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Biomedical subjects

V J Ferrans

Publications and source records attributed to V J Ferrans.

At least 235 records · Page 13Linked to original sources
PubMed1985

Comparison of the effectiveness of (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles.

This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.

Acetylcysteine↗
PubMed1985

Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters.

Comparisons were made of the protective activity of ICRF-187 and a series of related bis-dioxopiperazine analogues against acute daunorubicin toxicity in Syrian golden hamsters. A single dose of daunorubicin (25 mg/kg) caused a marked decrease in body weight and was lethal to 84% of the animals within 1 to 4 weeks. Pretreatment with ICRF-187, the d-isomer of ICRF-159, ameliorated the lethal effects of daunorubicin. Over 70% of the animals given 50 to 200 mg of ICRF-187 before daunorubicin were alive at 8 weeks. Similar results were obtained with ICRF-186, the 1-isomer of ICRF-159, indicating that the protective activity is not stereospecific. Eighteen other analogues were also evaluated for protective activity; only bimolane, a central chain desmethyl analogue of ICRF-187 with N-morpholinomethyl substituents in each dioxopiperazine ring, was as effective as ICRF-187 in reducing the mortality of daunorubicin. The role of the N-morpholinomethyl groups in the biological activity of bimolane needs further study since ICRF-154, a similar compound without these substituents, exerted only minimal protective activity. Protection against daunorubicin lethality was minimal or absent when hamsters were pretreated with various doses of ICRF analogues in which slight changes had been made in dioxopiperazine rings (ICRF-158, ICRF-198) or in the central chain (ICRF-161, ICRF-192, ICRF-193, ICRF-197, ICRF-198, and ICRF-202). Similarly, animals pretreated with a number of conformationally constrained cyclopropane analogues of bis-dioxopiperazine compounds before receiving daunorubicin died at the same rates as those given only daunorubicin. These results confirm the effectiveness of ICRF-187 against daunorubicin toxicity and indicate that very little alteration can occur in the basic structure of ICRF-187 without loss of this protective activity.

Animals↗
PubMed1985

Poikilocytosis in dogs with chronic doxorubicin toxicosis.

Peripheral blood smears made during 2 studies of chemical antidotes for doxorubicin (DRB) cardiotoxicity in dogs were examined to determine the incidence of poikilocytosis. The 1st study had significantly (P less than 0.05) increased numbers of poikilocytes in 3 groups of 5 dogs, each treated with DRB alone, DRB plus thyroxine (0.5 mg/day), and DRB plus thyroxine (2.0 mg/day), respectively, compared with 1 group of 5 dogs treated with thyroxine alone (2.0 mg/day). In addition, the DRB-treated dogs had regenerative anemia characterized by an increased reticulocyte index. The 2nd study had a significant (P less than 0.05) increase in poikilocytes in 4 groups of 6 dogs, each treated with DRB alone, DRB plus +/- -1,2-bis(3-5-dioxopiperazinyl-1-yl; ICRF-187), DRB plus N-acetylcysteine (NAC), and drb plus ICRF-187 plus NAC, respectively, compared with 4 groups of 3 dogs, each treated with ICRF-187 plus saline solution (SS), NAC plus SS, ICRF-187 plus NAC plus SS, and SS alone, respectively. In both studies, the poikilocytes were identified as echinocytes, spiculated erythrocytes, and schizocytes. Administration of thyroxine and ICRF-187 did not prevent the occurrence of poikilocytosis in DRB-treated dogs. Administration of NAC with DRB resulted in a mild decrease in the extent of poikilocytosis compared with that observed in dogs given DRB alone. The hematologic changes observed in both studies were not accompanied by adverse clinical signs referable to the DRB-induced alterations in erythrocytes.

Acetylcysteine↗
PubMed1985

Cardiac and red blood cell glutathione peroxidase: results of a prospective randomized trial in patients on total parenteral nutrition.

Oxygen derived free radicals and peroxides result from many antitumor treatments, including radiation and anthracyclines. Doxorubicin cardiotoxicity is thought to result from free radical induced lipid peroxidation. The heart has less active detoxification enzymes than does the liver and depends on selenium dependent glutathione peroxidase (GSH-PX) for this function. We did a sequential prospective trial in patients with totally controlled parenteral diets to examine the activity of red blood cell GSH-PX in patients with and without malignant disease. Decreased GSH-PX activity was found in 54% of the patients on parenteral nutrition and was more common in the older of these patients and in those with the greatest weight loss. In the absence of selenium supplementation, the RBC GSH-PX activity declines steadily, but with supplementation this was prevented or reversed. Because selenium deficiency can manifest as a cardiomyopathy, we measured the enzyme activity in the hearts of five patients who had died. The cardiac enzyme activity correlated strongly with the RBC levels. Significantly decreased GSH-PX has been shown in animals to be associated with changes in other enzymes critical both to activation and detoxification of carcinogens as well as antitumor drugs. Abnormality of selenium status might be a previously unsuspected contributor to interpatient variation in drug effects.

Adult↗
PubMed1985

Characterization of mononuclear phagocyte subpopulations in the human lung by using monoclonal antibodies: changes in alveolar macrophage phenotype associated with pulmonary sarcoidosis.

Current concepts of pulmonary sarcoidosis suggest that the alveolar macrophage plays a central role in the pathogenesis of the disease. To help define the population of alveolar macrophages in sarcoidosis, we compared the surface phenotype of alveolar macrophages from patients with sarcoidosis and from normal individuals by using monoclonal antibodies (63D3, OKM1, M phi P-9, M phi S-1, 61D3, and M phi S-39) that detect surface antigens on cells of monocyte/macrophage lineage. Although almost all blood monocytes expressed surface antigens detected by each of these antibodies, only a minority of normal alveolar macrophages expressed the same surface antigens (p less than 0.05, each comparison). However, in sarcoidosis, the percentage of alveolar macrophages expressing these surface antigens was increased (p less than 0.05, each comparison with normal alveolar macrophages). Several findings supported the conclusion that the increased expression of these monocyte-lineage surface antigens on sarcoid alveolar macrophages resulted from increased recruitment of monocytes to the lung in sarcoidosis and not from abnormal "activation" of alveolar macrophages. First, alveolar macrophages expressing these antigens had an immature morphology. Second, in vitro cultivation of blood monocytes and alveolar macrophages in the presence of immune and inflammatory mediators, including mediators known to be present in the lung in sarcoidosis, did not prevent the loss of expression of monocyte-lineage surface antigens from monocytes or induce reexpression of monocyte-lineage surface antigens on alveolar macrophages. Third, the expression of monocyte-lineage surface antigens was only increased on sarcoid macrophages from patients whose lower respiratory tract contained an increased number of T lymphocytes, cells known to release monocyte chemotactic factor in sarcoidosis. Consistent with the knowledge that corticosteroids usually suppress the alveolitis of active sarcoidosis, when the expression of alveolar macrophage surface antigens was evaluated before and during therapy, the percentage of alveolar macrophages expressing monocyte-lineage surface antigens returned to normal after 1 to 3 mo of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1985

Ultrastructural alterations in allylamine cardiovascular toxicity. Late myocardial and vascular lesions.

The late myocardial and vascular ultrastructural changes in rat hearts following consumption of the cardiovascular toxin allylamine were studied. Rats were given 0.1% allylamine HCl in drinking water for 10-104 days. From 10 to 21 days, there was organization of acute myocardial necrosis by macrophages and scattered polymorphonuclear leukocytes with prominent interstitial-cell proliferation. Alterations at 21-104 days included extensive scarring with formation of dense mature collagen with scattered fibroblasts present, grossly evident left-ventricular aneurysm, and gross and microscopic changes similar to those observed in the secondary form of endocardial fibroelastosis. Areas of scar contained highly cellular foci of smooth-muscle cells, myofibroblasts, and abundant extracellular elastin. Cardiac myocytes frequently showed markedly disorganized myofilaments, bizarrely distorted mitochondria with condensed cristae, and other severe degenerative changes. Small vessels within and adjacent to scar showed proliferation of intimal smooth-muscle cells. Endothelial lesions or recent or organized thrombi were not seen. Focal endocardial metaplasia, consisting of both chondroid and osseous tissue, was found in areas of transmural scarring, or ventricular aneurysm. Chondrocytes had the overall nuclear and cellular morphology, abundant rough endoplasmic reticulum, and surrounding lacunae typical of mature fibrocartilage. In some areas, the collagen matrix was undergoing calcification with the typical cross-banded pattern of calcifying connective tissue. Osteocytes were located in a densely calcified bone matrix and displayed characteristic cellular extensions into surrounding canaliculi. These findings indicate a severe myocardial, small-vessel, and endocardial injury during the course of chronic allylamine intoxication.

Acute Disease↗
PubMed1984

Modification by the Hancock T6 process of calcification of bioprosthetic cardiac valves implanted in sheep.

The effectiveness of the T6 process (surfactant treatment) to decrease calcification of porcine aortic valvular (PAV) and bovine pericardial (BPV) bioprostheses was investigated. Morphologic and biochemical studies were made of standard and T6-treated PAVs and BPVs that had been implanted for a mean of 20 weeks in the tricuspid position in young sheep. Gross, radiographic, histologic and ultrastructural observations showed that the calcific deposits were less severe in T6-treated (n = 9) than in standard PAVs (n = 7), but were similar in severity in T6-treated (n = 6) and standard BPVs (n = 7). This was confirmed by results of quantitative analyses for calcium in half of each cusp of each explanted valve. Because these results showed large differences in standard deviations in the 4 groups of sheep, natural logarithmic and square-root transformations were used for statistical comparisons. The mean calcium content (milligrams of calcium per gram of dry tissue) of standard PAVs (111 +/- 53) was greater than that of T6-treated PAVs (11 +/- 3) (p = 0.0037). The calcium content of T6-treated PAVs was lower than that of T6-treated BPVs (96 +/- 26) (p = 0.031). However, the calcium content of standard BPVs (35 +/- 13) was not different from that of T6-treated BPVs or standard PAVs. Thus, under conditions of relatively short-term implantation in the sheep model, the T6 process is useful for decreasing the extent of calcification in PAVs, but not in BPVs.

Animals↗
PubMed1984

Development of elastic fibers of nuchal ligament, aorta, and lung of fetal and postnatal sheep: an ultrastructural and electron microscopic immunohistochemical study.

The morphogenesis of elastic fibers of the nuchal ligament, aorta, and lung of sheep was studied by light microscopy, transmission electron microscopy, and immunohistochemical methods for the detection of elastin. The degree of maturation of the amorphous materials of elastic fibers was assessed morphologically in preparations stained by the tannic acid and periodic acid methenamine-silver methods. With both of these methods, the amorphous components of mature fibers stained less intensely than did those of immature fibers. Elastic fibers in early stages of development consisted of many microfibrils and few, small, branching masses of immature amorphous material. Thicker fibers were formed by the coalescence of growing masses of amorphous materials. In late stages of formation of elastic fibers, the mature amorphous materials were associated with few microfibrils; and they were partially surrounded by immature amorphous materials associated with many microfibrils. Antielastin antibody reacted evenly with amorphous materials in very early stages of elastic-fiber development, but reacted only with the other zones of amorphous materials in later stages; it also reacted with the microfibrils in all stages. These findings were interpreted as indicating that the microfibrils were associated with small amounts of elastin on their surfaces. This conclusion is in agreement with ultrastructural observations showing 1) that development of microfibrils precedes that of the amorphous material and 2) that the microfibrils adjacent to the immature amorphous materials are covered with small amounts of tannic acid-positive amorphous materials. These observations suggest that microfibrils serve as sites for elastin deposition, both in early elastogenesis and in subsequent growth of elastic fibers. However, the nature of the interaction between elastin and microfibrils remains unknown.

Animals↗
PubMed1984

Cardiac morphologic alterations in acute minoxidil cardiotoxicity in miniature swine.

Minoxidil, a vasodilating antihypertensive drug, was given orally at 10 mg/kg daily for 2 days to twelve 25- to 35-kg miniature pigs. Twelve control pigs were also studied. Minoxidil-treated pigs had tachycardia and hypotension and were killed 24 hr after the second dose. Gross examination showed diffuse hemorrhage in left atrial epicardium in all pigs, and also in ventricular epicardium (2 of 12 pigs) and endocardium (3 of 12 pigs). Pale areas of necrosis were observed on incision of the left ventricular papillary muscles in 3 pigs. Light and electron microscopic studies showed acute vascular damage with hemorrhage in the left atrial epicardium. Affected arterioles had endothelial cell swelling and transmural and perivascular accumulations of leukocytes, edema fluid, fibrin clumps, and erythrocytes. The swollen endothelial cells had large, irregularly shaped nuclei with abundant euchromatin; mitotic figures were frequent. The cytoplasm contained numerous polysomes and cisterns of rough endoplasmic reticulum. Fibroblasts adjacent to damaged vessels had edematous cytoplasm and increased amounts of rough endoplasmic reticulum. In the affected left ventricular papillary muscles, necrotic myocytes showed contraction bands, mitochondrial matrical densities, lipid accumulation, initial lysis of I bands, and pyknotic nuclei. The lesions were judged to result from two mechanisms: (1) hemorrhagic lesions from drug-induced vascular injury centered on epicardial and subepicardial arterioles and (2) papillary muscle necrosis from ischemic injury from hypoperfusion during minoxidil-induced tachycardia and hypotension.

Animals↗
PubMed1984

DNA synthesis in rat atrial myocytes as a response to left ventricular infarction. An autoradiographic study of enzymatically dissociated myocytes.

An autoradiographic study was performed on enzymatically isolated atrial muscle cells to examine the DNA synthetic response of atria to left ventricular infarction. DNA synthesis was studied in left and right atrial myocytes and nonmyocytes of: young Sprague-Dawley rats 11 days after ligation of the left coronary artery; rats subjected to a sham surgical procedure without coronary artery ligation; unoperated rats. Each animal received a series of ten injections of tritiated thymidine at 12-h intervals, beginning on the fifth post-operative day; cells were isolated 36 h after the last injection. In infarcted animals, 37.1% of the left atrial myocytes were labeled and binucleated, and 6.5% were labeled and mononucleated; 13% of the right atrial myocytes were labeled and binucleated, while 12.7% were labeled and mononucleated. For both the left and right atria, the incidence of tritiated thymidine label in myocytes of the sham-operated group was similar to that of the unoperated controls, indicating that the surgical procedure did not stimulate DNA synthesis in atrial myocytes. In both left and right atria of the infarcted group, non-muscle cells were labeled to a greater extent (49.9% and 47.1%) than in the sham-operated group (22% and 20.8%), which in turn showed labeling to a greater extent than did the unoperated control group (10.9% and 11.6%), indicating that DNA synthesis was stimulated in non-myocytes of the atria by the sham operation and was further stimulated by experimental infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Toxic interactions of benzyl alcohol with bacterial endotoxin.

Acute toxic interactions of intravenously administered benzyl alcohol and Escherichia coli O55:B5 (Boivin preparation) endotoxin were examined in rodents. Lethality studies in male CD-1 mice demonstrated that these agents were more toxic when administered in combination than when either was administered alone. Prophylactic treatment with diazepam (5 mg/kg intraperitoneally) protected against lethality induced by either the combination or the endotoxin yet offered little, if any, protection against the lethal effects of benzyl alcohol. Similar treatments with naloxone (5 mg/kg intraperitoneally) failed to protect against either endotoxin-induced or benzyl alcohol-induced lethality, but they significantly protected against the lethal effects of the combination. Although hexobarbital-induced sleeping time was prolonged in endotoxin-treated mice (but was normal in benzyl alcohol-treated mice), a more protracted effect on sleeping time was observed in mice treated with both benzyl alcohol and endotoxin. Moreover, male Wistar rats treated with benzyl alcohol (40 mg) showed no evidence of hepatic lesions, but rats treated in combination with sublethal doses of the alcohol (40 mg) and the endotoxin (0.4 mg) developed hepatic lesions which were severe than those observed in rats treated with endotoxin (0.4 mg) alone. A correlation between altered blood chemistry values and severity of hepatic lesions was demonstrated. These data show in vivo toxic interactions between benzyl alcohol and bacterial endotoxin. In addition, our results indicate that the toxic effects induced by the benzyl alcohol-endotoxin combination are due to an enhancement of the lethal properties of bacterial endotoxin.

Animals↗
PubMed1984

Paraquat-induced pulmonary fibrosis. Role of the alveolitis in modulating the development of fibrosis.

Paraquat, a widely used herbicide, can cause severe and often fatal pulmonary fibrosis in humans and in laboratory animals. Although paraquat is known to be directly cytotoxic to lung parenchymal cells, the mechanism by which this leads to pulmonary fibrosis is not completely understood. In a model of paraquat-induced pulmonary fibrosis using the cynomolgus monkey, the administration of paraquat (10 mg/kg/wk subcutaneously for 2 consecutive wk) was followed by an alveolitis comprised of neutrophils and macrophages in the exposed animals as evaluated by lung morphologic examination and bronchoalveolar lavage. The lungs of the exposed animals showed typical interstitial fibrosis within 4 to 8 wk. At 1 to 2 wk after paraquat exposure, bronchoalveolar lavage cells harvested from the paraquat-exposed animals were spontaneously releasing a chemotactic factor for neutrophils, thus providing a possible mechanism for the recruitment of neutrophils to the alveolar structures. Lavage fluid from paraquat-exposed animals contained increased amounts of the fibroblast chemoattractant fibronectin (paraquat, 3.1 +/- 0.3 ng/micrograms albumin; control, 1.6 +/- 0.7 ng/micrograms albumin; p less than 0.05), and alveolar macrophages from these animals showed increased fibronectin production suggesting that local production accounted for part of the increased amounts of this glycoprotein (paraquat, 6.1 +/- 2.5 ng/10(6) cell/h; control, 1.4 +/- 0.5 ng/10(6) cell/h; p less than 0.05). In addition, alveolar macrophages from the exposed animals were spontaneously releasing a growth factor for fibroblasts, and normal alveolar macrophages exposed to paraquat in vitro were induced to release this growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis.

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.

Animals↗
PubMed1984

Role of pleural mesothelial cells in the production of the submesothelial connective tissue matrix of lung.

The pleura is comprised of a single layer of mesothelial cells resting on a complex layer of connective tissue. The ability of mesothelial cells to produce the components of this connective tissue was investigated using cultured rat mesothelial cells. These cells produced several components of extracellular matrix, including 6.8 +/- 0.2 X 10(5) collagen pro-alpha-chains per cell per hour, which represented 3.09 +/- 0.05% of all proteins synthesized by these cells. Chemical and immunologic criteria were used to demonstrate that these collagen chains included those of collagen types I, III, and IV. In addition, these cells produced elastin, as well as the connective tissue glycoproteins laminin and fibronectin. Moreover, electron microscopic studies revealed that lung mesothelial cells were capable of organizing these components into complex structures that resembled components of the extracellular matrix (thick collagen fibers, the amorphous component of elastic fibers, and basement membranelike structures), and restricted the formation of these structures to the basal region below the cells in culture. Thus, pleural mesothelial cells are active sources of a variety of connective tissue macromolecules found beneath mesothelial cells in situ, and can assemble these components into structures resembling the pleural extracellular matrix.

Animals↗
PubMed1984

Accurate quantification of cells recovered by bronchoalveolar lavage.

Quantification of the differential cell count and total number of cells recovered from the lower respiratory tract by bronchoalveolar lavage is a valuable technique for evaluating the alveolitis of patients with inflammatory disorders of the lower respiratory tract. The most commonly used technique for the evaluation of cells recovered by lavage has been to concentrate cells by centrifugation and then to determine total cell number using a hemocytometer and differential cell count from a Wright-Glemsa-stained cytocentrifuge preparation. However, we have noted that the percentage of small cells present in the original cell suspension recovered by lavage is greater than the percentage of lymphocytes identified on cytocentrifuge preparations. Therefore, we developed procedures for determining differential cell counts on lavage cells collected on Millipore filters and stained with hematoxylin-eosin (filter preparations) and compared the results of differential cell counts performed on filter preparations with those obtained using cytocentrifuge preparations. When cells recovered by lavage were collected on filter preparations, accurate differential cell counts were obtained, as confirmed by performing differential cell counts on cell mixtures of known composition, and by comparing differential cell counts obtained using filter preparations stained with hematoxylin-eosin with those obtained using filter preparations stained with a peroxidase cytochemical stain. The morphology of cells displayed on filter preparations was excellent, and interobserver variability in quantitating cell types recovered by lavage was less than 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1984

Alveolar macrophage replication. One mechanism for the expansion of the mononuclear phagocyte population in the chronically inflamed lung.

Within any chronically inflamed tissue, there is an increased number of macrophages, pluripotential phagocytic cells that, while critical to host defenses, are also able to profoundly damage parenchymal structure and function. Because of their central role in the inflammatory response, considerable attention has been focused on the mechanisms resulting in an expansion of the macrophage population within an inflamed tissue. Although recruitment of precursor monocytes from the circulation into inflamed tissues clearly plays an important role in macrophage accumulation, it is also possible that replication of tissue macrophages contributes to the expansion of macrophage numbers in inflammation. Because of the accessibility of tissue macrophages with the technique of bronchoalveolar lavage, the lung provides an ideal opportunity to test this hypothesis in humans. To accomplish this, bronchoalveolar lavage was performed to obtain alveolar macrophages from normals (n = 5) and individuals with chronic lung inflammation (normal smokers [n = 5], idiopathic pulmonary fibrosis [n = 13], sarcoidosis [n = 18], and other chronic interstitial lung disorders [n = 11]). Alveolar macrophage replication was quantified by three independent methods: (a) DNA synthesis, assessed by autoradiographic analysis of macrophages cultured for 16 h in the presence of [3H]thymidine; (b) DNA content, assessed by flow cytometric analysis of macrophages fixed immediately after recovery from the lower respiratory tract; and (c) cell division, assessed by cluster formation in semisolid medium. While the proportion of replicating macrophages in normals was very low, there was a 2- to 15-fold increase in this proportion in patients with chronic lung inflammation. In addition, morphologic evaluation demonstrated that individuals with chronic lung inflammation had alveolar macrophages undergoing mitosis. These results suggest that local tissue macrophage replication may play a role in the expansion of the macrophage population in chronic inflammation.

Adult↗
PubMed1984

The electron microscopic immunohistochemistry of elastase-treated aorta and nuchal ligament of fetal and postnatal sheep.

In conjunction with the immunoperoxidase and the immunoferritin methods, antielastin antibody was used to study the localization of elastin in untreated and elastase-treated elastic fibers of the nuchal ligament and the aorta of fetal and young adult sheep. In tissues not treated with elastase, the staining reaction for antielastin antibody was localized in the outer zones of the amorphous components and along the surfaces of the microfibrils ; the central zones of the amorphous components were unreactive. After mild elastase treatment, incompletely digested amorphous components showed staining both in their central and outer zones, and some of the microfibrils became unreactive. After extensive elastase treatment, small scattered amorphous components were still found in association with bundles of microfibrils. These components were stained diffusely by the antielastin antibody method but were not detectable by staining with uranyl acetate and lead citrate or with Kajikawa 's method for elastin; elastin was not detected on the surfaces of the microfibrils by any of the methods used. These findings were interpreted as indicating that the surfaces of the microfibrils are associated with small amounts of elastin, and that evenly stained amorphous components are composed of elastin, which is loosely arranged and allows the penetration of antielastin antibody. These observations support the concept that microfibrils serve an important role as a scaffold for elastin deposition in elastogenesis. Because of their high sensitivity, immunohistochemical methods for detecting elastin are useful to study partially degraded elastic fibers.

Age Factors↗