Prediction of therapeutic response in steroid-treated pulmonary sarcoidosis.
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Humans↗
Biomedical subjects
G L Snider
Publications and source records attributed to G L Snider.
Eglin-c, a polypeptide derived from the medicinal leech, prevents human neutrophil elastase-induced emphysema and bronchial secretory cell metaplasia in the hamster.
Eglin-c (Eg-c), a polypeptide with a molecular mass of 8,100 daltons, was purified from the medicinal leech Hirudo medicinalis. The Eg-c was tritiated by reductive methylation for in vitro studies. Incubation of 2.1 X 10(-10) moles of human neutrophil elastase (HNE) with 3H-elastin in the presence of 8.2 X 10(-10) moles of 3H-Eg-c inhibited 98.7% of the elastolytic activity of the enzyme. Using Sephadex G 100 chromatography and 1.7 moles of 3H-Eg-c per mole of HNE, a 34,000-dalton complex (3H-Eg-c-HNE) was observed. The stability of the complex formed between 3H-Eg-c and HNE that had been inactivated with succinyl-ala2-pro-val CH2Cl was much less than that of the 3H-Eg-c-HNE complex. In vivo studies were carried out in weight-matched groups of anesthetized golden Syrian hamsters given 100, 300, 500, or 2,000 micrograms of Eg-c in 0.5 ml saline intratracheally 1 h before 300 micrograms HNE was administered intratracheally. Control animals received saline followed by HNE or 2 doses of saline 1 h apart. Eight weeks later, lung statics and dynamics were measured in anesthetized animals, followed by histologic study of lung parenchyma and the mucosa of the large intrapulmonary airways. There were no deaths, and final mean body weights were similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Distinguishing among asthma, chronic bronchitis, and emphysema.
The history holds the central role in distinguishing among asthma, chronic bronchitis, and emphysema. A personal or family history of atopy, a history of seasonal worsening of disease in response to a known environmental agent, perhaps seasonal, and marked variability in the severity of airflow obstruction, often with dramatic responsiveness to bronchodilator drugs, strongly support the diagnosis of asthma. Exacerbation of wheezing by exposure to cold air or following the ingestion of a drug, and asthma variants, such as nocturnal cough responsive to bronchodilator agents or exercise-induced asthma, all support the diagnosis of asthma. Peripheral blood eosinophilia or sputum eosinophilia support the diagnosis of asthma providing other known causes of eosinophilia can be excluded. Positive skin tests are helpful in establishing the atopic state and indicating its possible etiology. An elevated serum IgE level supports the diagnosis of asthma; a normal one does not exclude it. Cigarette smoking is a common background factor in both chronic bronchitis and emphysema, and both diseases are infrequently observed in the absence of this history. Long-standing mucous hypersecretion preceding airflow obstruction suggests the presence of chronic bronchitis. Progressive dyspnea on effort as the predominant symptom suggests the possibility of emphysema. Reversibility of airflow obstruction suggesting the presence of asthma can be obtained either from physical examination or serial pulmonary function studies. Apart from this, neither of these techniques is very useful in differential diagnosis. Evidence of emphysema in the chest roentgenogram and a low value of the Dco/VA are sensitive tests for the presence of emphysema but are not highly specific. The main value of making the differentiation among these three conditions now lies in establishing a prognosis and guiding the use of corticosteroid therapy. As new information accumulates on the pathogenesis, prevention, and treatment of asthma, chronic bronchitis, and emphysema, precise diagnosis is likely to acquire increased significance.
Adult↗
Proteolytic activity of human neutrophil elastase and porcine pancreatic trypsin causes bronchial secretory cell metaplasia in hamsters.
The authors wished to determine whether secretory cell metaplasia (SCM) induced in the bronchi of hamsters by human neutrophil elastase (HNE) was enzymatically mediated. We also wished to determine whether SCM could be induced by a proteolytic enzyme devoid of elastolytic activity. Accordingly, groups of weight-matched hamsters were given a single intratracheal instillation of 0.5 ml of saline solution containing one of the following: 300 micrograms of HNE purified from blood neutrophils, n = 14; 300 micrograms of HNE inactivated with Suc-Ala-Ala-Pro-Val chloromethyl ketone (CMK), n = 10; 500 micrograms of porcine pancreatic trypsin treated with CMK to eliminate residual active elastase, n = 10; 500 micrograms of trypsin inactivated by tosyl lysine chloromethyl ketone, n = 10; 2 micrograms CMK, n = 10; and saline alone, n = 10. Seven untreated animals served as additional controls. Twenty-one days post treatment, 5-6 micron paraffin-embedded sections, from the left lung hilar region, stained by Alcian blue and periodic acid-Schiff reaction were graded on a five-point scale for determination of the secretory cell index, which reflects SCM. Both elastase and trypsin produced severe SCM: mean +/- SEM secretory cell indices were 2.96 +/- 0.11 and 2.72 +/- 0.19, respectively, compared with values of 0.90 +/- 0.35 for the untreated group and 0.93 +/- 0.46 for the saline group (p less than .05). The secretory cell indices of the groups treated with inactivated elastase or trypsin were comparable to those of the saline-treated and untreated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Myeloperoxidase-induced inactivation of alpha 1-antiprotease in hamsters.
While numerous studies have demonstrated that the myeloperoxidase system found in neutrophils can oxidize and functionally inactivate alpha 1-proteinase inhibitor in vitro, there is little direct evidence that this phenomenon is relevant in vivo. Using incubation with tritiated porcine pancreatic elastase followed by column chromatography to quantitate binding, we demonstrated recovery of microgram amounts of functional alpha 1-protease inhibitor from bronchoalveolar lavage of hamster lungs. When exposed to the myeloperoxidase system in vitro, hamster alpha 1-protease inhibitor was 97% inactivated. Functional alpha 1-protease inhibitor recovered by bronchoalveolar lavage 20 minutes after hamsters were given intratracheal injections with myeloperoxidase and either hydrogen peroxide or glucose plus glucose oxidase was only half that recovered from control animals. These studies suggest that the myeloperoxidase system is effective in oxidizing alpha 1-protease inhibitor in vivo. They support the concept that oxidation of alpha 1-protease inhibitor by myeloperoxidase from neutrophil granules in the presence of H2O2 and halide may produce elastase-antielastase imbalance in vivo and contribute to the development of acute lung injury and emphysema in humans.
Animals↗
Quantitative study of secretory cell metaplasia induced by human neutrophil elastase in the large bronchi of hamsters.
To explore the time course and the mechanism of development of bronchial secretory cell metaplasia (SCM) induced by human neutrophil elastase (HNE), anesthetized hamsters were injected intratracheally with 300 micrograms highly purified HNE in 0.5 ml saline solution; saline-injected and untreated animals served as controls. At 3, 8, 16, and 21 days after treatment, animals were killed and their lungs fixed by vascular perfusion. Samples from the hilar region of the left lung, containing the main axial airway and its proximal branches, were embedded in Epon-Araldite, and 1 micron sections were stained with methylene blue. Epithelial cells with a luminal border were categorized into three cell types and expressed as a percent of total cells counted (mean 1900 per animal); cells containing at least three mucin granules were classified as secretory, ciliated cells displayed cilia or basal bodies, and cells with none of these characteristics were classified as indeterminate. Percentages of the three cell types in saline-treated animals, at all time points, were comparable to those in the untreated controls. With HNE treatment the secretory cell percentages were higher at 16 days (mean +/- SEM, 36.4% +/- 3.2%) and at 21 days (35.7% +/- 2.9%) than in the untreated animals (18.2% +/- 1.8%, P less than 0.05). The percentage of the indeterminate cells in the HNE group was decreased at days 8, 16, and 21 (7.2% +/- 1.6%, 5.0% +/- 1.4%, and 8.2% +/- 2.5%, respectively) compared with that in the untreated group (21.7% +/- 2.5%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Biochemical properties and possible therapeutic role of the elastase inhibitor eglin C.
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Animals↗
Eglin c, a pharmacologically active elastase inhibitor.
Eglin c is an elastase/cathepsin G inhibitor from leech Hirudo medicinalis. The gene for this 70 aminoacid peptide was synthesized chemically, cloned and expressed by E. coli. Here we report biochemical and pharmacological studies. The rate of complex formation between Eglin c and human leukocyte elastase (HLE) or human cathepsin G (H. Cat. G) was determined and compared to those of a number of other proteinase/proteinase-inhibitor interactions (alpha 1 PI and alpha 2M). The association rate constants of Eglin c with the leukocyte enzymes are of the same order of magnitude as those with the naturally occurring inhibitors alpha 1 PI and alpha 2M. The association rate constant of Eglin c (extracted from leech) and Eglin c (biotechnology product) with HLE was found to be identical. The equilibrium constants Ki of the Eglin c/HLE and the Eglin c/H. Cat. G interactions are in the order of 10(-10) M. In an experiment with the hamster emphysema model, 0.5 mg or 2 mg of Eglin c applied intratracheally one hour before an HLE-insult completely protected the animals against emphysema and no signs of toxicity due to Eglin c were observed.
Animals↗
Two decades of research in the pathogenesis of emphysema.
Alpha 1 antiprotease is the major antiprotease (or antielastase) in the lungs. Neutrophils are the major source of elastase. Elastases damage interstitial elastic fibers giving rise to elastase-antielastase imbalance and to emphysema. Lung volume and volume-pressure (VP) curve is shifted up and to the left in elastase treated hamsters compared to the controls; quasi-static compliance increases from 0.52 ml/cm to 0.92 ml/cm in the elastase treated animals. The histologic, stereologic and physiologic data of hamster's emphysema are all similar to the changes observed in human emphysema. Cigarette smoke is rich in oxidants inactivating alpha 1 antiproteases. There is also a decrease in the level of alpha 1 antiproteases in lavage fluid of smokers. An intensive search is now underway for synthetic antielastases which might be safely given to persons who are at risk of developing emphysema.
Amino Acid Chloromethyl Ketones↗
Treatment of chronic pancreatitic pleural effusion by percutaneous catheter drainage of abdominal pseudocyst.
A 53-year-old man entered the hospital with a large, right chronic pancreatitic pleural effusion. Computed tomographic examination of the abdomen and chest demonstrated a pancreatic pseudocyst that had extended into the mediastinum. After conventional closed-chest tube thoracotomy drainage failed to empty the pleural space, percutaneous abdominal pseudocyst drainage was instituted using computed tomographic guidance. The pleural effusion cleared promptly, and the pancreatic pseudocyst resolved gradually over seven weeks. Following termination of pseudocyst drainage, the patient has remained well for over two years with no recurrence of pancreatitis, pseudocyst, or pleural effusion. In contrast, three earlier patients with a chronic pancreatitic effusion managed conventionally had a complicated hospital course and required surgical intervention; two had recurrent pancreatitis following hospital discharge. Percutaneous catheter placement was unsuccessful in one of these three and, in retrospect, was infeasible in the other two. It is recommended that thoracoabdominal computed tomography be performed in all patients with a chronic pancreatitic pleural effusion, and that percutaneous abdominal catheter drainage be attempted in all patients with an accessible pancreatic or mediastinal pseudocyst. Such treatment may relieve respiratory insufficiency, minimize the risk of empyema or fibrothorax, and may promote pseudocyst closure without the need for surgery.
Chronic Disease↗
Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products.
Purified human neutrophil elastase (HNE) and a crude extract of human neutrophils (EXT) were administered intratracheally to hamsters, and their effects were determined 21 and 56 days later by measurement of lung statics and dynamics and by light microscopy and morphometry of the lungs. A dose of 450 micrograms of HNE (HNE 450) produced focal emphysema of moderate severity. The combination of HNE 450 and EXT (HNE 450 + EXT) produced no more severe emphysema than HNE 450 alone; EXT alone did not produce emphysema. The HNE 450, HNE 450 + EXT, and EXT all produced persistent secretory cell metaplasia in large intrapulmonary airways. In a second experiment, 40 micrograms of HNE (elastolytic activity equivalent to that in EXT), designated HNE 40, did not produce secretory cell metaplasia. Neither EXT nor EXT treated with the elastase inhibitor suc-ala-ala-pro-val chloromethyl ketone (EXT + CMK), which had a residual elastolytic activity equivalent to 15 micrograms of HNE, produced emphysema; both preparations caused bronchial secretory cell metaplasia 21 days after treatment. Values of maximal expiratory flow, measured 21 days after treatment, were reduced at points between 20 and 50% of vital capacity for HNE 450 and between 30 and 80% of vital capacity for HNE 450 + EXT; maximal expiratory flows were not significantly different from saline controls for HNE 40, EXT, or EXT + CMK.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A controlled trial of intermittent positive pressure breathing, incentive spirometry, and deep breathing exercises in preventing pulmonary complications after abdominal surgery.
Controversy exists regarding the routine use of aids to lung expansion in the prevention of pulmonary complications after abdominal surgery. We prospectively randomized 172 patients into 1 of 4 groups: the control group (44 patients) received no respiratory treatment, the IPPB group (45 patients) received intermittent positive pressure breathing therapy for 15 min 4 times daily, the IS group (42 patients) was treated with incentive spirometry 4 times daily, and the DBE group (41 patients) carried out deep breathing exercises under supervision for 15 min 4 times daily. Roentgenographic changes, observed 24 h after surgery, were comparable in the 4 groups (20.5 to 36.6%). Pulmonary complications were defined as the development of 3 or more of 6 new findings: cough, phlegm, dyspnea, chest pain, temperature greater than 38 degrees C, pulse rate more than 100 beats/min. The frequency of development of pulmonary complications was 48% in the control group, 22% in the IPPB group (p less than 0.05), 21% in the IS group (p less than 0.05), and 22% in the DBE group (p less than 0.05). Side effects of respiratory treatment were observed only in the IPPB group (18%; p less than 0.05). Hospital stay in patients undergoing upper abdominal surgery was significantly shorter in the IS group (mean +/- SD, 8.6 +/- 3 days) than in the control group (13 +/- 5 days). This difference was not observed for the other 2 treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Abdomen↗
Interstitial pulmonary fibrosis induced in hamsters by intratracheally administered chrysotile asbestos. Histology, lung mechanics, and inflammatory events.
The development of interstitial pulmonary fibrosis (IPF) is associated with persistent cellular infiltration and progressive connective tissue accumulation in the alveolar walls. To develop and characterize an animal model of IPF in which pulmonary fibrosis evolves slowly, as well as to develop an inexpensive, easily produced, model of asbestosis, Syrian golden hamsters received single intratracheal injections of either UICC chrysotile asbestos or saline. Animals were then examined at time points up to 180 days for pulmonary histologic and physiologic changes, cytologic characteristics of cells recovered by bronchoalveolar lavage, and spontaneous release of neutrophil chemoattractant activity by alveolar macrophages. Within days after asbestos treatment, hamsters developed a patchy bronchopneumonia centered around terminal airways, which progressed peripherally with time to involve the alveolar walls with persistent inflammation and the gradual development of interstitial and peribronchiolar fibrosis. These histologic changes were accompanied by physiologic findings of air-flow obstruction with air trapping. Bronchoalveolar lavage revealed a persistent neutrophilia that began within 24 h of asbestos treatment; this was associated with the spontaneous release of neutrophil chemotactic activity by cultured alveolar macrophages. In this animal model, pulmonary inflammation and fibrosis can be predictably produced by a single intratracheal instillation of chrysotile asbestos. It represents a useful tool for studying both asbestosis and pulmonary fibrosis in general.
Animals↗
Alveolar macrophage modulation of proteolysis by neutrophil elastase in extracellular matrix.
An extracellular connective tissue matrix, made up of components found in the pulmonary alveolar interstitium, was generated in vitro and used as a culture surface and substrate for proteolysis by human alveolar macrophages (AM) and neutrophil elastase (NE). The ability of human AM to modulate NE-mediated degradation of elastin and collagen in the surrounding matrix was studied to gain insights into the inflammatory process that accompanies the pathogenesis of emphysema in humans. Neutrophil elastase that had been internalized by AM showed a diminished but more prolonged time course of matrix proteolysis than did a similar amount of NE added to the matrix in the absence of AM. Collagen and elastin degradation were quantitated by release of hydroxylysine and desmosine, respectively, into the culture medium. Significantly more hydroxylysine and desmosine were released by AM that had internalized NE than by AM or by culture medium alone. When 14 X 10(6) AM were added to the extracellular matrix, followed 2 h later by addition of 2 micrograms of NE, collagen and elastin degradation measured at 24 h were not significantly different from that which occurred when matrix was incubated with NE in the absence of AM. Collagen degradation, determined in the same cultures during the period from 24 to 96 h, was significantly greater when matrix was incubated with both AM and NE. These findings suggest that AM can release previously internalized NE in an enzymatically active form and that AM may enhance collagen degradation in matrix that was also exposed to NE.
Animals↗
Rehabilitation of ventilator-dependent subjects with lung diseases. The concept and initial experience.
Sixteen ventilator-dependent patients were enrolled in an in-patient pulmonary rehabilitation (PR) program in a university medical center with the goals of achieving independent self-care, mobility and discharge home. Ten patients had chronic obstructive pulmonary disease and six had restrictive respiratory disorders. PR by a multi-disciplinary team consisted of five phases: 1) stabilization; 2) evaluation; 3) rehabilitation planning including motivation by allowing speech and mobility; 4) rehabilitation training encouraging independent performance of activities of daily living (ADL); and 5) discharge planning with training of patients and families in home respiratory care techniques. A key aspect of the program is improving independence early in the program through the use of mobile ventilators. Periods of weaning from ventilatory support for two or more hours per day were of great importance in improving patient mobility and independence in ADL. Twelve patients were discharged home; except for two individuals who were severely limited by neuromuscular disease, all patients were largely independent in ADL in the home. This preliminary report demonstrates the feasibility of training ventilator-dependent persons to be independent and to participate in their own care in the home.
Activities of Daily Living↗
Errant placement of nasoenteric tubes. A hazard in obtunded patients.
We describe a case of intubation of both main-stem bronchi with a narrow-bore nasoenteric tube on two separate occasions, with the subsequent development of pleural effusions of enteral solution, in an elderly semicomatose woman with a properly positioned cuffed endotracheal tube. Neither aspiration of fluid from the tube nor propulsion of air with auscultation of gastric borborygmi are positive proof of proper positioning. We recommend that in obtunded patients, especially if there is the possibility of impaired mucosal integrity, appropriate placement of the tube should be confirmed by chest roentgenogram.
Aged↗
American College of Chest Physicians (ACCP)--National Heart, Lung, and Blood Institute (NHLBI) Conference on oxygen therapy.
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Humans↗