Showing papers in "American Journal of Pathology in 1979"

Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage.

Abstract: Bronchoalveolar lavage is an invaluable means of accurately evaluating the inflammatory and immune processes of the human lung. Although lavage recovers only those cells and proteins present on the epithelial surface of the lower respiratory tract, comparison with open lung biopsies shows that these constituents are representative of the inflammatory and immune systems of the alveolar structures. With the use of these techniques, sufficient materials are obtained from normal individuals to allow characterization of not only the types of cells and proteins present but their functions as well. Such observations have been useful in defining the inflammatory and immune capabilities of the normal lung and provide a basis for the study of lung disease. Lavage methods have been used to characterize inflammatory and immune processes of the lower respiratory tract in destructive, infectious, neoplastic, and interstitial disorders. From the data already acquired, it is apparent that bronchoalveolar lavage will yield major insights into the pathogenesis, staging, and therapy decisions involved in these disorders. (Am J Pathol 97:149--206, 1979).

Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages.

Abstract: Hypercholesterolemia was induced in pigs by feeding a chow diet supplemented with 1.5% cholesterol and 19.5% lard for periods up to 12 weeks. The aortic intima from areas of spontaneously differing permeability to proteins, as demarcated by their uptake of Evans blue dye, was examined using light microscopy and both scanning and transmission electron microscopy to describe the earliest detectable changes in intimal morphology induced by the diet. After 2, 4, and 6 weeks of feeding, cholesterol/lardfed pigs demonstrated monocyte adherence to the endothelium in areas of enhanced permeability (blue areas) in 86% of samples examined, as compared to 52% in areas of lesser permeability (white areas) and 17% in control animals. Similarly, the number of monocytes in the intima was higher in blue areas than in adjacent white areas or blue areas from control animals. After 12 weeks of feeding, all blue areas showed intimal monocytes, with fewer seen in white areas. Aortic endothelial cells in hypercholesterolemic pigs were normal in ultrastructural appearance, except they contained more lysosomes and cytoplasmic filaments than those from control animals. No lesions were observed at 2, 4, and 6 weeks, although plasma cholesterol levels were substantially elevated (200-400 mg/dl) at these times. A marked hyper-beta-lipoproteinemia was evident from 4 weeks onward, but no elevation of serum triglycerides was evident at any stage. Plasma phospholipid concentrations increased but not in direct proportion to cholesterol levels. At 12 weeks, foam cell lesions were observed in areas of enhanced permeability but not in adjacent areas of normal permeability. Lesion foam cells appeared to be derived from the monocytes which adhered to and penetrated the endothelium at earlier stages, since no intimal involvement, or lipid engorgement, by medial smooth muscle cells was observed.

The selection and characterization of an invasive variant of the B16 melanoma

Abstract: Several in vitro properties of two variant cell lines of the B16 melanoma (B16-F10 and B16-BL6) with markedly different spontaneous metastatic behavior were examined. The two cell lines were compared with regard to their in vitro growth rate, ability to migrate, ability to adhere to a variety of substrata, detachment rates, production of plasminogen activator, and cell surface proteins as determined by lactoperoxidase-catalyzed iodination. Growth rates in vitro, attachment rates, and qualitative patterns of cell surface proteins were almost identical. B16-F10 cells (the less spontaneously metastatic line) produced greater amounts of plasminogen activator, were more motile in vitro, and detached more readily from plastic than the more invasive B16-BL6 cells. The study of tumor cell variants, selected for different biologic behavior, is a valuable approach to the elucidation of those mechanisms responsible for their malignant activity.

Bleomycin-induced pulmonary fibrosis in the rat: inhibition by indomethacin.

Abstract: A model for pulmonary fibrosis in the rat has been developed using intratracheal administration of bleomycin The histopathologic features of the reaction are similar to those reported in the hamster model Increases in vascular permeability are seen in the lung within 24 hours and persist over a 2-month period Extractable collagen, as measured by hydroxyproline, increases during this time by a factor greater than 15 times the reference control values of normal lung During this same period, a prominent eosinophilia develops The continued treatment of bleomycin-injected rats with indomethacin markedly diminishes the amount of extractable lung collagen at 60 days and the histopathologic evidence of pulmonary fibrosis The eosinophilia over the first 3 weeks is also markedly suppressed Less dramatic effects were seen with the permeability changes These findings indicate that the rat is a reliable and useful model for the study of blemoycin-induced pulmonary fibrosis and that treatment with indomethacin ameliorates the lung changes

Induction of diabetes in animals by parenteral administration of ferric nitrilotriacetate. A model of experimental hemochromatosis.

Abstract: Rats and rabbits parenterally treated with a large daily dose of ferric nitrilotriacetate manifested diabetic symptoms such as hypergycemia, glycosuria, ketonemia, and ketonuria after approximately 60 days fo treatment. The blood insulin response to oral glucose loading was poor. Heavy iron deposits were found in liver parenchymal cells and in pancreatic exocrine cells, although some iron was deposited in the macrophages and reticuloendothelial cells of the organs. Faint iron staining was found in some pancreatic islet cells, with a reduction in beta granules and weak zinc staining. Cirrhotic liver changes and skin pigment deposition were not observed. Repeated blood withdrawals from ferric-nitrilotriacetate-treated animals resulted in disappearance of hypergycmia, glycosuria, ketonemia, and ketonuria; disappearance of iron from the liver and pancreas; and restoration of islet beta granules to the control level.

The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat.

Abstract: Trimethyltin, when given by gavage to rats, has an LD50 of 12.6 mg/kg. Signs of poisoning include tremors, hyperexcitability, aggressive behavior, weight loss, and convulsions. After single (10 mg/kg) or repeated weekly doses (a maximum of four) of 4 mg/kg, rats, up to a survival time of 70 days, were perfusion-fixed for light microscopy. Trimethyltin was assayed in brain and blood in rats after similar treatments. Trimethyltin is cumulative and persistent and binds with high affinity to hemoglobin. Trimethyltin, unlike triethyltin, does not produce white matter edema in rats but does cause bilateral and symmetrical neuronal alterations involving the hippocampus (largely sparing the Sommer sector), pyriform cortex, amygdaloid nucleus, and neocortex. The earliest alteration was loss or dispersal of Nissl substance, then clumping of nuclear chromatin, followed by shrinkage and fragmentation of the nucleus within shrunken eosinophilic cytoplasm. These changes were associated with approximately 1.4 microgram trimethyltin/g wet weight in brain tissue 1 day after the second dose of 4 mg/kg or 2 days after a single dose of 10 mg/kg. Signs of poisoning gradually disappeared, and 4 rats surviving 70 days appeared normal, although their brains had severe damage with cell loss in the hippocampi and each pyriform cortex. Treatment of rats with trimethyltin, therefore, provides a chronic preparation with consistent lesions in the hippocampus of use in other behavioral and neuroanatomic studies. (Am J Pathol 97:59--82, 1979).

Atheroarteriosclerosis induced by infection with a herpesvirus.

Abstract: Atheroarteriosclerosis closely resembling that in humans was induced in normocholesterolemic and hypercholesterolemic chickens by infection with Marek's disease herpesvirus (MDV). Four comparably sized groups of chickens were used. Each group was initially fed a diet relatively poor in cholesterol. Group I and II were inoculated intratracheally at 2 days of age with MDV. At 15 weeks, one group of virus-infected chickens (Group II) and one group of uninfected controls (Group IV) were fed a 2% cholesterol supplement for an additional 15 weeks. Group I, infected, and III, uninfected, were continued on a cholesterol-poor diet. All groups were killed at 30 weeks. Striking grossly visible atherosclerotic lesions were seen in large coronary arteries, aortas, and major aortic branches of both Groups I and II but not in those of Groups III and IV. Microscopically, arterial changes in infected animals were characterized by occlusive fibromuscular intimal thickening, which formed fibrous caps overlying areas of atheromatous change. This change closely resembled chronic atherosclerosis in humans. These results may be important to our understanding of human arteriosclerosis, since there is widespread and persistent infection of human populations with as many as five herpesviruses.

Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy.

Abstract: This report presents the light microscopic morphology found at autopsy in 59 patients who participated in an organized controlled trial of extracorporeal oxygenation as therapy for acute respiratory failure. Observations were recorded as objectively as possible and were analyzed by computer. The experimental therapy produced no specific alteration in the observed pulmonary lesions. Many of the lesions tabulated had significant correlation coefficients with time, all of which were higher when correlated with the duration of respiratory failure than with the duration of the entire acute illness. The rapid progression of the lesions to fibrosis is emphasized as is the predilection of both early and late lesions to involve alveolar ducts to a far greater degree than the distal alveolar spaces. A unifying mechanistic hypothesis consistent with these observations, as well as others, is that the lesions may result as much from oxygen damage as from the original acute illness.

The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature.

Abstract: Twenty-seven small cell carcinomas of the lung and three tumors of the large intestine with combined adenocarcinomatous and small cell and/or anaplastic carcinoid-type histologic features were studied by light and electron microscopy. It was shown that the small cells have morphologic characteristics of APUD cells. Also presented are the histologic features of a carcinoma of the lung with large cell undifferentiated carcinoma, adenocarcinoma, squamous cell carcinoma, and giant cell carcinoma areas in the primary site and in several metastatic foci. Two of the renal metastases showed small cell carcinoma. The combined tumors and the numerous other similar neoplasms described in the literature and reviewed here suggest an endodermal origin for digestive and respiratory tract APUD cells based on the hypothesis that cancer is a clonal proliferation, and mucous and squamous cell differentiation is an endodermal rather than neural crest characteristic. The ultrastructural features of tumors of cells of known neural crest origin, including a medullary carcinoma of the thyroid, three carotid body tumors, a pheochromocytoma, and two cutaneous melanomas were compared with those of other APUD cell tumors including small cell carcinomas of the lung, two bronchial carcinoids, a carcinoid of the appendix, and a carcinoid of the kidney. Cells of the latter group sometimes possessed cytoplasmic tonofibrils, round compact masses of cytoplasmic microfilaments, and ductal lumina. These features were lacking in the former group and may signify a different embryologic origin. The histologic, histopathologic, and embryologic evidence regarding the origin of digestive and respiratory tract APUD cells is reviewed, showing that the former are, and the latter probably are, of endodermal and not neuroectodermal origin.

Hypoxia and incorporation of 3H-thymidine by cells of the rat pulmonary arteries and alveolar wall.

Abstract: In the pulmonary arterial circulation hypoxia produces increase in thickness of the medial muscle coat as well as of the adventitia; in addition muscle appears in smaller arteries than is normal and the number of small arteries that fill on Micropaque-gelatin injection is reduced. To assess the role of hyperplasia in these changes, the uptake of 3H-thymidine by the cells of the pulmonary arterial wall has been studied in rats exposed to hypobaric hypoxia (exposure to 380 torr) after 1, 3, 5, 7, 10, and 14 days. Using autoradiographs of 1-micron sections, the glutaraldehyde-distended intrapulmonary hilar muscular artery, the peripheral, intraacinar arteries less than 100 micron in external diameter, and the alveolar wall had different patterns of uptake. In the hilar pulmonary artery, after 24 hours of exposure, the labeling index for adventitial fibroblasts is increased eightfold over the control value, and for endothelial cells, threefold, while for medial smooth muscle cells, there is a gradual and small increase to Day 14. Newly muscularized intraacinar arteries are first apparent at Day 3, when they comprise 40% of the intraacinar arteries, increasing to 80% at Day 7. No decrease in density of arteries is found. Uptake of 3H-thymidine by new muscle cells is not apparent until Day 5 when labeling is maximum. The endothelial cells of the newly muscularized arteries show an increased labeling index only at Days 7 and 10. The veins and normally muscular arteries do not show these changes. In the alveolar walls, the concentration of labeled cells is significantly above the control value at Days 3, 5, and 7 and significantly below, at Day 14. At this level, the interstitial, epithelial, and endothelial cells contribute to the increase.

Ischemic myocardial cell injury. Prevention by chlorpromazine of an accelerated phospholipid degradation and associated membrane dysfunction.

Abstract: Ligation of the left coronary artery of an adult rat heart results in the reproducible ischemic cell death of the entire free wall of the left ventricular myocardium. The time course of the development of the cellular changes is biphasic. The subendocardial and subepicardial cells die within the first few hours. The main mass of free-wall myocardium reacts more slowly, with morphologic evidence of irreversible cell injury developing after 12 hours. Measurement of the increases in total free wall Ca++ reflected this biphasic pattern. There was a rapid 3-fold rise in total Ca++ during the first 4 hours. Between 4 and 12 hours the Ca++ was constant. Between 12 and 30 hours there was a second increase that reached a level some 8-10 times the control value. Treatment with chlorpromazine before and subsequent to surgery prevented the appearance of ischemic cell death in the main portion of the free-wall myocardium for at least 24 hours without affecting the reaction of the subepicardial and subendocardial cells. Chlorpromazine also inhibited the second phase of Ca++ accumulation. An accelerated degradation of phospholipids was observed with a 33% decrease in total phospholipids by 12 hours. Phosphatidylethanolamine was reduced by 50% and phosphatidylcholine by 25% without increases in the corresponding lysophospholipids. Chlorpromazine prevented the accelerated degradation and consequent loss of phospholipid. Isolated sarcoplasmic reticulum showed a time-dependent loss of phospholipid with a parallel loss of active Ca++ uptake that reach 60% with a total lipid depletion from these membranes of 33% by 12 hours. Twelve-hour ischemic sarcoplasmic reticulum exhibited a 6--7-fold increase in passive permeability to Ca++. Chlorpromazine protected against the loss of phospholipids, the inhibition of Ca++ uptake, and the increased Ca++ permeability of the sarcoplasmic reticulum. These observations indicate that rat myocardial cells react to lethal doses of ischemia in a manner similar to the reaction of liver cells described previously. In both cases the evidence implies that a disturbance in phospholipid metabolism and its associated membrane dysfunction is the critical alteration that produces irreversible cell injury in ischemia.

Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion.

Abstract: The influence of age and mammary gland differentiation on the incidence of tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) was studied by correlating the development of the mammary glands of 20-180-day-old, virgin Sprague-Dawley rats with the number and type of tumors induced by DMBA administered at those various ages. The number of terminal end buds (TEBs), terminal ducts (TDs), and alveolar buds (ABs)/sq mm and their DNA-labeling indices (DNA-LI) were determined. Highest density of TEB occurred when the rats were 20 days old, decreasing thereafter. DNA-LI ranged between 25.2 and 29 in TEB of rats aged 30-55 days, which was coincident with the highest incidence of carcinomas. With aging, the number of TEBs and their DNA-LI decreased and the number of TDs and ABs increased, although with a low DNA-LI, which correlated with a lower incidence of carcinomas and higher incidence of benign lesions.

Eosinophilic fasciitis. A pathologic study of twenty cases.

Abstract: This report presents a detailed light-microscopic evaluation of biopsies obtained from 20 patients with eosinophilic fasciitis, a newly recognized disorder characterized by inflammation and thickening of the deep fascia, hypergammaglobulinemia, and peripheral and tissue eosinophilia. Early in the course of the disease, the deep fascia and lower subcutis are edematous and infiltrated with lymphocytes, plasma cells, histiocytes, and eosinophils; these features are associated with impressive peripheral eosinophilia. As the illness progresses, these structures and eventually the dermis become collagenized, thickened, and sclerotic. Tissue eosinophilia may be focal or diffuse and is usually observed in the fascia and/or lower subcutis. Extracutaneous involvement has been limited to a chronic synovitis and tenosynovitis, the latter frequently associated with the carpal tunnel syndrome. Deposits of immunoglobulin and/or complement were found in five of eight biopsies studied by direct immunofluorescence, which suggests that an immunologic stimulus may be responsible for initiating this syndrome. Differential diagnoses are discussed.

Lung injury induced by leukocytic proteases.

Abstract: Human polymorphonuclear neutrophilic leukocytes (PMNs) contain large amounts of neutral proteases that can degrade elastin, collagen, proteoglycan, and basement membrane. The instillation of one of the purified enzymes (elastase) into dog lungs in vivo causes degradation of elastic fibers and other alveolar septal components and results in anatomic changes similar to those of human pulmonary emphysema. Cigarette smoking is a major risk factor associated with pulmonary emphysema in man. One mechanism for this association may be interference with the regulation of PMN elastase activity by alveolar antiproteases. This possibility is supported by the observation that the oxidizing activity of tobacco smoke inactivates alpha 1-proteinase inhibitor in vitro. Macrophages also secrete an elastolytic protease, albeit at low levels. The short-term exposure of cultured mouse macrophages to cigarette smoke augments the rate of elastase secretion by these cells. Mouse macrophage elastase is not inhibited by alpha 1-proteinase inhibitor or alpha 2-macroglobulin. This unusual property of macrophage elastase may facilitate its attack upon elastin over prolonged intervals despite very low levels of macrophage elastase production. A unified hypothesis of lung injury in pulmonary emphysema is presented, involving both PMN and macrophage elastases and the actions of cigarette smoke. (Am J Pathol 97:111--136, 1979).

Lysophosphatidic acids. Influence on platelet aggregation and intracellular calcium flux.

Abstract: Decanoyl-, palmitoyl-, and oleoyl-lysophosphatidic acid (LPA) were studied for their effects on platelet aggregation and intracellular calcium flux. Palmitoyl-LPA and oleoyl-LPA both caused a concentration-dependent aggregation of human blood platelets at concentrations of 12--300 microM. Aggregation by adenosine diphosphate (ADP) was enhanced at slightly lower concentrations. First-wave aggregation induced by these LPAs was not blocked by aspirin, indomethacin, or heparin, suggesting similarities to ADP aggregation. However, in washed platelets with a high calcium concentration, no serotonin secretion was observed, even though full aggregation occurred, suggesting that aggregation was not due to released ADP. This concept was supported by studies of platelets deficient in the storage pool of ADP and serotonin, which had a normal first-wave aggregation response to palmitoyl-LPA. Aggregation induced by palmitoyl LPA was inhibited by prostaglandin E1 (PGE1), theophylline, and ethylenediaminotetraacetate (EDTA), though in the presence of EDTA shape change occurred. Aggregation stimulated by palmitoyl-LPA or oleoyl-LPA was characterized by changes in the shape of the platelets with development of pseudopods and centralization of granules closely surrounded by contractile microfilaments and supporting microtubules. The addition of palmitoyl-LPA and oleoyl-LPA, but not decanoyl-LPA, caused the release of calcium from a platelet membrane fraction that contains elements of the intracellular calcium storage system and actively concentrates this cation in the presence of adenosine triphosphate (ATP) and magnesium. It is suggested that LPAs cause aggregation by stimulating the release of calcium intracellularly.

Ultrastructural studies of the gray platelet syndrome.

Abstract: The gray platelet syndrome (GPS) is a rare inherited disorder in which peripheral blood platelets are relatively large, vacuolated, and almost devoid of cytoplasmic granulation In the present study we have evaluated the ultrastructure and cytochemistry of platelets from 2 patients with the GPS to determine precisely which organelles are missing from their cells The findings indicate that gray platelets contain normal numbers of mitochondria, dense bodies, peroxisomes, and lysosomes but specifically lack alpha-granules Preliminary studies of megakaryocytes from 1 of the 2 patients suggest that the defect in granule formation may lie at the level of the Golgi zone

Superoxide production induced in rabbit polymorphonuclear leukocytes by synthetic chemotactic peptides and A23187.

Abstract: Synthetic formyl methionyl chemotactic peptides induce the various manifestations ofthe respiratory burst: increased 02 consumption, activation of the hexose mono-phosphate shunt, and increased production of superoxide (02-) and H202. They do soalone but to a much greater extent when in the presence of cytochalasin B. Superoxidegeneration by the chemotactic peptides in the presence of cytochalasin B shows thesame relationship of structure to activity as does the stimulation of chemokinesis andchemotaxis, granule enzyme secretion, and neutrophil aggregation by these sameagents. Carbobenzoxy-phenylalanyl-methionine, CBZ-Phe-Met, competitively inhibitsthe induced stimulation of locomotion, granule enzyme secretion, and neutrophilaggregation caused by the synthetic peptides. It also is a competitive inhibitor of O2- generation by the same peptides. The structure-activity and the competitive inhibitor studies lead to the conclusion that in polymorphonuclear leukocytes the chemotactic peptides induce superoxide formation and presumably the other manifestations of the respiratory burst by interacting with the same membrane receptor responsible for the stimulation of chemokinesis, chemotaxis, granule enzyme secretion, and neutrophil aggregation. The effectiveness of formyl-methionyl-leucyl-phenylalanine, F-Met-Leu-Phe, in generating 02- is greatly reduced but not abolished by removing calcium from the external medium. The calcium ionophore A23187 induces 02- generation that requires external calcium and is greatly enhanced by cytochalasin B. From these findings we hypothesize that the proximate cause of the induction of 02- formation and other manifestations of the respiratory burst by the chemotactic peptides is the influx into the neutrophil of Ca2+ and/or possibly Na+ previously shown to be induced by the peptides.

In vivo demyelination induced by intraneural injection of anti-galactocerebroside serum: a morphologic study.

Abstract: Intraneural injection of rabbit anti-galactocerebroside (anti-GC) serum produced focaldemyelinative lesions in rat sciatic nerves. Recipient rats developed a sensory motordeficit of the toes and feet on the side injected with anti-GC serum. Schwann cellabnormalities in recipient nerves were apparent by 20 minutes, followed by myelinsplitting and vesiculation over the next 8 hours. Macrophages first appeared in moder-ate numbers by 15 hours, and degraded myelin was completely phagocvtized by 5 days.An acute inflammatory reaction consisting of endoneurial edema, polymorphonuclearcell infiltration, and fibrin extravasation also was prominent. In vivo demyelinativeactivity of rabbit anti-GC serums was removed by pre-incubation with GC or central orperipheral nervous system myelin and was also lost when the serums were heated at 56C for 30 minutes and injected into nerves of rats previously injected with cobra venomfactor. Anti-GC antibodies are present in the serum of rabbits with experimentalallergic neuritis (WNV-EAN) and encephalomyelitis (WM-EAE) produced, respectively,by immunization with whole peripheral nerve or brain white matter and may play arole in the pathogenesis of demyelination in GC-induced EAN, WN-EAN, or WM-EAE.

Role of endothelium and hypercholesterolemia in intimal thickening and lipid accumulation.

Abstract: In experiments reported here we tested the hypothesis that persistent absence of endothelium favors intimal thickening, lipid accumulation, and atherosclerosis. Rabbit aortas were de-endothelialized with a balloon catheter at Day 0. Initially, all rabbits were fed a diet low in lipid. Some rabbits (Group I) were continued on a diet low in lipid for 8 to 20 weeks after de-endothelialization. Beginning 4 to 9 weeks after de-endothelialization, other rabbits were fed semisynthetic lipid-rich diets (Group II) or cholesterol-supplemented diets (Groups III) for 4 to 20 weeks. Lipid accumulation in all groups was significantly greater in the re-endothelialized intima than in adjacent intima lacking an endothelial lining. In aortas of Groups I, II, and III the degree of intimal thickening was significantly greater in re-endothelialized areas than in adjacent areas lacking endothelium. Intimal thickness was enhanced in re-endothelialized areas of hypercholesterolemic rabbits of Group III compared with normocholesterolemic rabbits of Group I but not in areas lacking endothelium. Thus, results of these experiments do not support the hypothesis that the absence of endothelium particularly favors intimal thickening and intimal lipid accumulation. Results indicate that intima covered by regenerated endothelium is significantly thicker and more likely to accumulate lipid.

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

Abstract: 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.

Morphologic studies in the skeletal dysplasias.

Abstract: Considerable progress has been made in the delineation of the genetic skeletal dysplasias, a heterogeneous group of disorders, that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these conditions, their diagnosis, and the investigation of their pathogenetic mechanisms. In certain diseases, the morphologic alterations are characteristic and pathognomonic. In others only nonspecific alterations are observed, whereas in still other disorders growth-plate structure is essentially normal. Histologic, histochemical, and electronmicroscopic studies of growth-plate cartilage have provided new insights into the complexity of morphogenetic events in normal growth through the demonstration of morphologic defects in the genetic disorders of skeletal growth. As yet, very little is known of the biochemical abnormalities underlying the morphologic abnormalities. However, the great variety of morphologic findings points to a number of different pathogenetic defects in the synthesis, release, and assembly of connective tissue macromolecules and in the cells involved in growth-plate metabolism.

The potassium permanganate method. A reliable method for differentiating amyloid AA from other forms of amyloid in routine laboratory practice

Abstract: Alterations in affinity of amyloid for Congo red after incubation of tissue sections with potassium permanganate, as described by Wright el al, were studied. The affinity of amyloid for Congo red after incubation with potassium permanganate did not change in patients with myeloma-associated amyloidosis, familial amyloidotic polyneuropathy, medullary carcinoma of the thyroid, pancreatic island amyloid, and cerebral amyloidosis. Affinity for Congo red was lost after incubation with potassium permanganate in tissue sections from patients with secondary amyloidosis and amyloidosis complicating familial Mediterranean fever (consisting of amyloid AA). Patients with primary amyloidosis could be divided into two groups, one with potassium-permanganate--sensitive and one with potassium-permanganate--resistant amyloid deposits. These two groups correlated with the clinical classification in typical organ distribution (presenting with nephropathy) and atypical organ distribution (presenting with cardiomyopathy, nephropathy, and glossopathy) and the expected presence of amyloid AA or amyloid AL. Potassium permanganate sensitivity seems to be restricted to amyloid AA. The potassium permanganate method can be important in dividing the major forms of generalized amyloidosis in AA amyloid and non-AA amyloid. This can be used for differentiating early stages of the disease and cases otherwise difficult to classify. It is important to define patient groups properly, especially in evaluating the effect of therapeutic measures. (Am J Pathol 97:43--58, 1979).

Morphologic and functional changes of the aortic intima during experimental hypertension.

Abstract: The morphology and permeability to horseradish peroxidase of the rat aortic intima have been investigated in three experimental models of hypertension having different values of plasma renin content and plasma aldosterone level. During hypertension the aortic endothelium shows three main changes: 1) increased arithmetic mean thickness, with prominent rough endoplasmic reticulum and polyribosomes; 2) the appearance of actin microfilament bundles; and 3) increased permeability to horseradish peroxidase. These changes are not present in all models, do not appear to depend on hypertension per se, and are independent of each other. The subendothelial layer of hypertensive animals shows an increased thickness that appears to be correlated with an increase of endothelial cell volume. Our results suggest that: 1) the aortic intima reacts differently to different types of hypertension, and 2) factors other than hypertension per se play a role in the development of vascular changes observed in animals with elevated blood pressure.

Isolation and tissue localization of type AB2 collagen from normal lung parenchyma.

Abstract: Type AB2 collagen was isolated from normal lung parenchyma by pepsin extraction followed by differential salt extraction. This collagen comigrates with AB2 collagen isolated from placental membranes when run on 5% polyacrylamide gel electrophoresis; it has an alpha A and alpha B polypeptide chain ratio of 1 : 2 and a cyanogen bromide peptide profile similar to known AB2 collagen on 7.5% polyacrylamide gel electrophoresis. This AB2 collagen isolated from lung tissue specifically inhibits passive hemagglutination of affinity-purified rabbit antibodies to AB2 collagen isolated from amnionic and chorionic membranes. By indirect immunofluorescence microscopy, AB2 collagen was found to be widely distributed throughout the lung and was found preferentially associated with cell surfaces (basement lamina) and basement membranes.

Complement fragments, alveolar macrophages, and alveolitis.

Abstract: Mechanisms of neutrophil infiltration into the rabbit alveolus have been investigated Complement activation in the circulation induced pulmonary vascular margination but not a significant level of alveolar infiltration Instillation of C5 fragments into the airways, however, attracted neutrophils into the alveolar airspaces The anaphylatoxin-inactive fragment of C5, C5a des Arg, was found to be much more active in this regard than C5a Furthermore, these fragments were shown to induce the production of a neutrophil-directed chemoctactic factor from pulmonary macrophages, raising the question of whether the C5a des Arg was acting directly to attract neutrophils or indirectly via the macrophage To substantiate a possible role for C5 and C5 fragments in alveolitis, active C5 was demonstrated in lavage fluids, and macrophage-derived C5 cleaving enzymes have been described Finally, a route of neutrophil infiltration via migration through the alveolar capillary wall into the interstitium is proposed, and subsequent penetration of the alveolar epithelium out into the airspace (Am J Pathol 97:93--110, 1979)

Development of pulmonary arterial changes in rats fed Crotalaria spectabilis.

Abstract: The early changes in pulmonary artery structure and the timing and development of right ventricular hypertrophy were examined in rats after ingestion of Crotalaria spectabilis; the arteries were distended with a Micropaque--gelatin mixture. The earliest change, detected at Day 3, is the appearance of new muscle in normally nonmuscular arteries. Increased medial wall thickness of the normally muscular arteries is apparent from Day 7, reaching significance in the smaller arteries from Day 10 and in the larger arteries from Day 14. A reduction in number of small, filled peripheral arteries is apparent at Day 14 and is significant at Day 21 as is the increase in the ratio of alveoli to arteries per unit area of section. Right ventricular hypertrophy is detected and significant at Day 21 and, like all the arterial changes, continues to increase to Day 35. Hypoxia produces similar changes to those described above, although without the inflammation seen after Crotalaria ingestion, but the time table is different. New muscle appears in both models at the same time, but the other changes appear more slowly after ingestion of Crotalaria spectabilis.

Organophosphorous neuropathy. I. A teased-fiber study of the spatio-temporal spread of axonal degeneraion.

Abstract: The spatio-temporal spread of axonal degeneration in organophosphorous neuropathy has been studied by means of the teased-fiber technique. Young adult cats were given a single intraperitoneal injection of di-isopropylfluorophosphate (DFP) and were killed 14, 18, 20, 21, and 28 days later by intracardiac perfusion with aldehydes. The cats developed clinical signs of delayed neurotoxicity 16 to 18 days after DFP injection. A histologic survey of the central and peripheral nervous systems revealed that the topographic distribution of axonal degeneration was characteristic of a dying-back neuropathy. In teased-fiber preparations from the left recurrent laryngeal nerve, we found that the axonal degeneration was initially focal and nonterminal but that the axonal degeneration subsequently spread in a somatofugal direction to involve the entire distal axon. Nerve fibre varicosities and paranodal demyelination preceded the axonal degeneration. It is concluded that neurotoxic organophosphates induce a focal, distal but not terminal axonal degeneration. This "chemical transection" of the axon then precipitates wallerian degeneration of the more distal axon. Thus, the traditional hypothesis that dying-back neuropathies evolve from a retrograde axonal degeneration is not valid for organophosphorous neuropathy.

Cellular pathology of homozygous familial hypercholesterolemia.

Abstract: Tissues were studied from four subjects with homozygous familial hypercholesterolemia (FH). The specimens consisted of tissues obtained from a 20-week-old fetus at autopsy, samples from a 9-year-old girl during open-heart surgery, and biopsies of cutaneous xanthomas from a 13-year-old girl and a 21-year-old man. The FH fetus, but not the 3 control fetuses, exhibited multifocal lipid deposition particularly involving the stromal cells of the thymus, spleen, and skin and both the stromal and parenchymal cells of the kidney. Only one minute focus of intimal lipid accumulation was found in the aorta and coronary arteries of the FH fetus. A segment of the ascending aorta from the 9-year-old girl showed: 1) foam-cell transformation of many medial smooth-muscle cells, 2) abnormal vascularization of the inner media and intima, and 3) intimal involvement by a typical artherosclerotic plaque with lipid deposits in thin, elongated cells that showed some myocytic features and in foam cells that lacked such features. The mitral and aortic valves of this patient also contained numerous foam cells and showed mild to moderate fibrous thickening. A segment of the saphenous vein, however, contained no lipid deposits. The three xanthomas from two FH homozygotes exhibited marked lipid accumulation in histiocytic foam cells but no lipid deposits in the endothelium of blood vessels in the lesions. The findings in this study, in conjunction with those reported in studies of other FH homozygotes, indicate that homozygous FH is characterized by accelerated atherosclerosis and prominent lipid accumulation in macrophages and other stromal cells of the aortic and mitral valves, skin, tendon, and, varibly, in other extravascular sites. Since most of the intracellular lipid was in the form of non-membrane-bound neutral lipid droplets, it appears that the cytoplasm is the major site of lipid storage in this disease.

Characterization of non-Hodgkin's lymphomas using multiple cell markers. Immunologic, morphologic, and cytochemical studies of 72 cases.

Abstract: Tissues from 72 cases (87 specimens) of various non-Hodgkin's lymphomas were analyzed for cell markers using multiple techniques. Cell suspensions were evaluated for E, EAC, and IgGEA rosette forming cells; Fc receptor cells; and surface immunoglobulin bearing cells. Cryostat section studies topographically defined EAC binding cells. Cytochemical determinations and immunoperoxidase methods for detection of intracellular immunoglobulin and lysozyme complemented other techniques in evaluating infiltrates containing large neoplastic cells. B-cell malignancies comprised 58 cases (80%) of this series and included well and moderately well differentiated lymphocytic lymphomas (10/10); nodular (23/23) and diffuse (10/18) poorly differentiated lymphocytic lymphomas; and lymphomas of mixed lymphocytic-“histiocytic” (3/3), “undifferentiated” (3/3), and “histiocytic” (9/13) types. Nodular lymphomas were characterized as B-cell neoplasms but also revealed a prominent population of T lymphocytes (39 ± 12%). Alkaline phosphatase activity, a cytochemical marker for lymphoid cells of follicular cuffs, was most consistently observed in B-cell lymphomas of moderately well differentiated lymphocytic type (4/6 cases). In some diffuse lymphomas, cryostat section studies (EAC rosettes) suggested a pre-existing nodular proliferation. One unusual B-cell lymphoma of large cell type exhibited IgGEA rosette formation and a strong receptor for the Fc portion of IgG. Ten lymphomas (14%) were of T-cell type and were represented by cases of diffuse poorly differentiated lymphocytic lymphoma (5/18, including 3 lymphoblastic lymphomas), Sezary syndrome (1), mycosis fungoides (1), and a cytologically distinctive large cell (“histiocytic”) lymphoma (3/13). Acid phosphatase activity was a consistent marker for the T-cell malignancies, some of which also revealed α-naphthyl butyrate esterase activity. No true histiocytic lymphomas were detected. Three cases of diffuse poorly differentiated lymphocytic lymphoma and one “histiocytic” lymphoma were null.