24 hours. Malonaldehyde, a lipid peroxidation metabolite by oxidants, gradually increased and reached a maximal value at 60 minutes of injection. The lung damage was histologically characterized by a rapid appearance of the alveolar edema and scattered infiltration of granulocytes. These suggested the endotoxin injection induced activation of granulocytes recruited from peripheral blood to cause oxidant reaction in lung tissues, which finally produced acute lung injury.

Publisher Summary This chapter describes the importance of the fibroblast of the human lung-alveolar structures. The postnatal lung is a complex organ with function to mediate the exchange of oxygen and carbon dioxide between the atmosphere and the blood. The lung brings air and blood into close proximity in structures termed “alveoli.” In the adult human lung, alveoli are comprised of four major cell types. The fibroblast significantly influences alveolar structure and function through its major role in maintaining the interstitial connective tissue. Morphological studies have demonstrated that human fibroblasts are also capable of ingesting collagen fibrils and thus use phagocytotic mechanisms to modulate the connective tissue matrix. Lungs were obtained from human fetuses following abortion and stored briefly in a sterile culture medium until processing could be initiated. After becoming confluent, pulmonary fibroblasts in the tissue culture measure up to 100 μpm in length and 10 pm in maximal width. The chromatin is evenly distributed with only minimal margination.