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PubMed2000

Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema.

It is claimed that lung volume reduction surgery (LVRS) improves inspiratory muscle function. As diaphragm structure and function are not directly appraisable in patients, we studied the effects of LVRS on the diaphragm in vitro contractile properties and morphology in hamsters with elastase-induced emphysema. Four months after intratracheal instillation of elastase (40 U/100 g), hamsters underwent either bilateral LVRS (LVRS, n = 11) or a sham operation (SHAM, n = 8). Four animals died during the perioperative period in LVRS (n = 7). Hamsters instilled with saline served as control (CTL, n = 8). Animals were studied at the age of 9 mo. LVRS was associated with a significant 25% decrease in functional residual capacity compared to SHAM (p < 0.05). Compared with CTL, LVRS and SHAM showed a significant 18% and 14% reduction in diaphragm mass, respectively (p = 0.02). LVRS had a significantly decreased twitch tension compared to CTL and SHAM (p < 0.01). Both LVRS and SHAM showed increased resistance to muscle fatigue compared with CTL. The histochemical analysis revealed a significant shift from type IIx/b toward type IIa fibers in LVRS and SHAM compared with CTL. In conclusion, emphysema is associated with functional adaptations but LVRS does not appear to beneficially alter the diaphragm contractile and morphological characteristics in hamsters with elastase-induced emphysema.

Animals↗
PubMed2001

Effects of emphysema on diaphragm microvascular oxygen pressure.

Pulmonary emphysema impairs lung and respiratory muscle function leading to restricted physical capacity and accelerated morbidity and mortality consequent to respiratory muscle failure. In the absence of direct evidence, an O2 supply-demand imbalance within the diaphragm and other respiratory muscles in emphysema has been considered the most likely explanation for this failure. To test this hypothesis, we utilized phosphorescence quenching techniques to measure mean microvascular PO2 (PO2m) within the medial costal diaphragm of control (C, n = 10) and emphysematous (E, elastase instilled, n = 7) hamsters. PO2m and mean arterial pressure (MAP) were measured in the spontaneously breathing anesthetized hamster at inspired O2 percentages of 10, 21, and 100, and across a range of mean MAPs from 40 to 115 mm Hg. At each inspired O2, diaphragm PO2m was significantly (p < 0.05) lower in E animals (10%: C, 19 +/- 3; E, 9 +/- 2; 21%: C, 32 +/- 2; E, 21 +/- 2; 100%: C, 60 +/- 8; E, 36 +/- 9 mm Hg). At 21% inspired O2, the PO2m decrease was correlated with reduced MAP in both C (r = 0.968) and E (r = 0.976) animals. We conclude that diaphragmatic PO2m (and therefore microvascular O2 content) is decreased in emphysematous hamsters reflecting a greater diaphragmatic O2 utilization at rest and a lower O2 extraction reserve. According to Fick's law, this lower PO2m will mandate an exaggerated fall in intramyocyte PO2, which is expected to accelerate muscle glycogen depletion and consequently fatigue. This provides empirical evidence in support of one possible mechanism for respiratory muscle failure in emphysema.

Analysis of Variance↗
PubMed2001

Relationship between extent of pulmonary emphysema by high-resolution computed tomography and lung elastic recoil in patients with chronic obstructive pulmonary disease.

We investigated the relationship between the extent of pulmonary emphysema, assessed by quantitative high-resolution computed tomography (HRCT), and lung mechanics in 24 patients with chronic obstructive pulmonary disease (COPD). The extent of emphysema was quantified as the relative lung area with CT numbers < -950 Hounsfield Units (HU). Patients with COPD had severe airflow obstruction (FEV(1) 35 +/- 15% pred) and severe reduction of CO diffusion constant (DCO/VA 37 +/- 19% pred). Maximal static elastic recoil pressure (Pst(max)) averaged 54 +/- 24% predicted, and the exponential constant K of pressure-volume curves was 258 +/- 116% predicted. Relative lung area with CT numbers < -950 HU averaged 21 +/- 11% (range 1 to 38%). It showed a highly significant negative correlation with DCO/VA (r = -0.84, p < 0.0001), a weak correlation with FEV(1)% predicted, and no correlation with either Pst(max) or constant K. A significant relationship was found between the natural logarithm of K and the full width at half maximum of the frequency distribution of CT numbers, taken as an index of the heterogeneity of lung density (r = 0.68, p < 0.0005). We conclude that currently used methods of assessing the extent of emphysema by HRCT closely reflect the reduction of CO diffusion constant, but cannot predict the elastic properties of the lung tissue.

Aged↗
PubMed1987

Pulmonary vascular structural and functional changes in papain-induced emphysema in dogs.

We evaluated the pulmonary circulatory effects of emphysema produced by papain in 6 dogs that received 4 weekly treatments of papain administered by aerosolization. A control group of 6 dogs received saline treatments. Hemodynamic measurements were performed during normoxic and hypoxic (10% oxygen) ventilation approximately 3 and 6 months after treatment. Baseline hemodynamic parameters were comparable in both groups and were unchanged at 6 months in the control group. In the papain-treated group at 6 months, there were significant reductions in PaO2 (95 +/- 4 to 79 +/- 3 mm Hg, p less than 0.005) and increases in mean pulmonary artery pressure (12 +/- 1 to 18 +/- 3 mm Hg, p less than 0.05) and pulmonary vascular resistance (2.0 +/- 0.3 to 6.2 +/- 2.1 units, p less than 0.01). Morphometric evaluation demonstrated increased medial thickness in muscular pulmonary arteries less than 50 mu in size. Morphologic evaluation confirmed the presence of panlobular emphysema with papain administration. We conclude that chronic emphysema produced in dogs by aerosol administration of papain results in elevated pulmonary artery pressure, which is characterized pathologically by medial hypertrophy of small pulmonary arteries. This model appears suitable for further study of the pathogenesis of pulmonary vascular disease associated with chronic lung disease.

Animals↗
PubMed1988

Effects of phospholipase A2 and its hydrolytic products on alveolar epithelial permeability and elastase-induced emphysema.

To cause emphysema, proteases that are instilled into the air spaces must first be transported across the alveolar epithelium, a barrier that is normally quite impermeable to macromolecules. It was postulated that phospholipase A2 (PLA2) exposure would potentiate porcine pancreatic elastase (PPE)-induced epithelial solute permeability in a manner similar to that which was previously shown with lysophosphatidylcholine (lysoPC), a naturally occurring, membrane-perturbing agent that is formed principally through the hydrolysis of phosphatidylcholine by PLA2. Groups of hamsters were given intratracheal injections of PLA2 (0.3 units) or one of the expected hydrolytic products of PLA2 in equimolar concentrations, lysoPC (135 micrograms), arachidonic acid (AA) (100 micrograms), or palmitic acid (PA) (70 micrograms) with or without PPE (4 units). Epithelial permeability surface area products (PS) of the alveolar epithelium to [14C]sucrose and 125I-labeled neutral dextran (MW, 70,000) were measured in isolated perfused lungs 30 min after instillation, and emphysema severity was assessed at 3 wk by pressure-volume relationships and by mean linear intercepts. Additionally, the effects of lysoPC, PA, and AA on the functions of PPE and alpha 1-antiprotease (alpha 1 PI) in vitro were evaluated. Sucrose and dextran 70 PS differed significantly from controls only in those groups of hamsters that received PLA2 of lysoPC (p less than 0.05). LysoPC and PLA2 also potentiated the severity of PPE-induced emphysema to a similar degree (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The effect of 60% oxygen on air-space enlargement and cross-linked elastin synthesis in hamsters with elastase-induced emphysema.

Hyperoxia is routinely administered to patients with severe emphysema. To gain insight into the possibly adverse effects of such treatment, hamsters were exposed to 60% oxygen for 5 days, beginning 48 h after induction of pulmonary emphysema by intratracheal instillment of pancreatic elastase. Control groups consisted of (1) animals instilled with elastase and exposed to room air, (2) animals instilled with saline and exposed to 60% oxygen, and (3) animals instilled with saline and exposed to room air. Cross-linked elastin content and synthesis in the lung were measured immediately following termination of hyperoxia, and the mean linear intercept was determined 4 wk later. Cytologic examination of bronchoalveolar lavage fluids was also performed. Statistical significance was determined by a two-way analysis of variance. Results indicate that exposure to 60% oxygen significantly affected (p less than 0.05) air-space size, causing a 51% increase among elastase-treated hamsters (124 versus 82 microns) but only a 4% increment among saline-treated animals (52 versus 50 microns). When compared to other groups, animals treated with both elastase and hyperoxia had a significantly greater (p less than 0.01) percentage of neutrophils (28%) in their lung lavage fluids immediately following exposure to 60% oxygen. Although total lung elastin content was not altered by hyperoxia at this time, labelling of elastin cross-links was significantly increased (p less than 0.05). These studies demonstrate that exposure to 60% oxygen enhances elastase-induced lung injury. They also raise the possibility that oxygen therapy may, under certain circumstances, accelerate the progression of human emphysema.

Animals↗
PubMed1991

Panlobular emphysema in young intravenous Ritalin abusers.

We studied a distinctive group of young intravenous Ritalin abusers with profound obstructive lung disease. Clinically, they seemed to have severe emphysema, but the pathologic basis of their symptoms had not been investigated previously. Seven patients have died and been autopsied: in four, the lungs were fixed, inflated, dried, and examined in detail radiologically, grossly, microscopically, and by electron probe X-ray microanalysis. All seven patients had severe panlobular (panacinar) emphysema that tended to be more severe in the lower lung zones and that was associated with microscopic talc granulomas. Vascular involvement by talc granulomas was variable, but significant interstitial fibrosis was not present. Five patients were tested for alpha-1-antitrypsin deficiency and found to be normal, as were six similar living patients. These findings indicate that some intravenous drug abusers develop emphysema that clinically, radiologically, and pathologically resembles that caused by alpha-1-antitrypsin deficiency but which must have a different pathogenesis. Talc from the Ritalin tablets may be important, but the mechanism remains to be elucidated.

Adult↗
PubMed1991

Centrilobular and panlobular emphysema in smokers. Two distinct morphologic and functional entities.

In order to investigate the hypothesis that different morphologic patterns of disease might correspond to different mechanical properties of the lung in emphysema, pulmonary function tests and lung mechanics were measured in 34 subjects undergoing lung resection for peripheral lung tumors. Using standard microscopic criteria, pure or predominant centrilobular (n = 18) or panlobular (n = 16) emphysema was diagnosed in lungs. The degree of emphysema measured by the mean linear intercept (Lm) was not significantly different between the two groups. However, the coefficient of variation of the interalveolar wall distance (CV) was significantly higher for the same Lm in CLE than in PLE. This indicates that CLE has an uneven pattern of destruction, whereas PLE is more homogeneous. CLE had a higher degree of abnormalities in the small airways (SAD) than did PLE (p less than 0.05) mainly because of significantly higher muscle score (p less than 0.001) and fibrosis. CLE also had a higher proportion of airways less than 400 microns in diameter than did PLE (p less than 0.05). Static compliance, specific compliance, and the exponential constant (K) were significantly lower (p less than 0.005, p less than 0.001, and p less than 0.05, respectively) in CLE than in PLE. FEV1/FVC was significantly correlated with SAD in CLE (r = -0.69, p less than 0.01) but not in PLE (r = 0.29 p greater than 0.05); conversely, FEV1/FVC was significantly correlated with elasticity (K) in PLE (r = -0.72, p less than 0.01) but not in CLE (r = 0.08, p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1992

Induction of emphysema in hamsters by intratracheal instillation of cathepsin B.

Current theories of pathogenesis suggest that pulmonary emphysema develops in humans because of progressive loss or derangement of lung elastin through a process mediated by elastolytic enzymes released by inflammatory cells. Neutrophils are considered primary etiologic factors because these cells produce and release two potent serine proteinases that cause emphysema when instilled into the lungs of animals. It has been suggested that alveolar macrophages also contribute to the development of emphysema through production of several enzymes with elastolytic activity, including the lysosomal cysteine proteinases cathepsin B and cathepsin L, but this has not been verified experimentally. In the current study, we instilled 115 micrograms of active cathepsin B into the lungs of hamsters three times at 48-h intervals. After 6 wk microscopic evaluation revealed that lung sections of five of seven animals given cathepsin B contained focal areas of enlarged and distorted alveoli, in the absence of fibrosis, which were similar to changes seen in the lungs of animals given papain intratracheally. Morphometrically, mean linear intercept (micron) values were significantly higher (p less than 0.025) in animals given cathepsin B (204.4 +/- 20.8) as compared with control animals (173.2 +/- 7.8), and internal surface area (sqcm) values were significantly lower (935 +/- 120 versus 1,083 +/- 56 in control animals), thereby confirming that airspace enlargement had developed after instillation of the enzyme. Lung volumes (ml) and compliance (ml/cm H2O) were not significantly higher in animals given cathepsin B.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Collagen and elastin in human pulmonary emphysema.

Studies of collagen and elastin in pulmonary emphysema have been controversial. The problems involve methodologic differences; often whole lungs have been sampled and the types of emphysema have not been classified. Quantification of collagen and elastin is important since the increase in collagen supports the inflammatory-repair hypothesis of emphysema, which has been recently revived. On the other hand, loss of elastin supports the protease-antiprotease hypothesis. Accordingly, we measured collagen (hydroxy-proline) and elastin (desmosine) in 147 small samples of human lungs removed for cancer. The amount and type of collagen were also assessed histochemically in tissue blocks adjacent to the tissue used for the biochemical analysis. We found that collagen in the homogenates was increased only in irregular airspace enlargement, but histochemically, collagen was consistently increased in centriacinar, distal acinar, and irregular air-space enlargement sections. Elastin was decreased in all grades of panacinar air-space enlargement and also in severe centriacinar air-space enlargement. Our data support both the protease-antiprotease imbalance hypothesis in panacinar and the inflammatory-repair hypothesis in centriacinar, distal acinar, and irregular air-space enlargement.

Aged↗
PubMed1994

The role of proteolytic enzymes in the development of pulmonary emphysema and periodontal disease.

Pulmonary emphysema and periodontal disease are each characterized by the uncontrolled proteolysis of connective tissue proteins by proteinases derived from human neutrophils. Although these diseases would not appear to be related in terms of the initial insult to individual tissues, the ultimate result in each disease is the accumulation and degranulation of neutrophils at inflammatory sites, apparently as a result of frustrated phagocytosis and specific activation of these phagocytic cells. This result is easily recognized in the case of emphysema, where there is clear evidence that the primary cause of the disease is the accumulation of foreign materials in the lung (e.g., smoke condensate), followed by the recruitment of neutrophils to the organ and the release of oxidative and hydrolytic enzymes. In periodontitis, however, the problem begins with the accumulation of plaque at the base of the teeth, followed by the growth of opportunistic anaerobic bacteria below the gum line. These parasitic microbes, which are resistant to killing by both monocytes and granulocytes, secrete proteinases that can activate the kallikrein-kinin pathway, degrade clotting factors, and release the potent neutrophil chemotactic factor, C5a, from complement. It is under such conditions that neutrophils are recruited to infected sites within the periodontium. After the neutrophil-recruitment stage, the two diseases become similar in that degranulation of neutrophils occurs during attempted phagocytosis of either cigarette smoke components (emphysema) or bacteria (periodontitis), followed by inactivation of tissue proteinase inhibitors and degradation of connective tissue proteins, the ultimate result being the destruction of the alveolus or gingiva, respectively.

Animals↗
PubMed1980

The effect of the specific elastase inhibitor, alanyl alanyl prolyl alanine chloromethylketone, on elastase-induced emphysema.

The chloromethylketone derivative of the tetrapeptide, alanyl alanyl prolyl alanine significantly diminishes the extent of experimental elastase-induced emphysema in hamsters. A total of 19 mg of alanyl alanyl prolyl alanine chloromethylketone was administered intraperitoneally in divided doses before and immediately after intratracheal instillation of a standard dose (4 units) of porcine pancreatic elastase. Morphologic evaluation and measurement of mean linear intercept, internal surface area, and lung volume performed 7, 45, and 120 days after exposure to elastase indicated a marked decrease in the extent of emphysema in the group treated with alanyl alanyl prolyl alanine chloromethylketone compared with the control group. Lung elastin content determined biochemically confirmed the preservation of elastin in the hamsters treated with alanyl alanyl prolyl alanine chloromethylketone. At postmortem examination by light microscopy, no pathologic abnormalities were observed in the organs of hamsters treated with alanyl alanyl prolyl alanine chloromethylketone. These data indicate that alanyl alanyl prolyl alanine chloromethylketone in the doses administered (1) had significant anti-elastase activity in vivo; (2) markedly decreased the extent of elastase-induced emphysema; and (3) produced no adverse toxic effect during the period covered by this study protocol.

Amino Acid Chloromethyl Ketones↗
PubMed1980

Immunologic identification of elastin-derived peptides in the serums of dogs with experimental emphysema.

Pulmonary emphysema is a disease in which peptides formed by the enzymatic degradation of the amorphous component of interstitial elastin may be release from the lung. In order to provide a test that can monitor the destruction of lung elastin invivo, we developed a hemagglutination inhibiton assay that specifically and quantitatively measure elastin-derived peptides in serum. Using this method, was measured the concentration of elastin-derived peptides in the serums of dogs developing emphysema through the administration of porcine pancreatic elastase. Elastin-derived peptides could be detected in the serums for a period of 12 days after the administration of a single 25- or 50-mg dose of elastase, and for at least 40 days after a 100-mg dose. There was a good correlation between the maximal concentration of elastin derived peptides found in the serums and the amount of elastase administered to the animal. This immunologic method may be useful in following the progression of experiment emphysema.

Animals↗
PubMed1981

Hereditary emphysema in the tight-skin (Tsk/+) mouse.

The tight-skin (Tsk/+) mouse represents an autosomal dominant mutation characterized by increased thoracic size, large lungs, and a variety of abnormalities of loose subcutaneous connective tissue, cartilage, tendon, and bone. Because an increase in the size of the lung and thorax may result from destruction of alveolar walls and a loss of elastic recoil of the lung, the present study was undertaken to determine if the Tsk/+ mouse exhibits morphologic and physiologic characteristics of emphysema. In contrast to the lungs of normal mice, examination of the lungs of Tsk/+ mice by light and scanning electron microscopy revealed generalized enlargement of air spaces with numerous subpleural cysts and scattered bullae. In addition, many alveolar walls were either markedly thinned or broken and there was an increase in the number and size of the pores of Kohn. Consistent with these morphologic observations, the lungs of the Tsk/+ mice also exhibited physiologic characteristics consistent with emphysema. Compared to the lungs of normal mice, the lungs of Tsk/+ mice had a markedly increased total lung capacity of (1.8 +/- 0.1 ml versus 3.3 +/- 0.1 ml, p less than 0.001); compliance (0.077 +/- 0.006 ml/cm H2O versus 0.345 +/- 0.025 ml/cm H2O, p less than 0.001), and specific compliance (4.23 +/- 0.34% TLC/cm H2O versus 10.64 +/- 1.01% TLC/cm H2O, p less than 0.001). These findings suggested that the Tsk/+ mouse is a genetically determined model of emphysema that may be useful in determining the pathogenesis of destructive lung disease.

Animals↗
PubMed1981

The moderation of elastase-induced emphysema in the hamster by intratracheal pretreatment or post-treatment with succinyl alanyl alanyl prolyl valine chloromethyl ketone.

The capacity of the synthetic elastase inhibitor, succinyl alanyl alanyl prolyl valine chloromethyl ketone (CMK), to moderate elastase-induced emphysema in hamsters was examined using morphometric and physiologic measurements. When 0.5 mg of CMK in saline was injected intratracheally 1 h before the intratracheal injection of 0.1 mg of porcine pancreatic elastase, the hamsters did not develop emphysema. When CMK was injected intratracheally 1 h after elastase, the severity of emphysema was reduced by approximately 50% compared with control animals receiving saline 1 h after elastase. The CMK was ineffective when administered intratracheally 4 h after elastase.

Amino Acid Chloromethyl Ketones↗
PubMed1981

Effects of oligopeptide chloromethylketone administered after elastase: renal toxicity and lack of prevention of experimental emphysema.

The effectiveness of N-acetyl-L-alanyl-L-alanyl-L-prolyl-L-alanine chloromethylketone (AAPACK) in preventing the development of experimental emphysema in hamsters, when administered 60 min after exposure to elastase, was studied. When 19 mg of AAPACK was injected intraperitoneally in divided doses commencing 60 min after the intratracheal instillation of pancreatic elastase, the development of emphysema was not prevented using morphologic, morphometric, and physiologic means of evaluation. Thirty-eight per cent of hamsters given AAPACK became ill and lost weight. At autopsy, these hamsters had a renal tubular nephropathy and focal interstitial disease. The glomeruli were spared. Five of these hamsters with renal tubular lesions had azotemia. Focal necrosis was observed in the heart of 3 and in the liver of 5 animals with renal lesions. These studies indicated that AAPACK, in the protocol followed where elastase precedes administration of the inhibitor, (1) does not prevent the development of elastase-induced emphysema, and (2) does produce a unique renal tubular nephropathy.

Acute Kidney Injury↗
PubMed1982

A copper-deficient, zinc-supplemented diet produces emphysema in pigs.

A mild form of emphysema was produced in pigs raised on a copper-deficient, zinc-supplemented diet. The copper-requiring enzyme, lysyl oxidase, catalyzes the cross-linking of tropoelastin into mature elastin. Zinc further inhibits the activity of lysyl oxidase. Lungs from animals raised on copper-deficient, zinc-supplemented diets of demonstrate perforations in alveolar walls and diminished amounts of elastin bronchi and pulmonary arteries. Mean linear intercepts are greater and alveolar internal surface areas are less than those in control animals, fulfilling the generally accepted definition of emphysema. Physiologic confirmation is provided by a leftward shift of the saline volume-pressure curves when compared with those in control animals. Ultrastructurally, the alveolar walls are effaced and pores of Kohn are enlarged. There are areas in which elastin is absent leaving remnant microfibrils, and there are other changes consistent with active elastin synthesis. Biochemical data demonstrate no difference in elastin content as micrograms/ml of fat-free dry weight but do demonstrate increased collagen content in experimental animal lungs compared with that in control lungs. Ultrastructural similarities to enzyme-induced models of emphysema suggest the presence of elastin degradation in our model. We speculate that although the copper-deficient, zinc-supplemented state may stimulate protein synthesis in general, elastin is being degraded by endogenous means, but collagen is not.

Air Pressure↗
PubMed1983

Small airways in severe panlobular emphysema: mural thickening and premature closure.

Histological measurements in cases of severe paniobular and centrilobular emphysema and in normal lungs disclosed a generalized thickening of the walls of small airways in the panlobular group. With mathematical models, this was depicted as a potential basis for airway closure at higher than normal lung volumes and trapping of air. Lungs with mixtures of panlobular and centrilobular emphysema predominate in the general population, and the obstructive component of airways in this setting is likely a net result of multiple lesions. These may be common in varying degrees to both varieties of disease but especially characteristic of one form. Bronchiolar thickening is one such general process. Present findings suggest that this is prone to be linked to emphysema with a panlobular pattern.

Aged↗