American Thoracic Society. Incoming president's address.
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Humans↗
Biomedical subjects
G M Turino
Publications and source records attributed to G M Turino.
The effectiveness of film and videotape in teaching cardiopulmonary resuscitation to the lay public.
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Audiovisual Aids↗
Increased synthesis of elastin in amiodarone-induced pulmonary fibrosis.
Both synthesis and total content of lung elastin were measured after induction of interstitial pulmonary fibrosis in hamsters by a single intratracheal insufflation of amiodarone. Elastin synthesis, as measured by 14C-lysine incorporation into desmosine and isodesmosine, was significantly elevated (P less than 0.05) above control values for a 3-week interval after induction of lung injury. Total lung elastin content in the amiodarone-treated animals was 32% greater than in controls (P less than 0.05) 2 weeks after insufflation of the agent. Furthermore, the time course of elastin synthesis in this experimental model was similar to that observed in bleomycin-induced pulmonary fibrosis in hamsters. Increases in elastin may therefore be a common feature of interstitial pulmonary fibrosis and may contribute to the altered lung mechanics seen in this disease.
Amiodarone↗
Interleukin 1 secretion from human alveolar macrophages in lung disease.
Interleukin 1 secretion from human alveolar macrophages was studied in patients with interstitial pulmonary fibrosis, sarcoidosis, and the acquired immunodeficiency syndrome with pneumonitis and compared to secretion from alveolar macrophages of normal volunteers. Macrophages lavaged from the lungs were stimulated with 10 micrograms/ml of lipopolysaccharide and cultured for 24 hr. In some cases macrophages were also stimulated with 1 microgram/ml lipopolysaccharide. After dialysis of the culture supernatants, interleukin 1 secretion was quantified by the thymocyte proliferation assay and probit analysis and expressed in terms of secretion from 1 million macrophages. Results showed that, on average, macrophages derived from patients secreted more interleukin 1 after stimulation with lipopolysaccharide compared to normal subjects. Mean secretion was significantly greater from macrophages of patients with acquired immunodeficiency syndrome and interstitial pulmonary fibrosis when stimulated with 10 micrograms/ml lipopolysaccharide. Of the 24 individuals studied, spontaneous interleukin 1 secretion was detected from unstimulated macrophages in only 1 patient and 1 normal volunteer. We conclude that alveolar macrophages lavaged from the lungs of patients with inflammatory lung disease have an increased capacity to secrete interleukin 1 on in vitro stimulation with lipopolysaccharide. Possible mechanisms for this increase are discussed.
Acquired Immunodeficiency Syndrome↗
The fibronectin content of canine lungs is increased in bleomycin-induced fibrosis.
Fibronectin (Fn), a high molecular weight glycoprotein, was found to constitute 0.43% of the normal adult beagle dog lung. The tissue Fn (TFn) was solubilized by sequential chemical extractions and quantified by ELISA (enzyme-linked immunoabsorbent assay). Subsequent plasmin digestion did not appear to solubilize significantly more Fn. Since 70% of the lung tissue was solubilized by the extractions and plasmin digestions, the TFn quantified represented the bulk of lung Fn. The TFn was identical to plasma fibronectin in the ELISA and one can infer that the Fn molecule is not significantly altered as it is incorporated into the lung connective tissue matrix. Lungs from beagles in which fibrosis had been induced with bleomycin contained 0.99% Fn, more than a twofold increase over normal. In the ELISA TFn from fibrotic lungs gave an inhibition curve of the same shape as did TFn from normal lungs. Thus, Fn from fibrotic lungs is not different qualitatively from Fn from normal lungs in any way detectable with this antiserum. The TFn content of plasmin digests of intact lung was less than that of extracts, which was the converse of results obtained on placenta (B. A. Bray (1985) Biochem. J. 226, 811-815). This difference between lung TFn and placental TFn may be due to differences in degree of glycosylation, which determines susceptibility to proteases.
Animals↗
Secretion of interleukin 1/leucocytic pyrogen from endotoxin-stimulated human alveolar macrophages is unaffected by indomethacin.
Human alveolar macrophages obtained from 7 normal volunteers and 7 patients with lung disease were stimulated with endotoxin (lipolysaccharide) to induce interleukin 1/leucocytic pyrogen (IL1/LP) secretion. Using the thymocyte assay we quantitated IL1/LP activity in macrophage supernatants obtained after 24 h. 10 micrograms/ml lipopolysaccharide stimulated alveolar macrophages to secrete significantly more IL1/LP activity than did 1 micrograms/ml. Apart from one patient with sarcoidosis, the presence of indomethacin did not significantly inhibit the quantity of IL1/LP secreted in response to LPS. We also demonstrated that the presence of indomethacin did not affect the response of thymocytes to IL1/LP. We conclude that the secretion of IL1/LP by human alveolar macrophages in response to endotoxin is not significantly reduced by the cyclooxygenase inhibitor indomethacin.
Animals↗
Interleukin-1 secretion by human alveolar macrophages stimulated with endotoxin is augmented by recombinant immune (gamma) interferon.
We investigated the role of the macrophage-activating factor gamma interferon (IFN) in the in vitro secretion of interleukin-1 (IL-1) from human alveolar macrophages. Macrophages were obtained from 6 normal volunteers and 5 patients by bronchoalveolar lavage. Macrophages were adhered to a plastic surface and then stimulated to secrete IL-1 with concentrations of endotoxin (LPS) ranging from 1 ng/ml to 10 micrograms/ml. Unstimulated macrophages served as a control. Recombinant gamma IFN was added to LPS-stimulated or unstimulated macrophage cultures in concentrations ranging from 0.25 to 1,000 U/ml. After 24 h of culture, supernatants were removed and IL-1 activity was measured by the thymocyte proliferation assay. Gamma IFN directly induced IL-1 secretion from macrophages of 2 of the subjects. In the presence of LPS, gamma IFN markedly augmented IL-1 secretion from macrophages of 10 of the 11 subjects. Gamma IFN could prime macrophages for increased response to LPS after 1 h of incubation. We conclude that gamma IFN provides a modulating signal for in vitro LPS-induced IL-1 secretion from alveolar macrophages and may enhance macrophage reactivity to inflammatory mediators in vivo.
Animals↗
Synthesis of crosslinked elastin by a mesothelial cell culture.
Synthesis of crosslinked elastin was measured in cultures of pleural mesothelial cells. Results indicate that mesothelial cells are a rich source of crosslinked elastin and may therefore be useful for in vitro studies of this connective tissue component.
Autoradiography↗
The future of the doctor-patient relationship.
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Education, Medical↗
Collagenous membrane from the surface of human visceral pleura.
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Adult↗
Stimulation of lung lysyl oxidase activity in hamsters with elastase-induced emphysema.
Lysyl oxidase activity was measured in lung extracts of hamsters with elastase-induced emphysema 8 days after administration of the enzyme and again after 2, 3, and 4 wk. Levels of activity rose rapidly to 7 times the base values determined in the lungs of saline-injected control animals. In parallel with the increase in lysyl oxidase activity, the rate of 14C-lysine incorporation into desmosine and isodesmosine was at its maximum 1 wk after elastase administration, reflecting the lysyl-oxidase-mediated cross-link formation, which is the final step in the resynthesis of the pulmonary elastin destroyed by the elastolytic insult.
Amino Acid Oxidoreductases↗
Cigarette smoke impairs elastin resynthesis in lungs of hamsters with elastase-induced emphysema.
The severity of pulmonary emphysema can be affected by exposure to cigarette smoke in several ways. Inactivation of alpha-1-antitrypsin and recruitment of leukocytes to lung airways shifts the protease-antiprotease balance towards increased elastolytic activity. The present study demonstrates an additional effect of cigarette smoke inhalation and retardation of the repair process and of the neosynthesis of cross-linked elastin. Hamsters with elastase-induced emphysema, exposed to cigarette smoke for 1 wk immediately after elastase administration, showed a 40% reduction of 14C-lysine incorporation into the elastin-specific cross-links, desmosine, and isodesmosine. Concomitantly, there was a decrease in the level of lung lysyl oxidase to that observed in uninjured control animals, in sharp contrast to the sevenfold increase in lysyl oxidase activity in hamsters with elastase-induced emphysema recovering under atmospheric conditions. These findings suggest that impairment of the production of lysyl oxidase and the resynthesis of cross-linked elastin by smoke inhalation exacerbates alveolar destruction.
Animals↗
The lung parenchyma--a dynamic matrix. J. Burns Amberson lecture.
The matrix of the lung parenchyma is composed predominantly of collagen, elastin, glycosaminoglycans, and fibronectin. This presentation focuses on the newer insights into injury and repair of lung elastin and glycosaminoglycans. Elastin and glycosaminoglycans respond in characteristic patterns to destructive and proliferative forms of lung injury. Elastin degradation induced by elastases induces a prompt and marked response by elastin resynthesis in situ. The signal for the stimulus remains unknown and deserves to be understood. The measurement of elastin peptides in plasma, urine, or bronchoalveolar lavage fluid can provide an objective index of elastin degradation in disease. Elastin depletion may be augmented by factors that interfere with elastin resynthesis such as exposure to tobacco smoke. Glycosaminoglycans participate in similar fashion in many different forms of lung injury as an early response to injury, which may then determine the subsequent cellular processes of repair. Studies of injury and repair in organ systems, other than the lung, suggest a general role for glycosaminoglycans in interstitial tissue and repair. The mediators that alter matrix chemical structure and function could provide powerful instruments for controlling the process of tissue injury and repair in the lung.
Airway Resistance↗
Impairment of elastin resynthesis in the lungs of hamsters with experimental emphysema induced by sequential administration of elastase and trypsin.
The nonelastolytic proteases trypsin and chymotrypsin were administered to hamsters 24 hours after intratracheal injection of elastase. Severity of the disease, extent of degradation and resynthesis, new cross-link formation, and the levels of the enzyme lysyl oxidase, which mediates the cross-link formation, were compared with the same parameters measured in hamsters with experimental emphysema induced by elastase alone. Increases in mean linear intercept indicated that a more severe form of the disease was produced. Although elastin degradation after 1 week was similar in both groups, resynthesis of the elastin destroyed by the elastolytic insult was significantly impaired in the animals injected sequentially with elastase and trypsin or chymotrypsin. Formation of new elastin as monitored by 14C-lysine incorporation into the elastin specific cross-links desmosine and isodesmosine was reduced approximately 40%, although there was no significant difference in the levels of lysyl oxidase activity. It is suggested that the most likely mechanism compatible with the recorded observations involves destruction of the microfibrillar component of the elastic fiber by trypsin or chymotrypsin, resulting in the absence of the requisite template for resynthesis of the pulmonary elastin.
Animals↗
Emphysema induced by intravenously administered endotoxin in an alpha 1-antitrypsin-deficient rat model.
The effect of repeated intravenous injections of Escherichia coli endotoxin on lung structure and lung parenchymal elastin proportions was studied in rats rendered deficient in alpha 1-antitrypsin by administration of galactosamine. Within 24 h after endotoxin administration, polymorphonuclear leukocyte sequestration was demonstrable by microscopy and differential cell counts of pulmonary lavage fluid. Measurement of the proportions of elastin in lung parenchyma at 24 h revealed values in the normal range; 10 wk after repeated galactosamine and endotoxin administration, there was a reduction in the proportions of lung parenchymal elastin. At 10 wk, these animals showed a significant increase in the mean linear intercept and pulmonary compliance. Animals treated with endotoxin alone developed some but not all of the changes seen in the animals deficient in alpha 1-antitrypsin.
Animals↗
Amiodarone-induced pulmonary fibrosis in hamsters.
Amiodarone, a cardiac antiarrhythmic agent, has been associated with the development of interstitial pulmonary fibrosis in patients receiving prolonged therapy with the drug. To further assess the toxic effects of amiodarone on lung tissue, Syrian hamsters were given a single intratracheal insufflation of the agent and evaluated for histologic evidence of lung injury. Control animals received intratracheal insufflations of the vehicle in which amiodarone was dissolved. After an initial, transient alveolitis in both experimental and control animals, the amiodarone-treated lungs developed increased interstitial thickening due to fibrinous exudates, alveolar epithelial hyperplasia, inflammatory cell infiltrates, and marked deposition of collagen manifested on trichrome staining. Controls, in contrast, showed nearly complete resolution of the initial alveolitis. An unusual feature of the amiodarone-induced lung injury was reemergence of the alveolitis between 5 and 14 days, which included a marked influx of eosinophils into the lung. Although the precise mechanism of the lung injury is not known, the persistence of the acute inflammatory cells as well as the presence of eosinophils suggests a hypersensitivity-type reaction. Furthermore, the progression of lung injury to fibrosis after a single insult with the drug suggests that mere discontinuation of amiodarone therapy in humans may not reverse the disease process, but that corticosteroid therapy may also be required. Amiodarone appears to be a useful agent to induce diffuse fibrotic reactions in the lung that morphologically resemble idiopathic pulmonary fibrosis in humans.
Amiodarone↗
Measurement of cross-linked elastin synthesis in bleomycin-induced pulmonary fibrosis using a highly sensitive assay for desmosine and isodesmosine.
Cross-linked elastin synthesis was measured in the intratracheal bleomycin model of interstitial pulmonary fibrosis by incorporation of 14C-lysine into the elastin-specific crosslinks, desmosine and isodesmosine. Detection of the labeled crosslinks was facilitated by development of a highly sensitive assay utilizing thin-layer electrophoresis. The results indicate that crosslinked elastin synthesis is significantly elevated from controls (p less than 0.05) at 1 to 3 weeks after exposure to bleomycin and returns to normal by 5 weeks. The increases in labeled elastin synthesis are not directly related to changes in either total lung protein synthesis or the pool size of the 14C-lysine. In comparison with collagen and glycosaminoglycan synthesis in this model of lung injury, maximal increases in cross-linked elastin formation occur later, but overlap with the elevated synthesis of these other connective tissue components. The marked increase from normal in cross-linked elastin synthesis in this model suggests that this tissue component is an important part of the fibrotic response of the pulmonary parenchyma and may play a role in the observed alterations in lung structure and function.
Amino Acids↗