Functional alpha 1-protease inhibitor in the lower respiratory tract of cigarette smokers is not decreased.

Cigarette smoking is the major risk factor for the development of pulmonary emphysema, a disorder that may result from an imbalance between the elastase and antielastase levels in the lungs. Decreased functional alpha 1-protease inhibitor, an inhibitor of neutrophil elastase, might render smokers susceptible to elastase-catalyzed destruction of pulmonary elastic fibers and the development of emphysema. Binding and inactivation of isotopically labeled porcine pancreatic elastase and human neutrophil elastase by alpha 1-protease inhibitor were measured in fluid obtained by bronchoalveolar lavage of volunteers. The inhibition of elastase-catalyzed solubilization of elastin and a tripeptide substrate were also determined. The mean level of functional alpha 1-protease inhibitor in the bronchoalveolar lavage fluid of smokers was found to be equal to or greater than that of nonsmokers, contradicting reports by other investigators. Increased elastase derived from pulmonary neutrophils, rather than decreased functional alpha 1-protease inhibitor, appears to be the main factor in the genesis of emphysema in smokers.

Desmosine as a biomarker of elastin degradation in COPD: current status and future directions.

Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without alpha(1)-antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.

Irreversible bronchial goblet cell metaplasia in hamsters with elastase-induced panacinar emphysema.

A single intratracheal instillation of pancreatic elastase in hamsters induces a lesion resembling human panacinar emphysema. This paper reports the occurrence of irreversible goblet cell metaplasia in the bronchial epithelium of hamsters similarly exposed to elastase. The goblet cell change was dose related; a dose of 0.1 mg/100 g body wt or less at 16 days, produced slight or moderate goblet cell metaplasia in fewer than half the animals, whereas 84% of animals treated with a dose between 0.2 and 0.5 mg/100 g body wt developed goblet cell metaplastic lesions, more than half of which were considered to be severe. The percentage of goblet cells in the epithelium of elastase-treated hamsters (32.5) was significantly higher (P less than 0.005) than that of unexposed (12.2) and saline-exposed controls (18.7). All hamsters examined 6 and 12 mo after elastase treatment showed the lesion. The pathogenesis of the changes is unclear but the possibility is raised that the bronchial changes may be due to disturbance of an endogenous protease-antiprotease system. The findings suggest the hypothesis that, under appropriate circumstances, a single pulmonary insult in man could lead to a permanent lung injury demonstrating the anatomic lesions of both chronic bronchitis and panacinar emphysema.

Role of alpha-macroglobulin-elastase complexes in the pathogenesis of elastase-induced emphysema in hamsters.

Radiolabeled, enzymatically active or chloromethyl ketone-inactivated porcine pancreatic elastase was endotracheally instilled into hamsters. Gel filtration of the bronchopulmonary lavage fluid revealed two major radioactive fractions: one, eluting at 780,000 daltons, corresponding to an alpha-macroglobulin-pancreatic elastase complex, and another, at 68,000 daltons, corresponding to an alpha-1-protease inhibitor-pancreatic elastase complex. Elastolytic activity was recovered in the bronchopulmonary lavage fluid up to 4 d after elastase instillation and was associated with the alpha-macroglobulin-pancreatic elastase complex. Small amounts of this complex were recovered 14 d after instillation. When less than 1% (1.5--1.7 micrograms) of the usual dose of elastase was instilled into hamsters, the major radioactive complex was alpha-1-protease inhibitor-pancreatic elastase complex, and little or no elastolytic activity was found in the lavage fluid. In contrast to the instillation of 220 micrograms of elastase, no disease or hemorrhagic reaction was detected with this low dose, and without hemorrhage only insignificant amounts of alpha-macroglobulin-pancreatic elastase complexes were recovered from the lungs. To study the interaction of circulating antiproteases with elastase, hamster plasma was allowed to interact directly with the radiolabeled elastase; alpha-macroglobulin bound much more of the elastase than alpha-1-protease inhibitor, confirming the findings in the lung lavage experiments. The hamster's susceptibility to pancreatic elastase-induced emphysema may depend on the preferential binding of elastase to alpha-macroglobulin, which protects the elastolytic potential, rather than to alpha-1-protease inhibitor, which inactivates elastase. We speculate that if even a fraction of the residual radioactivity found in the hamster lungs as long as 144 d after instillation of elastase represents enzymatically active alpha-macroglobulin-pancreatic elastase complex, this could serve as a source of persistent elastolytic activity, which might explain the progressive nature of the pulmonary lesion.

Partial purification and characterization of a gelatin-specific protease from the culture media of human pulmonary alveolar macrophages.

A gelatin-specific protease from the culture media of human pulmonary alveolar macrophages has been partial purified by gel filtration and characterized. The macrophages were obtained by bronchopulmonary lavage from the lungs of disease-free smoking volunteers. The gelatin-specific protease initially requires trypsin activation. After chromatographing the culture media on a Sephadex G-200 column, trypsin is no longer required for activation. The gelatin-specific protease reported here shares many properties of previously reported gelatinases. It is inhibited by EDTA, cysteine, dithiothreitol and serum. It is unaffected by other protease inhibitors: phenylmethylsulfonyl fluoride, tosyllysine chloromethyl ketone and p-chloromercuribenzoate. Of all substrates tested activity was observed only with gelatin. It was inactive toward collagen, elastin and methemoglobin. This enzyme may have a role in the digestion of collagen which has been cleaved by a mammalian collagenase.

Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity.

We conclude that chronic necrotizing pulmonary aspergillosis is a clinical entity which has not usually been recognized as one of the forms of pulmonary disease due to Aspergillus species. Patients are middle-aged, and often have some evidence of impairment of host defenses such as diabetes mellitus, a connective tissue disorder, poor nutrition, chronic obstructive lung disease or low dose corticosteroid therapy. They are almost always symptomatic with fever and a productive cough, and their chest roentgenogram shows infiltrative and cavitary disease, typical of a chronic destructive lung process such as tuberculosis or anaerobic infection. Cavity formation is often accompanied by the development of a mycetoma. The disease is usually of 1 to 6 months duration but can be present for years prior to diagnosis. The diagnosis is suggested by the clinical course and the isolation of the fungus from pulmonary secretions; negative cultures for other pathogens and failure to respond to antibacterial or antimycobacterial therapy are characteristic. The diagnosis is confirmed by pathologic evidence of tissue invasion by the fungus or a response to specific antimycotic therapy. The symptomatic response to antifungal chemotherapy, at times combined with surgical drainage or resection, is favorable. However, roentgenographic resolution is not uniform, and many patients have residual cavitary disease. The long-term prognosis is uncertain.

Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease.

Arterial blood gases were measured during 7 hours of sleep in 15 patients with severe stable chronic obstructive pulmonary discrease (COPD); 6 awake patients with COPD studies in recumbency for an average of 5 hours served as controls. Mean maximal decrease in arterial oxygen partial pressure (PaO2) (plus or minus SD) was 13.5 plus or minus 3.9 mm Hg for sleeping patients (p less than 0.005) and 5.5 plus or minus 1.7 mm Hg for controls (p less than 0.1), respectively. Changes in pH during sleep were of the magnitude expected with acute changes in arterial carbon dioxide partial pressure (PaCO2) in patients with chronic hypercapnia. Consistent changes in heart rate, respiratory frequency or cardiac rhythm were not observed during sleep. Nocturnal worsening of hypoxemia could be explained by alveolar hypoventilation in six sleeping patients and in five controls; in nine sleeping patients, further impariment of ventilation-perfusion mismatch also contributed to worsening of hypoxemia. There was no relationship between the decrease in PaO2 during sleep and the degree of airways obstruction or the PaO2 level when awake. Because of low PaO2, when awake, a fall in PaO2 during sleep brings values into the steep part of the oxyhemoglobin dissociation curve where slight changes in PaO2 result in marked changes in oxygen content. All patients with COPD whose waking PaO2 was below 60 mm Hg had PaO2 below 50 mm Hg during sleep; nocturnal oxygen therapy should be considered in such patients, particularly in the presence of polycythemia or troublesome right-sided heart failure.

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.

Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult.

In order to define the roentgenographic manifestations of pulmonary tuberculosis in the adult, we reviewed a 12 month experience with newly diagnosed patients with active pulmonary tuberculosis in two Boston hospitals. Of 88 patients, 30 (34 per cent) presented with roentgenographic manifestations other than those associated with "usual" postprimary disease. At least 12 patients (13.5 per cent) had primary tuberculosis, including two subjects over 60 years of age. Six patients (6.8 per cent) had disease confined to the lower lung fields, eight patients (9 per cent) had tuberculomas and four (4.5 per cent) had miliary tuberculosis. Twenty per cent of the patients were totally asymptomatic. With the shift of tuberculosis care to community hospitals, knowledge of the varied roentgenographic manifestations is of increasing importance for the practicing internist.

Electron microscopic study of human lung tissue after in vitro exposure to elastase.

Much of the experimental evidence supporting the hypothesis that pulmonary emphysema results from an imbalance between elastases and anti-elastases in the lung comes from animal models. The present study was designed to examine the effects on human lung tissue of the two elastases that have been most widely used to produce these animal models. Lung tissue was exposed in vitro to human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE). Although both enzymes solubilized protein at similar rates, PPE solubilized elastin five times faster than did HNE. Ultrastructurally, HNE-exposed tissue exhibited fewer damaged elastic fibers as well as some fibers that were damaged at the edges, whereas the interior of the fiber appeared intact. Elastic fibers showing damage only at the periphery were not seen in tissue exposed to PPE. Immunocytochemical studies in which antibodies to HNE and PPE were applied to thin sections of Lowicryl-embedded tissue indicated that both of these elastases could be detected in association with elastic fibers, but only in areas of the fiber that showed morphological evidence of elastase injury. Both HNE and PPE removed fibronectin from basement membranes (as determined by loss of binding of fibronectin antibodies after exposure to elastase), but neither elastase was detected on basement membrane. Loss of epithelial cells usually accompanied elastic fiber damage by HNE but not PPE.

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.

Interstitial pulmonary fibrosis.

The study of animal models of IPF has demonstrated that there is a stereotyped response of the respiratory airspace walls to a wide variety of injuries. Inflammatory and immune effector cells play a major and complex role in the fibrosing process. They may contribute to the injury of the lung beyond the original insult. These cells secrete substances that play an important role in determining cell traffic in the lungs and in controlling the connective tissue-producing cells. Products derived from the inflammatory response may interfere with protection of normal lung matrix, although injury to lung matrix itself does not lead to fibrosis. Injury to endothelial cells and especially type I epithelial cells appears to play a major role in the fibrogenic response. Further understanding of the factors that injure these cells, the development of methods of protecting them from injury, and a clear understanding of their role in the fibrogenic process appear to be key to developing better methods of preventing and treating interstitial pulmonary fibrosis.

Parker B. Francis Lecture. Animal models of chronic airways injury.

Airways SCM is induced by a wide variety of noxious agents that perturb but do not kill the epithelial cells. Discharge of mucus soon after first exposure to a noxious agent is frequently observed, but discharge of mucus may or may not be followed by development of SCM. Treatment with steroidal and nonsteroidal antiinflammatory agents protects against development of SCM in some models, such as tobacco smoke-induced SCM, but not in others, such as enzyme-induced SCM. In general, SCM regresses slowly or not at all spontaneously. Recovery of some models, such as tobacco smoke-induced SCM, is hastened by nonsteroidal antiinflammatory agents. Experimental protection against induction of enzyme-induced SCM by secretory leukocyte protease inhibitor, which is secreted by airways secretory cells, suggests that such protection may be the in vivo role of that antiprotease. The response of the airways to injury is heterogeneous, with patterns of response of the secretory cells varying according to agent, species, and longitudinal localization of epithelial cells in the airways. The longitudinal heterogeneity of response of secretory epithelial cells to injury is summarized in Table 1. Anatomic heterogeneity of epithelial cells may make a minor contribution to longitudinal variation in response of secretory cells to injury. Molecular heterogeneity of the cellular milieu seems the more likely explanation for this variation in cellular response.

Reduction pneumoplasty for giant bullous emphysema. Implications for surgical treatment of nonbullous emphysema.

A review of the literature on reduction pneumoplasty for giant bullous emphysema was undertaken to identify current criteria for this surgical treatment and in the hope of obtaining insights into evaluating reduction pneumoplasty for nonbullous emphysema. Twenty-two retrospective case series, published since 1950, were retrieved by a computer search of the literature and a search of the Index Medicus prior to 1966. Reduction pneumoplasty is most effective when bullae are larger than one third of a hemithorax with evidence of compression of adjacent lung tissue and an FEV1 of less than 50% predicted; the presence of emphysema in nonbullous lung and the amount of compression are best judged by CT. The rationale for reduction pneumoplasty for nonbullous emphysema is supported by the similar early functional changes after reduction pneumoplasty for bullous and nonbullous-improvement of blood gas values and lung mechanics. A single study showing that decline of lung function after surgery for bullous emphysema was less in those who stopped smoking than in those who continued to smoke supports the need for preoperative and maintained smoking cessation in patients receiving reduction pneumoplasty. After 4 decades, the duration of improvement in lung function, whether worsening of emphysema occurs in remaining lung, and late morbidity and mortality after reduction pneumoplasty for bullous emphysema are not well defined. A registry with an unoperated-on comparison group could more rapidly accumulate such data after reduction pneumoplasty for nonbullous emphysema.

A prospective cooperative study of complications following flexible fiberoptic bronchoscopy.

The frequency of complications following flexible fiber-optic bronchoscopic procedures was studied prospectively in 908 patients from 13 cooperating hospitals. Major complications (respiratory arrest, pneumonia, pneumothorax, and obstruction of airways) occurred in 1.7 per cent (15) of the procedures. There was one death, yielding a mortality of 0.1%. Minor complications, including vasovagal reactions, fever, cardiac arrhythmias, bleeding, obstruction of airways, nausea and vomiting, pneumothorax, psychotic reaction, and aphonia, occurred in 6.5% of the procedures. Pneumothorax occurred after 5% (four) of 85 transbronchial biopsies. Although serious complications occur more frequently than previously reported from retrospective studies, complications after fiberoptic bronchoscopic procedures are still quite infrequent. The relative risks and benefits must always be carefully weighed in patients being considered for a fiberoptic bronchoscopic procedure.

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.

Bronchial brushing in bronchogenic carcinoma. Factors influencing cellular yield and diagnostic accuracy.

In a prospective study, varying the bronchial brushing technique through the flexible fiberoptic bronchoscope was examined for the effects of cellular yield and diagnostic accuracy. The yield of cells obtained from the 1.7-mm brush was increased by more than twofold when the brush and bronchoscope were withdrawn as a unit through the pharynx and nose, (nonwithdrawn brushing), rather than withdrawing the brush alone through the aspiration channel of the bronchoscope (withdrawn brushing). The greater number of total cells in the nonwithdrawn brushing specimen was largely due to squamous cells, and the yield of tumor cells by the two methods was similar. The yield of cells from the same brush withdrawn through a new suction adapter available on the bronchoscope (Olympus BF-B2) was significantly decreased, as compared with the withdrawn brushing. There was a further decrease using a shielded 1-mm brush. In 23 of 30 cases of proven carcinoma, the diagnosis was made by the single withdrawn brushing, and in 26 of the 30 by the single nonwithdrawn brushing, a difference which was not statistically significant. We conclude that diagnostic accuracy is not significantly enhanced by withdrawing the brush and bronchoscope as a unit through the pharynx and nose; use of a small shielded brush offers no advantage over a larger unshielded brush; modifications of flexible bronchoscopes, such as the adapter to improve efficacy of suction, should be evaluated for effects on harvests of cells from bronchial brushes before being put into general use.

Prolonged rate of decay of arterial PO2 following oxygen breathing in chronic airways obstruction.

Nine patients with moderate to severe chronic obstructive lung disease were grouped according to results of pulmonary function testing. After a short period of 100 percent oxygen breathing, it took on the average 20 minutes (range--18 to 24 minutes) for their partial pressure of arterial oxygen to return to baseline levels. These data suggest that, after discontinuing supplemental oxygen in patients with chronic airways obstruction, more than 25 minutes should elapse if a blood gas measurement is to reflect with certainty conditions during room air breathing.

Bronchial brushing through the flexible fiberoptic bronchoscope in the diagnosis of peripheral pulmonary lesions.

Bronchial brushing was performed concomitantly with transnasal flexible fiberoptic bronchoscopy in 44 patients with localized peripheral pulmonary lesions and absence of visible bronchial abnormality down to subsegmental level. Fluoroscopic confirmation of brush placement was obtained. A diagnosis of malignancy was made by bronchial brushing in 12 of 23 patients (52 percent) proved to have neoplasm, although diagnostic accuracy rose to six of seven patients (86 percent) in the final quarter of the study. There was no relationship between diagnostic accuracy and tumor location. Diagnostic accuracy was highest for squamous cell carcinoma, intermediate for adenocarcinoma, and lowest for undifferentiated carcinoma. A diagnosis of tuberculosis was made in two of 21 patients found not to have malignancy, and bronchial brushing was the only procedure to yield diagnostic material in these two patients. There were no false-positive cytologic examinations and no complications. Fluoroscopic control of placement of the bronchial brush passed through the fiberoptic bronchoscope allows a single, highyield, diagnostic procedure to be performed with minimal risk to the patient. In selected cases, thoracotomy may be avoided by this procedure.

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.