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PubMed1980

The effect of lathyrogens on the evolution of elastase-induced emphysema.

When pancreastic elastase is introduced into the lungs of hamsters to produce emphysema, there is an initial rapid destruction of elastin followed by a subsequent resynthesis. In order to investigate its pathologic significance, we attempted to interfere with this resynthesis by feeding inhibitors of elastin cross-linking. The feeding of the lathyrogens beta-aminoproprionitrile (beta APN) or penicillamine resulted in a marked worsening of the elastase-induced emphysema, as measured by the average distance between alveolar walls and the internal alveolar surface area, when compared with the effect of elastase in animals fed a normal diet. The lathyrogens produced no effect on lung morphology without elastase injections. In elastase-injected animals, the principlal biochemical effect of beta APN was a decrease in the aldehyde content of the elastin without a measurable decrease in desmosine cross-links. These results indicated that the formation of normal connective tissue proteins during the replair of elastolytic injury helps to limit the degree of anatomic deformity that is produced.

Aminopropionitrile↗
PubMed1981

Emphysema-like changes in the lungs of starved rats.

We examined the effects of starvation on lung structure in rats allowed only one fifth of their measured daily food consumption until they lost 40% of their initial body weight, and evaluated volume-pressure relationships in saline-filled lungs, lung morphometric and connective tissue morphologic features and lung ultrastructure by scanning electron microscopy. Compared with rats fed full rations, the volume-pressure curve was shifted upward and to the left and the chord compliance was significantly increased. In the starved rats, enlargement of air spaces and alveolar wall destruction was associated with a significant increase in mean linear intercept and a decrease in internal surface area. Elastic fibers appeared short, irregular, and fewer in number in starved lungs. Scanning electron microscopy showed enlarged air spaces, thin, irregular, and effaced alveolar walls, and an increased number and size of interalveolar pores in the starved group. We concluded that starvation results in mechanical and morphologic changes in the lung similar to those seen in emphysema, and that starved lung may be a useful experimental model for the study of emphysema.

Animals↗
PubMed1981

The effects of small doses of oligopeptide elastase inhibitors on elastase-induced emphysema in hamsters: a dose-response study.

Our previous studies have indicated that the synthetic elastase inhibitor N-acetyl-L-alanyl-L-alanyl-L-prolyl-L-alanyl chloromethylketone (AAPACK) administered intraperitoneally in divided doses totaling 19 mg, prior to and after a single intratracheal injection of elastase, substantially inhibited the development of experimental emphysema. The present studies evaluated the effects of 1.1, 4.1 and 8.0 mg AAPACK administered in divided doses 10 min prior to and 10, 30, and 50 min after a single intratracheal dose of elastase. The development of emphysema was essentially eliminated by 4.1 and 8.0 mg of AAPACK and markedly diminished with 1.1 mg AAPACK. The AAPACK was excreted rapidly in the urine at 30 to 60 min after its administration. Elastase inhibitory capacity (EIC) in urine was elevated to 14 times that in serum at the corresponding collection times. The plasma elastase inhibitory capacity was only slightly increased after administration of AAPACK and was not a sensitive indicator of elastase inhibition in the plasma.

Amino Acid Chloromethyl Ketones↗
PubMed1982

Dose response of elastase-induced emphysema in hamsters.

Elastase-induced emphysema in hamsters was studied using pulmonary function tests in an effort to develop techniques for determining the effects of air pollutants on the progression of this disease. Single intratracheal injections of 6, 12, or 24 units of porcine pancreatic elastase produced dose-related changes in pulmonary function after 4 wk when compared with sham-injected control animals. Boyle's law end-expiratory volume and residual volume, measured by gas dilution, increased (p less than 0.05) at 12 and 24 units, respectively, whereas vital capacity, determined plethysmographically, and total lung capacity wee increased (p less than 0.05) at all 3 elastase doses. Respiratory system compliance, calculated by a nonlinear least squares regression fit of the deflation pressure-volume curve, increased (p less than 0.05) at 24 units only. The multiple-breath nitrogen washout slope (N2 slope) and the single-breath diffusing capacity for carbon monoxide (DLCO) decreased (p less than 0.05) at all 3 doses of elastase. Both histologic and physiologic evaluation showed dose-related pulmonary impairment. It appears, therefore, that as little as 6 units of elastase produces mild emphysema in hamsters, which is detectable by pulmonary function testing. Of these tests, the DLCO and N2 slope were the most effective in detecting the degree of impairment.

Animals↗
PubMed1982

Effect of chloromethyl ketone on the progression of elastase-induced emphysema in hamsters.

Intratracheal administration of an elastase inhibitor (Succinyl alanyl alanyl prolyl valine chloromethyl ketone) into hamsters 20 days after induction of emphysema by porcine pancreatic elastase did not affect the lesion seen at 120 days. This study suggests that the progressive increase in lung volume between 20 and 120 days after emphysema induction was not due to a residue of active elastase in the lungs.

Amino Acid Chloromethyl Ketones↗
PubMed1982

Correlation of regional breath sound with regional ventilation in emphysema.

We measured regional breath sound intensities (Ib) by a microphone amplifier system in 8 subjects with emphysema. We also measured regional white noise transmissions (Tn) from the same areas in all subjects. The recorded areas were 5, 10, 15, and 20 cm from the apex of the lung just lateral to the right anterior midclavicular line. Xenon ventilation indexes (xenon tidal raw counts, an index of total regional ventilation; xenon equilibration raw counts, an index of ventilating lung volume; xenon ventilation per unit volume (Vr), an index of ventilation per unit volume) were also recorded from the same areas. The Ib, Tn, Ib/Tn (an index of sound generation), and xenon ventilation indexes were all expressed as a fraction of the mean value of all four recorded areas. The Ib and Ib/Tn correlated best with the xenon tidal raw counts, correlated well with the xenon equilibration raw counts, and correlated poorly with Vr. We conclude that Ib and Ib/Tn can be used to quantify regional ventilation in subjects with emphysema.

Auscultation↗
PubMed1982

The effects of emphysema on oxygen toxicity in rats.

In order to determine if lungs with emphysema respond to oxygen toxicity in a different way from normal lungs, the effects of hyperoxia on pulmonary function, morphologic aspects, and survival were studied in rats with enzyme-induced emphysema. A hyperoxic pulmonary syndrome similar to adult respiratory distress syndrome (ARDS) was produced by a continuous 48-h exposure to 100% oxygen at 1 atm. An emphysematous condition was induced by intratracheal instillation of porcine pancreatic elastase. The 4 study groups consisted of (1) control, (2) oxygen-treated, (3) elastase-treated, and (4) combined oxygen-elastase-treated rats. The emphysematous rats exposed to 100% O2 had reductions in quasi-static compliance and CO diffusing capacity similar to those in oxygen-treated normal animals. They also had reductions in forced expiratory volumes and flow rates similar to those in rats treated with elastase alone. Histologically, there was no enhancement or attenuation of emphysematous or ARDS lesions in the combined oxygen-elastase lungs compared with that in lungs treated with only one agent. Emphysematous and normal rats were also exposed for 96 h to a similar hyperoxic atmosphere to evaluate survival. The survival curves for these 2 groups were not statistically different. These results indicate that the severity of ARDS alterations was not affected by the emphysematous condition, and hyperoxia did not enhance or attentuate preexisting emphysematous lesions. These findings suggest that emphysematous lungs respond to hyperoxia in a similar fashion to normal lungs, and that the functional and structural manifestations of oxygen toxicity are simply superimposed over preexisting emphysematous changes.

Animals↗
PubMed1983

The role of oxidative processes in emphysema.

Elastase/elastase inhibitor imbalance in the lung has been implicated in the pathogenesis of pulmonary emphysema. In light of this, it may be significant that the activity of two major elastase inhibitors, alpha 1-proteinase inhibitor (alpha 1-antitrypsin, alpha 1Pi) and bronchial mucous proteinase inhibitor, can be decreased by oxidizing agents. The effect can be observed with ozone, substances present in cigarette smoke, and oxygen metabolites generated by lung macrophages as well as peroxidative systems released by other phagocytic cells. Thus alpha 1Pi recovered from lung washings of cigarette smokers has only half the predicted normal activity per mg inhibitor and contains 4 moles of methionine sulfoxide (oxidized methionine) per mole of inactive inhibitor. By contrast, alpha 1Pi purified from nonsmokers' lung washings is fully active and contains only native methionine. At the same time, lung washes from some smokers show significantly greater hydrolytic activity against a specific synthetic elastase substrate than do lung washes of nonsmokers. These findings suggest that some smokers may develop an acquired imbalance between elastase and elastase inhibitor in their lungs, favoring activity of the enzyme. In addition to the potential effect of cigarette smoking on lung elastase/elastase inhibitor balance, smoking also may interfere with elastin repair mechanisms. Specifically, acidic water-soluble gas phase components of cigarette smoke prevent synthesis of desmosine cross-links during elastinogenesis in vitro. This report will attempt to correlate the foregoing information on biochemical changes in the lung induced by cigarette smoking with the development of emphysema in the smoker.

Drug Synergism↗
PubMed1983

Synthetic elastase inhibitors: prospects for use in the treatment of emphysema.

Human polymorphonuclear leukocyte elastase is the enzyme primarily responsible for the destruction of lung tissue observed in pulmonary emphysema. A number of potent reversible and irreversible inhibitors have been developed for human leukocyte elastase. Several of these inhibitors have been shown to be effective at preventing emphysema in animal models of the disease. There are excellent prospects for the development of a synthetic elastase inhibitor for use in treatment of human disease.

Animals↗
PubMed1984

Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis.

The tight-skin (Tsk/+) mouse is a genetically determined model characterized by alveolar enlargement and physiologic evidence of emphysema. Morphologic evaluation of the lungs of these animals demonstrated increased numbers of potential protease-secreting cells (alveolar macrophages and neutrophils) in the lower respiratory tract prior to development of the emphysematous lesions. Quantitation of the neutrophils in the lungs of these animals was carried out by bronchoalveolar lavage. In the Tsk/+ mice, neutrophils constituted 3.5 +/- 2% of all inflammatory and immune effector cells present compared with 0.4 +/- 0.1% in control (+/+) mice (p less than 0.01). The Tsk/+ animals had no evidence of infection to explain the presence of the neutrophils and had normal proportions of lung T- and B-lymphocytes, suggesting that their lungs were immunologically normal. There was no evidence that the Tsk/+ mice have an antiprotease deficit; the capacity of serum of Tsk/+ mice to inhibit neutrophil elastase was no different from that of control +/+ animals. However, the fact that these animals have a persistent low level macrophage-neutrophil alveolitis prior to the development of the emphysematous lesion implies that the lung destruction may be associated, in part, with a chronic protease-antiprotease imbalance, similar to that hypothesized for human emphysema.

Animals↗
PubMed1985

Urinary excretion of desmosine (elastin cross-links) in subjects with PiZZ alpha-1-antitrypsin deficiency, a phenotype associated with hereditary predisposition to pulmonary emphysema.

To evaluate the concept that lung elastin degradation is accelerated in homozygous alpha-1-antitrypsin (AAT) deficient persons, we prepared acid hydrolysates of urine and used a radioimmunoassay for desmosine to measure urine concentrations of this elastin-specific cross-link in such persons and in control subjects. Excretion of desmosine in 17 homozygous AAT-deficient (PiZZ) patients with emphysema was compared with that in 27 patients with interstitial lung diseases (16 sarcoid, 5 idiopathic pulmonary fibrosis, 6 other interstitial lung diseases) and 26 healthy subjects. Both smokers and nonsmokers were present in all groups. Urinary desmosine concentration (microgram/100 mg creatinine) was 2.35 +/- 0.93 in the PiZZ patients, 2.49 +/- 1.01 in those with interstitial lung disease, and 2.05 +/- 0.54 in the healthy control subjects (p greater than 0.1, all comparisons). Because abnormal pulmonary elastolysis may be largely completed before symptoms of emphysema develop in AAT-deficient persons, we also tested 6 asymptomatic adults with homozygous AAT deficiency (PiZZ) and 5 PiZZ children. Urine desmosine (microgram/100 mg creatinine) was not significantly elevated in either group compared with that in the age-matched control subjects, although children (PiZZ and age-matched controls) showed higher excretions than did adults (6 asymptomatic PiZZ adults, 2.60 +/- 0.91; 5 PiZZ children, 3.27 +/- 0.62; 10 control children, 3.61 +/- 0.62). These data suggest that pathologic lung elastolysis in the PiZZ subject may constitute too small a fraction of total-body elastin turnover to be detected by this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

A comparison of the effects of almitrine or oxygen breathing on pulmonary arterial pressure and right ventricular ejection fraction in hypoxic chronic bronchitis and emphysema.

Almitrine bismesylate is a new, orally administered, respiratory stimulant that improves arterial blood gas tensions in patients with chronic bronchitis and emphysema, and it may have an effect on the pulmonary circulation and on right ventricular performance. We have, therefore, compared the effects of Almitrine with those of oxygen (given as 3 L/min by nasal prongs) on arterial blood gas tensions, mean pulmonary arterial pressure (Ppa), and right ventricular ejection fraction (RVEF) measured both at rest and during exercise in patients with chronic hypoxemia caused by chronic bronchitis and emphysema. Arterial oxygen tension improved significantly both at rest and during exercise after either 100 mg Almitrine by mouth or when breathing oxygen, both at rest and during exercise. Almitrine increased the mean Ppa at rest from 22 +/- 4 to 35 +/- 5 mmHg (p less than 0.001), and mean Ppa rose further during exercise from 38 +/- 5 mmHg before Almitrine to 49 +/- 7 mmHg (p less than 0.001) after Almitrine. In contrast, oxygen breathing did not change Ppa when at rest but reduced the amount of rise in Ppa during exercise. The change in Ppa after Almitrine correlated with the plasma Almitrine concentration (r = 0.69, p less than 0.05) and was associated with a fall in RVEF at rest from 0.38 +/- 0.03 to 0.32 +/- 0.02 (p less than 0.001). In 5 of the patients who received 50 mg of Almitrine by mouth twice daily for 3 months, the Ppa both at rest and during exercise remained significantly higher than in the control study before receiving Almitrine, but RVEF was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Ventilation asymmetry after transplantation for emphysema: role of chest wall and mediastinum.

After single-lung transplantation for emphysema, the hyperinflated native lung and the graft have different extents and rates of inflation and emptying. This requires that breathing produces asymmetrical expansion of the chest wall, displacement of the mediastinum, or both. In a first study in four seated transplant recipients, we measured the volumes of the two hemithoraces with optoelectronic plethysmography. Functional residual capacity and total lung capacity were identical on the native and transplanted sides, and changes in chest wall volume during CO(2)-induced hyperpnea and FVC maneuvers were similar on both sides. Studies with computerized tomography in three of these patients and in four additional patients in supine posture indicated that the mediastinum was shifted toward the graft at functional residual capacity and total lung capacity. The mediastinum moved toward the native lung during tidal and full inspiration and toward the graft during tidal and forced expiration; additional studies with fluoroscopy showed qualitatively similar changes in upright posture. In summary, the two hemithoraces assume identical static volumes and show similar volume changes during CO(2)-induced hyperpnea and FVC maneuvers in patients with single-lung transplantation for emphysema; displacement of the mediastinum accommodates part, if not all, of the unequal lung volumes and asymmetrical ventilation.

Female↗
PubMed2005

Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema.

RATIONALE: Matrix metalloproteinase 9 (MMP-9) has proteolytic activity against connective tissue proteins and appears to play an important role in the development of chronic obstructive pulmonary disease (COPD). The functional polymorphism of MMP-9 (C-1562T) is considered as one of the candidate genes in the susceptibility to COPD. OBJECTIVES: To determine if MMP-9 (C-1562T) is related to the development of COPD in the Japanese population and whether it is associated with development of pulmonary emphysema assessed by high-resolution computed tomographic (HRCT) parameters. METHODS: MMP-9 (C-1562T) genotypes of 84 patients with COPD and 85 healthy smokers (control subjects) were determined by the restriction fragment length polymorphism method. We investigated the relationship between the genotypes using automatically analyzed HRCT parameters, such as percentage of low attenuation area (LAA%) and average computed tomography (CT) value density (Hounsfield units; mean CTv) in upper, middle, and lower lung fields in all patients with COPD. MEASUREMENTS AND MAIN RESULTS: There was no difference in polymorphism of MMP-9 (C-1562T) between patients with COPD and control subjects. In the HRCT study, patients with COPD with a T allele (C/T or T/T) showed larger LAA% (95% confidence interval of difference, 0.5-18.7; p = 0.04), and smaller mean CTv (confidence interval, -34.3 to -1.0; p = 0.04) in the upper lung compared with patients without T alleles (C/C). However, pulmonary function tests showed no difference between the two patient groups. Patients with a T allele showed a decrease in LAA% and an increase in mean CTv from upper to lower lung fields (p = 0.006 and p = 0.002, respectively). CONCLUSIONS: Polymorphism of MMP-9 (C-1562T) was associated with upper lung dominant emphysema in patients with COPD.

Aged↗
PubMed2006

Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema.

RATIONALE AND OBJECTIVES: Hepatocyte growth factor (HGF) is a potent regenerative factor generated after a lung injury, and HGF supplementation after surgical reduction has been shown to enhance compensatory growth in remnant lungs and improve pathophysiologic conditions in a rat model of emphysema. Adipose tissue-derived stromal cells (ASCs) produce a large amount of angiogenic factors, including HGF. After lung volume reduction surgery (LVRS), we treated rats by implanting HGF-secreting ASCs with a scaffold onto the remnant lung tissue to determine the usefulness of this technique for treating respiratory dysfunction. METHODS AND MAIN RESULTS: Cells were isolated from rat inguinal adipose tissue and characterized by flow cytometry. ASCs were cultured on a polyglycolic acid felt sheet as a sealant material, and were shown to secrete significantly greater amounts of HGF than other angiogenic factors. Next, ASCs on polyglycolic acid felt sheets were used to cover the cut edge of the remaining lungs after LVRS for emphysema in rats. One week after implantation of the ASCs, both alveolar and vascular regeneration were significantly accelerated as compared with the rats that underwent LVRS alone. Consequently, gas exchange and exercise tolerance were also significantly restored, with these good results persisting for more than 1 mo. CONCLUSIONS: The present findings demonstrate the therapeutic potential of cell therapy using ASCs with a scaffold for selective delivery of HGF to remnant lungs, which resulted in enhancement of compensatory growth, after surgical resection. This approach may provide a new strategy for lung tissue engineering to improve LVRS outcome.

Adipose Tissue↗
PubMed2002

Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema.

The lung pathology of severe chronic obstructive pulmonary disease (COPD) has been poorly investigated. We examined surgical specimens obtained from patients with severe (forced expiratory volume in 1 second [FEV(1)] = 29 +/- 3% predicted, n = 9) or mild/no airflow limitation (FEV(1) = 86 +/- 5% predicted, n = 9) and similar smoking history. With histochemical and immunohistochemical methods we quantified the structural changes and the inflammatory cells in small airways and in muscular pulmonary arteries. As compared with smokers with mild/no COPD, smokers with severe COPD had an increased number of leukocytes in the small airways, which showed a positive correlation with the radiologic score of emphysema and with the value of residual volume, and a negative correlation with the values of FEV(1) and carbon monoxide diffusing capacity. The inflammatory process was characterized by an increase in CD8(+) and CD4(+) T-lymphocytes in the airway wall and by an increase in macrophages in the airway epithelium. When all smokers were considered together, the smoking history was correlated with both the airway wall and smooth muscle thickness, suggesting that smoking itself may play a role in the development of structural changes. No structural and cellular differences were observed in pulmonary arteries between smokers with severe COPD and smokers with mild/no COPD. In conclusion, in the small airways of smokers with severe COPD, there is an increased number of leukocytes, which is correlated with reduced expiratory flow, lung hyperinflation, carbon monoxide diffusion impairment, and radiologic emphysema, suggesting a role for this inflammatory response in the clinical progression of the disease.

Case-Control Studies↗
PubMed2002

Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.

Plasma deficiency of alpha(1)-antitrypsin is most commonly due to the Z mutation ((342)Glu--> Lys) and is associated with early-onset panlobular emphysema. The lung disease in these patients is attributed to the relative deficiency of circulating alpha(1)-antitrypsin resulting in uncontrolled neutrophil-derived proteolytic activity. We have previously demonstrated that the local deficiency of Z alpha(1)-antitrypsin is exacerbated by the formation of polymers within the lung and now show that this polymerization not only inactivates alpha(1)-antitrypsin but also converts the molecule to a chemoattractant for human neutrophils. The chemotactic action of polymeric alpha(1)-antitrypsin was substantially greater than that seen with other conformers, was of similar magnitude to C5a, and was apparent over a range of physiologically relevant concentrations (EC(50) 0.0045 +/- 0.002 mg/ml). The biologic activity of polymeric alpha(1)-antitrypsin was confirmed by the demonstration that polymers, but not native alpha(1)-antitrypsin, induced neutrophil shape change and stimulated myeloperoxidase release and neutrophil adhesion. Polymeric alpha(1)-antitrypsin had no effect on basal or N-formyl-Met-Leu-Phe- stimulated superoxide anion release or constitutive apoptosis. The chemotactic properties of polymeric alpha(1)-antitrypsin may provide an explanation for the excessive neutrophils found in the lungs of Z alpha(1)-antitrypsin homozygotes and suggests a new paradigm for the pathogenesis of emphysema in these patients.

Apoptosis↗
PubMed1977

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.

Animals↗