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PubMed1976

Congenital lobar emphysema: long-term evaluation of surgically and conservatively treated children.

The clinical conditions, roentgenographic findings, and pulmonary function tests of 6 children (mean age, 10.9 years) with surgically treated congenital lobar emphysema (group 1) were compared with those of 5 children (mean age, 10.3 years) with congenital lobar emphysema who had been treated conservatively, i.e., nonsurgically (group 2). At the time of this study, patients in both groups were asymptomatic. Patients in group 1 were surgically treated because of severe respiratory distress in the newborn period, with the exception of one patient, who was eupneic as a newborn and was not operated on until the age of 9 years. Patients in group 2 were eupneic or mildly distressed in the neonatal period and received only conservative treatment. Two patients in group 1 had occasional wheezing and labored breathing, but no patient in group 2 had recurrent respiratory distress. Roentgenographically, at the time of the study, patients in group 1 had generalized overinflation, whereas those in group 2 had only localized overinflation of the involved lobe and minimal compression of remaining lung tissue. Pulmonary function studies in both groups were not significantly different (P greater than 0.05). Both groups had reduced forced vital capacities, large trapped gas volumes, and reduced forced expiratory flows at low lung volumes. Reductions in forced vital capacity were proportional to the unventilated volumes of lung either excised because of congenital lobar emphysema (group 1) or chronically obstructed by congenital lobar emphysema (group 2). These studies suggest that lung growth was not different in these 2 groups and that asymptomatic or midly symptomatic patients do not benefit from surgical treatment.

Adolescent↗
PubMed1982

Impaired lung uptake of propranolol in human pulmonary emphysema.

First-pass lung uptake of propranolol was studied in 10 patients with normal lungs, 8 patients with severe pulmonary emphysema, and 1 patient with primary pulmonary hypertension. Propranolol uptake was measured by comparing the ratio of [14C]propranolol (0.5 mg) to indocyanine green (5 mg) injected into the right atrium with the ratio of their concentrations in arterial blood collected over the duration of the first-pass dye outflow curve. Mean uptake was 69 +/- 4% (n = 18) in patients with normal lungs; 55 +/- 7% (n = 13) in patients with emphysema (p less than 0.001), and 51% in the patient with primary pulmonary hypertension. Cardiac index in the normal group (2.78 +/- 0.48 L/min/M2, n = 16) was not significantly different from the group with emphysema (2.90 +/- 0.48, n = 12). There was no correlation between lung uptake and conventional lung function indexes in patients with emphysema. We conclude that propranolol uptake is reduced when the pulmonary vascular bed is damaged. This may have pharmacologic consequences, and it is possible that other pharmacokinetic functions of the lung may similarly be impaired in pulmonary disease. The method is relatively simple, and may be suitable for assessing pulmonary endothelial function in patients with lung disease.

Adult↗
PubMed1982

Emphysema mortality is increased in Colorado residents at high altitude.

Emphysema mortality is higher in Colorado than in the nation as a whole despite the younger age of Colorado's population Colorado death records from 1959 to 1976 were examined to determine if emphysema mortality increases with altitude within the state and if altitude adversely affects survival from chronic lung disease. Because the proportion of persons older than 65 yr of age in Colorado decreases with altitude (r = -0.6, p less than 0.01), emphysema mortality was age-standardized. The age-standardized rate increases with altitude among males (r = 0.9, p less than 0.01; y = 0.003(x) + 42.1). Emphysema deaths at higher altitudes in Colorado (greater than or equal to 7,000 ft) occur at a younger age (68.1 +/- 0.6 yr (mean +/- SEM) versus 70.1 +/- 0.6 yr at lower altitudes), after a shorter duration of illness, and more commonly from cor pulmonale than at lower altitudes (less than or equal to 4,500 ft) where pneumonia is more common as the immediate cause of death. The mechanism by which high altitude residence interacts unfavorably with survival is not known but may stem from augmented pulmonary hypertension caused by the hypoxia of lung disease added to the hypoxia of high altitude.

Adult↗
PubMed1983

Cigarette smoke inhalation potentiates elastase-induced emphysema in hamsters.

Cigarette smoke is shown, in this study, to potentiate emphysema induced by intratracheal administration of elastase, whereas elastase alone caused minimal disease. Elastase-treated hamsters with prior or ongoing smoke exposure uniformly had severe emphysema with decreases in lung elastic recoil and increases in mean linear intercept (Lm). In contrast, hamsters receiving elastase alone, cigarette smoke alone, or postelastase cigarette smoke developed no or barely detectable histopathologic evidence of emphysema. Lungs from these animals had normal elastic recoil and Lm. These data support the idea that cigarette smoke exposure may unmask or amplify protease-induced emphysema caused by acute lung injury.

Animals↗
PubMed1984

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↗
PubMed1985

Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes.

To determine whether purified human neutrophil cathepsin G (Cat-G) can act by itself or in concert with purified human neutrophil elastase (HNE) in the induction of emphysema and bronchial secretory cell metaplasia (SCM), we gave golden Syrian hamsters 100 micrograms of HNE alone or in combination with either 100 or 200 micrograms of Cat-G. Other groups of animals received intratracheal doses of up to 600 micrograms of Cat-G alone. The severity of emphysema was determined from measurements of lung volumes, compliance, forced expiratory flow, and the mean linear intercept. The severity of SCM in the main airways was graded on sections stained by the alcian blue and periodic acid-Schiff reaction. The Cat-G was a weak inducer of SCM; significant SCM was produced by 400 and 600 micrograms but not by 100 or 200 micrograms or 200 micrograms of Cat-G. The Cat-G (100 and 200 micrograms) did not potentiate the SCM induced by 100 micrograms of HNE. The Cat-G alone did not produce emphysema, and neither 100 nor 200 micrograms of Cat-G potentiated the mild emphysema induced by 100 micrograms of HNE. These results were not consonant with a report that Cat-G and HNE were synergistic in solubilizing human lung elastin. We therefore measured the ability of Cat-G and HNE to solubilize several radiolabeled elastins. The combination of Cat-G and HNE did not solubilize significantly more hamster lung elastin (23%) than the sum of their individual activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Comparisons of asthma, emphysema, and chronic bronchitis diagnoses in a general population sample.

This report is an analysis of cases of obstructive lung disease diagnosed during the first 8 yr of a community study. Of 351 subjects who received a new diagnosis of asthma, emphysema, or chronic bronchitis from community physicians, 152 (44.5%) had a prior or concomitant diagnosis of another obstructive disease. Asthma developed most often in young subjects, emphysema in older subjects, and chronic bronchitis occurred in all age groups. Among older subjects, disease groups were surprisingly similar, with wheeze, dyspnea, and attacks of shortness of breath with wheeze all occurring frequently in diagnosed subjects, including those with emphysema. The majority of subjects who developed emphysema were males. In contrast, 72.8% of the asthma and chronic bronchitis subjects were females. These results suggest that physician bias may result in labeling male patients as emphysematous and female patients as asthmatic or bronchitic.

Adolescent↗
PubMed1987

The predictors of emphysema in South African gold miners.

Environmental and host factors have been implicated in the pathogenesis of emphysema. To assess the role of gold mining exposure (an environmental factor) and of various clinical features recorded early in a miner's career (host factors), a case control study was carried out as follows. From whole lung sections made routinely at all full autopsy examinations on South African gold miners, we selected 44 cases of emphysema and 42 controls without emphysema from among men 51 to 71 yr of age who died during 1980 and 1981. Exposure information was gathered and clinical records were reviewed for smoking history, symptoms, and the presence of rhonchi by decade before death. The presence and grade of silicosis (abstracted from the routine autopsy reports) was similar in both groups; so was bronchitis in the 49 cases and controls with histologic material adequate for review. However, cases were on average older, had worked more shifts in high dust, and had smoked more than controls; they had also exhibited symptoms and rhonchi more frequently before 1950, i.e., 30 yr before death. When these factors were examined in a multiple logistic regression analysis, shifts worked in high dust, smoking, and age were all shown to be strong and independent predictors of emphysema at autopsy; prediction, however, was not improved by addition of any of the clinical features examined. These findings agree with previous cross-sectional studies in South African gold miners showing an exposure response relationship between mining service and air-flow limitation measured by lung function tests in life.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2003

alpha-1-Antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse.

Serine elastase inhibitors have been proposed as a treatment for cigarette smoke-induced emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic serine elastase inhibitor, ZD0892, provided some protection against emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human alpha-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette smoke for up to 6 months; some animals received 20 mg of human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and elastase inhibitory capacity and abolished smoke-induced elevations in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) measured from 2 to 30 days of smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (emphysema) and abolished smoke-mediated increases in plasma tumor necrosis factor-alpha. We conclude that A1AT therapy ameliorates smoke-induced inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to tumor necrosis factor-alpha suppression, and provides partial protection against emphysema.

Animals↗
PubMed2006

Cigarette smoke-induced emphysema: A role for the B cell?

RATIONALE: Little is known about what drives the inflammatory reaction in the development of chronic obstructive lung disease. B cells have been found. OBJECTIVE: To study the involvement of B cells in the development of emphysema. METHODS: The presence of B-cell follicles and their interaction with other cells were investigated in lungs of patients with chronic obstructive pulmonary disease and of smoking mice. B cells were isolated from lymphoid follicles by laser microdissection and analyzed for the presence of immunoglobulin rearrangements and somatic mutations. MAIN RESULTS: Lymphoid follicles consisting of B cells and follicular dendritic cells with adjacent T cells were demonstrated both in the parenchyma and in bronchial walls of patients with emphysema. A clonal process was observed in all follicles and the presence of ongoing somatic mutations was observed in 75% of the follicles, indicating oligoclonal, antigen-specific proliferation. Similar lymphoid follicles were detected in mice that had developed pulmonary inflammation and progressive alveolar airspace enlargement after smoking. The increase in the number of B-cell follicles was progressive with time and correlated with the increase in mean linear intercept. Specific bacterial or viral nucleic acids could not be detected. CONCLUSIONS: B-cell follicles with an oligoclonal, antigen-specific reaction were found in men and mice with emphysema. In mice, the development was progressive with time and correlated with the increase in airspace enlargement. We hypothesize that these B cells contribute to the inflammatory process and/or the development and perpetuation of emphysema by producing antibodies against either tobacco smoke residues or extracellular matrix components.

Animals↗
PubMed2006

Alveolar cell senescence in patients with pulmonary emphysema.

RATIONALE AND OBJECTIVES: The prevalence of chronic obstructive pulmonary disease (COPD) is age-dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging. In this study we investigated whether the senescence of alveolar epithelial and endothelial cells is accelerated in emphysematous lungs. METHODS: Samples of lung tissue were obtained from patients with emphysema, asymptomatic smokers, and asymptomatic nonsmokers. Paraffin-embedded lung tissue sections were evaluated for cellular senescence by quantitative fluorescence in situ hybridization to assess telomere shortening, and by immunohistochemistry to assess the expression of senescence-associated cyclin-dependent kinase inhibitors. Tissue sections were also immunostained for proliferating cell nuclear antigen (PCNA), surfactant protein A, and CD31. MAIN RESULTS: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers. They had also significantly higher percentages of endothelial cells positive for p16INK4a than the asymptomatic smokers and nonsmokers, and higher percentages of endothelial cells positive for p21CIP1/WAF1/Sdi1 than the asymptomatic nonsmokers. Telomere length in alveolar type II cells and endothelial cells was significantly shorter in the patients with emphysema than in the asymptomatic nonsmokers. The level of p16INK4a expression was negatively correlated with the level of PCNA expression. The level of alveolar cell senescence was positively correlated with airflow limitation. CONCLUSIONS: These results suggest that the senescence of alveolar epithelial and endothelial cells is accelerated in patients with emphysema. Cellular senescence may explain the abnormal cell turnover that promotes the loss of alveolar cells in emphysematous lungs.

Cell Proliferation↗
PubMed1998

Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema.

Patients with alpha1-antitrypsin (alpha1-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of alpha1-AT is most commonly due to the Z mutation (342Glu--> Lys), which results in a block in alpha1-AT processing within the endoplasmic reticulum of hepatocytes. The retained alpha1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of alpha1-AT is due to the Z mutation perturbing the structure of alpha1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha1-AT molecule and the A beta-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of alpha1-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of alpha1-AT in dilute samples of bronchoalveolar lavage fluid (BALF). This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z alpha1-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha1-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ alpha1-AT controls. Because alpha1-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z alpha1-AT homozygote, and so exacerbate tissue damage.

Bronchoalveolar Lavage Fluid↗
PubMed2000

Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life.

Homozygous mutant klotho (KL(-/-)) mice exhibit multiple phenotypes resembling human aging. In the present study, we focused on examining the pathology of the lungs of klotho mice and found that it closely resembled pulmonary emphysema in humans both histologically and functionally. Histology of the lung of KL(-/-) mice was indistinguishable from those of wild-type littermates up to 2 wk of age. The first histologic changes appeared at 4 wk of age, showing enlargement of the air spaces accompanied by destruction of the alveolar walls, and progressed gradually with age. In addition to these changes, we observed calcium deposits in type I collagen fibers in alveolar septa and degeneration of type II pneumocytes in 8- to 10-wk-old KL(-/-) mice. Pulmonary function tests revealed prolonged expiration time in KL(-/-) mice, which is comparable with the pathophysiology of pulmonary emphysema. The expression level of messenger RNA for type IV collagen, surfactant protein-A and mitochondrial beta-adenosine triphosphatase was significantly increased in KL(-/-) mice, which may represent a compensatory response to alveolar destruction. Additionally, the heterozygous mutant klotho mice also developed pulmonary emphysema late in life, around 120 wk of age. These findings indicate that klotho gene expression is essential to maintaining pulmonary integrity during postnatal life. The klotho mutant mouse is a useful laboratory animal model for examining the relationship between aging and pulmonary emphysema.

Aging↗
PubMed2003

Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade.

We have previously demonstrated that a failure of pulmonary endothelial cell survival induced by vascular endothelial growth factor (VEGF) receptor blockade results in lung alveolar septal cell apoptosis and emphysema. Because apoptosis and oxidative stress may be pathobiologically linked, we hypothesized that oxidative stress has a central role in alveolar septal cell apoptosis and emphysema induced by VEGF receptor blockade. When compared with control animals, rats treated with the VEGF receptor blocker SU5416 showed increased alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress, all of which were prevented by the superoxide dismutase mimetic M40419. The preservation of lung structure in SU5416+M40419-treated lungs was associated with increased septal cell proliferation, and enhanced phosphorylation of the prosurvival and antiapoptotic Akt, when compared with SU5416-treated lungs. Consistent with a positive feedback interaction between oxidative stress and apoptosis, we found that apoptosis predominated in areas of oxidative stress, and that apoptosis blockade by a broad spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. Oxidative stress and apoptosis, which cause lung cellular destruction in emphysema induced by VEGF receptor blockade, may be important mediators common to human and experimental emphysema.

Angiogenesis Inhibitors↗
PubMed2004

Gene expression profiling of human lung tissue from smokers with severe emphysema.

The mechanism by which inhaled smoke causes the anatomic lesions and physiologic impairment of chronic obstructive pulmonary disease remains unknown. We used high-density microarrays to measure gene expression in severely emphysematous lung tissue removed from smokers at lung volume reduction surgery (LVRS) and normal or mildly emphysematous lung tissue from smokers undergoing resection of pulmonary nodules. Class prediction algorithms identified 102 genes that accurately distinguished severe emphysema from non-/mildly emphysematous lung tissue. We also defined a number of genes whose expression levels correlated strongly with lung diffusion capacity for carbon monoxide and/or forced expiratory volume at 1 s. Genes related to oxidative stress, extracellular matrix synthesis, and inflammation were increased in severe emphysema, whereas expression of endothelium-related genes was decreased. To identify candidate genes that might be causally involved in the pathogenesis of emphysema, we linked gene expression profiles to chromosomal regions previously associated with chronic obstructive pulmonary disease in genome-wide linkage analyses. Unsupervised hierarchical clustering of the LVRS samples revealed distinct molecular subclasses of severe emphysema, with body mass index as the only clinical variable that differed between the groups. Class prediction models established a set of genes that predicted functional outcome at 6 mo after LVRS. Our findings suggest that the gene expression profiles from human emphysematous lung tissue may provide insight into pathogenesis, uncover novel molecular subclasses of disease, predict response to LVRS, and identify targets for therapeutic intervention.

Aged↗
PubMed2006

Early emphysema in the tight skin and pallid mice: roles of microfibril-associated glycoproteins, collagen, and mechanical forces.

The nature of the development of emphysema in the tight skin (Tsk) and the pallid (Pa) mice are not well understood. We assessed the mechanical and nonlinear properties of the respiratory system, the alveolar structure, and the levels of microfibril-associated glycoproteins (MAGP) 1 and 2 in Tsk mice with developmental emphysema; in Pa mice, which are thought to develop adult onset emphysema; and their background, the C57BL/6 mice, at an age of 7 wk. Minor differences between collagen-related elastic properties of the lungs of the Pa and C57BL/6 mice were seen at this early age. The lungs of the Tsk mice were significantly softer yet more nonlinear than those of the Pa and C57BL/6 mice. The MAGP-1 levels were similar in all three groups. However, the level of MAGP-2, which is associated with both fibrillin-1 and collagen, was higher in the Tsk than in the Pa mice, which also had more MAGP-2 than the C57BL/6. Both the mean and the variance of alveolar diameters were larger in the Tsk than in the other two groups, while the variance in the Pa was larger than in the C57BL/6 mice, implying early development of heterogeneity. Using a network model of the parenchyma, we linked the pathophysiologic changes in the Tsk mice to mechanical forces and failure of the alveolar walls. Our findings suggest the possibility that MAGP-2-related abnormal collagen assembly, combined with mechanical forces, is involved in the progression of emphysema in the Tsk mice.

Animals↗
PubMed2004

Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice.

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMedDate not supplied

Large subconjunctival emphysema causing diplopia and lagophthalmos.

PURPOSE: To describe a patient who developed diplopia, lagophthalmos and exposure keratopathy due to a large subconjunctival emphysema. METHODS: A 24-year-old man sustained an injury in his left eye from a compressed air hose. The patient complained of pain and diplopia. He underwent slit-lamp examination, funduscopy and computed tomography. RESULTS: Ophthalmic examination revealed a decrease in vision in the left eye to 0.5, a conjunctival laceration adjacent to the medial limbus, subconjunctival hemorrhage, a large subconjunctival emphysema, lagophthalmos, hypertropia and superficial punctate keratopathy. The posterior pole was intact as were the orbital bones. Two weeks after the injury the conjunctival emphysema, diplopia, lagophthalmos and superficial keratopathy resolved, and visual acuity improved to 1. CONCLUSIONS: Large subconjunctival emphysema can result in diplopia, lagophthalmos and exposure keratopathy.

Adult↗