Emphysematous Subjects Research Articles

Effect of Bronchoscopic Lung Volume Reduction in Advanced Emphysema on Energy Balance Regulation

Background: Hypermetabolism and muscle wasting frequently occur in patients with severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction (BLVR) might contribute to muscle maintenance by decreasing energy requirements and alleviating eating-related dyspnoea. Objective: The goal was to assess the impact of BLVR on energy balance regulation. Design: Twenty emphysematous subjects participated in a controlled clinical experiment before and 6 months after BLVR. Energy requirements were assessed: basal metabolic rate (BMR) by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water, whole body fat-free mass (FFM) by deuterium dilution, and physical activity by accelerometry. Oxygen saturation, breathing rate, and heart rate were monitored before, during, and after a standardized meal via pulse oximetry and dyspnoea was rated. Results: Sixteen patients completed follow-up, and among those, 10 patients exceeded the minimal clinically important difference of residual volume (RV) reduction. RV was reduced with median (range) 1,285 mL (−2,430, −540). Before BLVR, 90% of patients was FFM-depleted despite a normal BMI (24.3 ± 4.3 kg/m²). BMR was elevated by 130%. TDEE/BMR was 1.4 ± 0.2 despite a very low median (range) daily step count of 2,188 (739, 7,110). Following BLVR, the components of energy metabolism did not change significantly after intervention compared to before intervention, but BLVR treatment decreased meal-related dyspnoea (4.1 vs. 1.7, p = 0.019). Conclusions: Impaired respiratory mechanics in hyperinflated emphysematous patients did not explain hypermetabolism. Clinical Trial Registry Number: NCT02500004 at www.clinicaltrial.gov.

Altered deposition of inhaled nanoparticles in subjects with chronic obstructive pulmonary disease

BackgroundRespiratory tract deposition of airborne particles is a key link to understand their health impact. Experimental data are limited for vulnerable groups such as individuals with respiratory diseases. The aim of this study is to investigate the differences in lung deposition of nanoparticles in the distal lung for healthy subjects and subjects with respiratory disease.MethodsLung deposition of nanoparticles (50 and 100 nm) was measured after a 10 s breath-hold for three groups: healthy never-smoking subjects (n = 17), asymptomatic (active and former) smokers (n = 15) and subjects with chronic obstructive pulmonary disease (n = 16). Measurements were made at 1300 mL and 1800 mL volumetric lung depth. Each subject also underwent conventional lung function tests, including post bronchodilator FEV1, VC, and diffusing capacity for carbon monoxide, DL,CO. Patients with previously diagnosed respiratory disease underwent a CT-scan of the lungs. Particle lung deposition fraction, was compared between the groups and with conventional lung function tests.ResultsWe found that the deposition fraction was significantly lower for subjects with emphysema compared to the other subjects (p = 0.001–0.01), but no significant differences were found between healthy never-smokers and smokers. Furthermore, the particle deposition correlated with pulmonary function tests, FEV1%Pred (p < 0.05), FEV1/VC%Pred (p < 0.01) and DL,CO (p < 0.0005) when all subjects were included. Furthermore, for subjects with emphysema, deposition fraction correlated strongly with DL,CO (Pearson’s r = 0.80–0.85, p < 0.002) while this correlation was not found within the other groups.ConclusionsLower deposition fraction was observed for emphysematous subjects and this can be explained by enlarged distal airspaces in the lungs. As expected, deposition increases for smaller particles and deeper inhalation. The observed results have implications for exposure assessment of air pollution and dosimetry of aerosol-based drug delivery of nanoparticles.

Short- and Long-Term Effects of Ambient Ozone and Fine Particulate Matter on the Respiratory Health of Chronic Obstructive Pulmonary Disease Subjects

To date, no study has evaluated the short- and long-term effects air pollution exposure on emphysematous subjects who have undergone lung volume reduction surgery (LVRS). Data from the National Emphysema Treatment Trial study (1998–2003) included 1,218 subjects, aged 39 to 84. Daily values of ambient fine particulate matter (aerodynamic diameter < 2.5 μm; PM2.5) and ozone were obtained. Mixed-effects models tested the association between short- and long-term pollutant concentrations and changes in pulmonary function. Cumulative air pollution exposure was strongly associated with worsened respiratory function and symptoms. Mean PM2.5 was associated with poorer lung function. Lagged exposures were poorly associated with respiratory health outcomes. There were detrimental respiratory and pulmonary effects observed in response to even low levels of ambient air pollutants among study participants. These results are indicative that exposures even below those of air quality standards may still pose significant risks to severe chronic obstructive pulmonary disease (COPD) subjects.

Autoreactivity to glucose regulated protein 78 links emphysema and osteoporosis in smokers.

RationaleEmphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders.ObjectivesTo discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.MethodsReplicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays.Measurements and Main ResultsCirculating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively).ConclusionsHumoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders.

Regional lung function and heterogeneity of specific gas volume in healthy and emphysematous subjects

The aim of our study was to study regional lung function by standard computed tomography (CT) and characterise regional variations of density and specific gas volume (SVg) between different lung volumes. We studied 10 healthy and 10 severely emphysematous subjects. Corresponding CT images taken at high and low lung volumes were registered by optical flow to obtain two-dimensional maps of pixel-by-pixel differences of density (ΔHU) and SVg (ΔSVg) at slice levels near the aortic arch, carina and top diaphragm. In healthy subjects, ΔHU was higher at all levels (p<0.001) with higher variability expressed as interquartile range (p<0.001), largely due to its differences between dorsal and ventral regions. In patients, median ΔSVg values were 3.2 times lower than healthy volunteers (p<0.001), while heterogeneity of ΔSVg maps, expressed as quartile coefficient of variation, was 5.4 times higher (p<0.001). In all patients, there were areas with negative values of ΔSVg. In conclusion, ΔSVg is uniform in healthy lungs and minimally influenced by gravity. The significant ΔSVg heterogeneity observed in emphysema allows identification of areas of alveolar destruction and gas trapping and suggests that ΔSVg maps provide useful information for evaluation and planning of emerging treatments that target trapped gas for removal.

The emphysematous lung is abnormally sensitive to TRAIL-mediated apoptosis

BackgroundAlveolar apoptosis is increased in the emphysematous lung. However, mechanisms involved are not fully understood. Recently, we demonstrated that levels of TRAIL receptor 1 and 2, levels of p53, and Bax/Bcl-xL ratio were elevated in the lung of subjects with emphysema, despite smoking cessation. Thus, we postulate that due to chronic pulmonary oxidative stress, the emphysematous lung would be abnormally sensitive to TRAIL-mediated apoptosis.MethodologyA549 cells were exposed to rTRAIL, cigarette smoke extract, and/or H2O2 prior to caspase-3 activity measurement and annexin V staining assessment. In addition, freshly resected lung samples were obtained from non-emphysematous and emphysematous subjects and exposed ex vivo to rTRAIL for up to 18 hours. Lung samples were harvested and levels of active caspase-3 and caspase-8 were measured from tissue lysates.ResultsBoth cigarette smoke extract and H2O2 were able to sensitize A549 cells to TRAIL-mediated apoptosis. Moreover, following exposure to rTRAIL, caspase-3 and -8 were activated in lung explants from emphysematous subjects while being decreased in lung explants from non-emphysematous subjects.Significance of the studyAlveolar sensitivity to TRAIL-mediated apoptosis is strongly increased in the emphysematous lung due to the presence of oxidative stress. This might be a new mechanism leading to increased alveolar apoptosis and persistent alveolar destruction following smoking cessation.

3D Airway Tree Reconstruction in Healthy Subjects and Emphysema

Several algorithms for the segmentation of the 3D human airway tree from computed tomography (CT) images have recently been proposed, but the effects of lung volume and the presence of emphysema on segmentation accuracy has not been investigated. Two different sets of CT images taken on nine healthy subjects and nine patients with severe emphysema (FEV(1) = 19 ± 4.1 SD % pred) were used to reconstruct the trachea-bronchial tree by a region-growing algorithm at two different lung volumes: total lung capacity (TLC) and residual volume (RV). The sixth generation was reached in 67% of the healthy subjects and 22% of the emphysematous patients at TLC. At RV, fifth generation was reached in 33 and 11% of healthy subjects and emphysematous patients. At TLC, 67 ± 2 and 39 ± 2% of airways belonging to the fourth generation were successfully reconstructed, respectively in healthy and emphysematous subjects. At RV, the percentage of successful reconstruction was 33 ± 2 and 16 ± 2%, respectively. Segmentation was significantly influenced by the presence of disease (P < 0.001) and lung volume (P < 0.001) at which the CT scans were acquired. Airway tree reconstruction performed by means of a region-growing algorithm depends on lung volume and presence of emphysema, both of which have significant effect, even at the level of lobar and segmental bronchi.

Abstract CN07-04: Neutrophil elastase as a chemopreventive target for lung cancer

Abstract When combined, lung cancer and chronic obstructive pulmonary disease (COPD) account for &amp;gt;260,000 American deaths each year. Although the link between declining FEV1 and increased lung cancer incidence was identified over 20 years ago, the responsible mechanisms have not been deciphered. Two independent studies have recently demonstrated that it is the presence of emphysema, and not airflow obstruction, that is responsible for the increased risk of lung cancer in COPD patients. Emphysema, unlike COPD, has a strict anatomic definition: permanent enlargement of the peripheral airspaces distal to the terminal bronchioles. The prevailing theory regarding the pathogenesis of emphysema remains the proteinase:antiproteinase hypothesis. Inflammatory cells and inflammatory cell-derived proteinases are recruited to the lung upon chronic cigarette smoke exposure. When the proteinase burden exceeds the host's antiproteinase capacity, lung matrix tissue is destroyed and, in the absence of repair, emphysema results. When proteinase vs. antiproteinase activity is balanced, tissue homeostasis persists. We propose that the presence of radiographic emphysema on CT scan, which confers increased lung cancer risk, represents a case where the proteinase burden has surpassed the protective capability of the antiproteinase shield. As such, patient's displaying radiographic emphysema represent a group at increased risk for lung cancer, and therefore amenable to a chemopreventative strategy, especially one that would address a target common to both emphysema and lung cancer. We propose that that neutrophil-derived proteinase, neutrophil elastase (NE), is a viable chemopreventive target in COPD patients at risk for lung cancer. A role for this elastolytic enzyme in the pathogenesis of emphysema has been clearly established in both mouse and human studies. The presence of severe emphysema in A1AT deficient subjects has been attributed to uncontrolled NE activity, and is universally accepted as the pathogenic mechanism. Although previously unstudied, we have recently shown that NE promotes lung tumor growth in vivo (Nature Medicine 2010, 16:219-223). The mechanism by which NE promotes tumor growth represents an entirely new means by which a secreted proteinase can impact tumor behavior. NE is released near the tumor cell surface where it is internalized into tumor endosomes. NE degrades a target substrate, insulin receptor substrate-1 (IRS-1), within these tumor endosomes, which ultimately leads to PI3K activation and tumor cell proliferation. We propose that subjects displaying radiographic emphysema possess excessive proteinase burden, and therefore, increased NE activity. When lung cancers arise in these subjects, they will arise within a tumor microenvironment enriched for NE activity, and thus these cancers will display increased growth rates. Additional clinical studies are underway to establish NE as a bona fide therapeutic target for lung cancers arising in emphysematous subjects. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN07-04.

Alveolar epithelial and endothelial cell apoptosis in emphysema: What we know and what we need to know

Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not fully understood. Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated. Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research. Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema. Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema. This review also includes some reflections and suggestions on the research to come.

Validation and pilot clinical study of a new bronchoscopic method to measure collateral ventilation before endobronchial lung volume reduction

Endobronchial lung volume reduction (ELVR) may be helpful in a selected group of patients with advanced stages of emphysema. However, collateral ventilation (CV) from adjacent lobes through collateral channels often prevents target lobe atelectasis, which presumably mediates clinical responses after ELVR. With the goal of identifying patients who are more or less likely to benefit, we propose endobronchial CV assessment (ECVA), a novel catheter-based endobronchial approach, to quantitatively determine the resistance of collateral channels (R(coll)). ECVA relies on the measurement of spontaneous airflow from the sealed and isolated target compartment during spontaneous respiration in an awake subject, thereby providing a direct, simple, and minimally invasive method of assessing R(coll) in lungs. In this study, we validated ECVA in a controlled laboratory setup and tested ECVA's clinical feasibility in 11 emphysematous human subjects undergoing ELVR treatment. To evaluate ECVA in a controlled laboratory setup with known CV levels, we built a benchtop model mimicking a simple one-compartment model of the lungs during temporary compartmental occlusion and spontaneous respiration, which could be adapted to hold restrictors of different sizes representing collateral airways, and applied ECVA to estimate the resistance of various benchtop model restrictors. We then rated ECVA's performance by direct comparison between estimated and actual restrictor resistance and found a correlation coefficient near one. To test ECVA's clinical performance, post-ELVR radiological assessments were made to determine the occurrence of atelectasis in the treated lobe, and interlobar R(coll) was estimated in the target lobe via ECVA pre-ELVR. ECVA could be completed in all patients with no adverse events, and a high R(coll) by ECVA predicted absorption atelectasis following ELVR ( P = 0.005). We believe that ECVA may be helpful to distinguish those patients with and without interlobar CV by identifying the critical value of R(coll) above which atelectasis is likely to occur.

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema

BackgroundIt is generally accepted that emphysematous lungs are characterized by an increase in the numbers of neutrophils, macrophages, and CD8+ T lymphocytes, the lasts having increased cytotoxic activity. Because systemic inflammation is also a component of emphysema, we hypothesize that peripheral CD8+ T lymphocytes of emphysematous smokers who show evidence of systemic inflammation will have higher expression of cytotoxic molecules.MethodsWe assessed parameters of systemic inflammation in normal individuals (smokers or non-smokers) and in emphysematous subjects with an active smoking history by measuring serum interleukine-6, C-reactive protein, and tumor necrosis factor. Expression of perforin, granzyme B, and FasL protein by CD8+ T lymphocytes, CD4+ T lymphocytes, and natural killer cells were assessed by flow cytometry while perforin, granzyme B, and FasL mRNA expression were measured on purified systemic CD8+ T lymphocytes by real-time PCR.ResultsEmphysematous smokers had higher levels of serum interleukine-6 than normal subjects. Even with the presence of systemic inflammation in emphysematous smokers, the percentage of peripheral CD8+ T lymphocytes, CD4+ T lymphocytes, and NK cells expressing perforin and granzyme B protein was not different between the three groups.ConclusionDespite evidence of systemic inflammation, peripheral T lymphocytes of emphysematous smokers did not show higher levels of cytotoxic markers, suggesting that increase of activated T lymphocytes in the emphysematous lung may be due to either activation in the lung or specific peripheral recruitment.

Body Composition and Resting Energy Expenditure in Clinically Stable, Non–Weight-Losing Patients With Severe Emphysema

To characterize the metabolic status of weight-stable and clinically stable individuals with advanced emphysema. Seventy-nine patients with severe emphysema (FEV(1), 29 +/- 13% of predicted [mean +/- SD]) evaluated for enrollment in the National Emphysema Treatment Trial and 20 age-matched healthy subjects were studied. Pulmonary function laboratory of university-affiliated teaching hospital. Data collection. We measured lung function, body composition, serum leptin levels, serum tumor necrosis factor receptors (sTNF-Rs), resting oxygen consumption (RVO(2)) normalized to weight in kilograms (RVO(2)/kg), and RVO(2) normalized to fat-free mass (FFM) [RVO(2)/FFM]. The patient group and healthy group had similar age, body mass index (BMI), and body composition. RVO(2)/kg, RVO(2)/FFM, and sTNF-R levels were higher in patients compared to healthy subjects. There were no differences in serum leptin levels between emphysematous and healthy subjects, and there was no correlation between leptin and sTNF-R and RVO(2)/kg. Furthermore, both groups had similar gender-related differences in FFM, percentage of body fat, and serum leptin levels. Patients with lower BMI showed the greatest differences from control subjects in RVO(2)/kg. In weight-stable subjects with advanced emphysema, RVO(2)/kg and RVO(2)/FFM were higher compared to healthy subjects, especially in those with BMI in the lower end of the normal range. RVO(2)/kg and RVO(2)/FFM did not correlate with leptin or sTNF-R levels. These data show that a higher metabolic rate is found in patients with emphysema who are clinically and weight stable. Thus, hypermetabolism is a feature of the disease and not sufficient to lead to weight loss.

Lack of a relationship of elastin peptide level to emphysema assessed by CT scans.

Clinical reports suggest that peptide (EP) concentration may be used as a subclinical marker of pulmonary emphysema. This hypothesis was tested in a clinical study by comparing EP concentration in male emphysematous patients with the level in two control groups, and by exploring the relation of elastin peptide level to high-resolution computed tomography (HRCT) scan emphysema score among emphysematous patients. Serum EP level was determined among male emphysematous patients with at least 20% of emphysema (n = 27) and in two populations of male workers, drawn from epidemiologic studies (227 coal miners and 310 policemen). No difference in elastin peptide concentration was observed between emphysematous patients and control subjects (mean +/- SD = 2.39 +/- 1.18 micrograms/ml in patients versus 2.55 +/- 1.34 micrograms/ml in policemen and 2.59 +/- 1.20 micrograms/ml in coal miners). The correlation of elastin peptide concentration with percentage of pulmonary emphysema was negative and of borderline significance (r = -0.36; p = 0.06). These results cast doubts on the usefulness of elastin peptide level as a predictive marker of pulmonary emphysema.

Plasma elastin-derived peptide levels in normal adults, children, and emphysematous subjects. Physiologic and computed tomographic scan correlates.

Pulmonary emphysema is likely to be the result of elastic tissue digestion by unrestrained elastase activity in the lung. Elastin breakdown by elastases results in the release of soluble elastin fragments (EDP), which may be measured in plasma by an ELISA. Plasma EDP levels measured using an ELISA were determined in the following groups: disease-free children (n = 24), 0.162 +/- 0.082 ng/ml; disease-free adult nonsmokers (n = 114), 1.74 +/- 0.8 ng/ml; smokers (n = 68), 2.76 +/- 4.59 ng/ml; reformed smokers (n = 43), 1.91 +/- 1.14 ng/ml. Adults with established pulmonary emphysema (n = 50), as defined by bullous formation on the chest radiograph, had levels of 50.83 +/- 24.8 ng/ml, significantly higher than the disease-free groups at p < 0.01. Pulmonary emphysema can be reflected by pulmonary function tests, especially those that measure the pulmonary elastic properties, and by computed tomographic (CT) scan percent emphysema score. We therefore examined the relationship of plasma EDP to these other indicators of pulmonary emphysema in a separate group of 26 subjects using elastic recoil measurements (K), and a further group of 30 subjects with CT scan percent emphysema score. A significant correlation of p < 0.001 was shown for plasma EDP and K and a significant correlation of p < 0.01 was shown for plasma EDP and CT scan percent emphysema score, these correlations suggesting that plasma EDP levels are indicators of the loss of pulmonary distensibility and of mild to moderate pulmonary emphysema. These findings suggest that pulmonary emphysema is characterized by active elastin breakdown.

Influence of Preexisting Pulmonary Emphysema on Susceptibility of Rats to Inhaled Diesel Exhaust

The susceptibilities of normal rats and rats with preexisting pulmonary emphysema to chronically inhaled diesel exhaust were compared. Rats were exposed 7 h/day, 5 days/wk for 24 months to diesel exhaust at 3.5 mg soot/m3, or to clean air as controls. Emphysema was induced in one-half of the rats by intratracheal instillation of elastase 6 wk before exhaust exposure. Measurements included lung burdens of diesel soot, respiratory function, bronchoalveolar lavage, clearance of radiolabeled particles, pulmonary immune responses, lung collagen, excised lung weight and volume, histopathology, and mean linear intercept of terminal air spaces. Parameters indicated by analysis of variance to exhibit significant interactions between the influences of emphysema and exhaust were examined to determine if the effects were more than additive (indicating increased susceptibility). Although 14 of 63 parameters demonstrated emphysema-exhaust interactions, none indicated increased susceptibility. Less soot accumulated in lungs of emphysematous rats than in those of nonemphysematous rats, and the reduced accumulation had a sparing effect in the emphysematous rats. The results did not support the hypothesis that emphysematous lungs are more susceptible than are normal lungs to chronic exposure to high levels of diesel exhaust. The superimposition of effects of emphysema and exhaust, however, might still warrant special concern for heavy exposures of emphysematous subjects.

Genetic Influences in the Development of Emphysema in Persons with Normal Serum Proteins

This review has failed to uncover convincing evidence to support the existence of familial emphysema in patients with normal serum proteins. Although a large number of studies have documented that non-A1PI hereditary factors are important in the development of nonspecific chronic obstructive pulmonary disease, it is far less certain that emphysema accounts for this familial occurrence. To the contrary, most existing evidence fails to support this possibility. Nevertheless, the issue remains unsettled and incompletely studied. Further investigations should include a major effort to identify young persons, 20 to 45 years of age, with emphysema alone but without A1PI deficiency. Based on prior reports, 76 it is likely that such persons will be found. As emphasized by Kazazian, "this is the group that should be studied for the presence of a single mutant gene in the homozygous state." 42 It is possible that several or many rare single-gene causes of emphysema await discovery. Careful family studies of young emphysematous subjects are indicated as well to determine whether emphysema-producing genes also constitute a risk factor in heterozygous persons. If such patients and families are discovered, further hypotheses will have to be drawn-up and carefully investigated to attempt a better understanding of the etiology and pathogenesis of emphysema.

Competition in Vivo between Serum α1 Anti-Trypsin and α2 Macroglobulin for Binding to Proteolytic Enzymes, as Assessed in Normal and Emphysematous subjects

Competition <u>in Vivo</u> between Serum α1 Anti-Trypsin and α2 Macroglobulin for Binding to Proteolytic Enzymes, as Assessed in Normal and Emphysematous subjects

The Induction of Lysosomal Enzyme Release from Leucocytes of Normal and Emphysematous Subjects and the Effects of Tobacco Smoke upon Phagocytosis

1. The lysosomal enzymes of circulating polymorphonuclear leucocytes contain a potent elastase; release of this enzyme within the lung is thought to be responsible for the destruction of elastic tissue in pulmonary emphysema. 2. The release of lysosomal enzymes from blood leucocytes of normal and emphysematous subjects during phagocytosis of particulate material was studied In vitro. Acid phosphatase and acid ribonuclease were used as markers of lysosomal enzyme release, no sufficiently sensitive assay for elastase being available. Cigarette smoke was separated into ‘particulate’ and ‘soluble’ fractions. In a preliminary study, the particulate fraction stimulated enzyme release; in the experiments reported here, latex particles were used to produce this effect. 3. Approximately one-third of the total lysosomal enzyme content was released to the exterior of the cell during phagocytosis of latex particles. In this respect there was no difference between normal and emphysematous subjects. 4. The effects of the non-particulate soluble fraction of cigarette smoke on phagocytosis-induced enzyme release were studied. This fraction inhibited enzyme release from polymorphonuclear leucocytes of normal subjects but not from those of emphysematous patients. When the ‘cigarette-smoke solution’ was replaced by the respiratory inhibitor, antimycin A, a similar inhibition of enzyme release occurred. The inhibition of phagocytosis in cells of normal subjects is presumed to be due to a respiratory inhibitor such as carbon monoxide in the soluble fraction of the smoke. We postulate that the polymorphonuclear leucocytes of emphysematous patients are adapted to hypoxic conditions so that inhibition of enzyme release does not occur.

The Induction of Lysosomal Enzyme Release from Leucocytes of Normal and Emphysematous Subjects and the Effects of Cigarette Smoke

The Induction of Lysosomal Enzyme Release from Leucocytes of Normal and Emphysematous Subjects and the Effects of Cigarette Smoke

The Regional Pulmonary Distribution of Inhaled Krypton-81M in Normal and Emphysematous Subjects at Rest and during Exercise

The Regional Pulmonary Distribution of Inhaled Krypton-81M in Normal and Emphysematous Subjects at Rest and during Exercise