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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to evaluate the role of neutrophils (PMNs) in the pathogenesis of emphysema. After administration of CdCl2 intratracheally to hamsters fed a lathyrogen, beta-amino propionitrile fumarate (BAPN), the classic lesions of emphysema developed. Administration of specific antineutrophil serum markedly reduced the PMN influx into the lungs which followed CdCl2 exposure and produced a substantial decrease in elastase and collagenase content of bronchoalveolar lavage fluid (BAL). The degree of emphysema in PMN-depleted hamsters given BAPN and CdCl2 was not different from that in hamsters given BAPN and CdCl2. Furthermore, the degree of acute lung injury following CdCl2, as determined by hydroxyproline content of BAL and by lung lipid peroxidation, was the same in PMN-depleted and non-depleted groups. Thus, PMNs were not necessary for the induction of emphysema in BAPN-CdCl2-treated hamsters. The results suggest that PMNs may not be obligate mediators of emphysema.
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PMID:The role of neutrophils in the development of cadmium chloride-induced emphysema in lathyrogen-fed hamsters. 299 Feb 23

The endotracheal deposition of pancreatic porcine elastase (EPP) at 40 u X kg-1 body weight provokes a typical pulmonary emphysema (alveoli disruption) in rats. This emphysema is significant (p less than 0.001) when quantitatively compared to a placebo (100% increase of the mean linear intercept, ILM). The EPP-treated lungs are very heterogeneous and the size of the alveoli vary as much as 30% versus 19% in controls. The emphysema is more effective at a 80 u X kg-1 dose and the individual disparities are reduced (dose effect). When bacterial collagenase (200 u X kg-1 body weight) is added to EPP, the pulmonary abnormalities (disruptions, ILM) are in no way increased (no enzymatic synergy, repair by collagenesis?). In contrast, alveolar dilation is slightly reduced 8 weeks after enzyme administration (p less than 0.05): EPP is not altered in vitro by collagenase and despite several hypothesis, the moderating effect of collagenase in vivo still remains unexplained. This result suggests that the joint presence of several proteases is not necessarily an aggravating factor in the etiopathogenesis of emphysema.
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PMID:[Pulmonary emphysema induced by elastase: influence of the dose and effect of added collagenase]. 303 67

Tissue proteolytic enzymes are currently believed to be critical to the pathogenesis of panacinar emphysema. Polymorphonuclear leukocytes (Polys) have several enzymes including elastase and cathepsin G in their azurophil granules. They have collagenase in their specific granules. We have found that this collagenase is doubly latent. It has the lysosomal type of latency that depends on the impermeability of the unit membrane that surrounds each specific granule. In addition it has a latency that is converted to activity by proteolytic enzymes. The cathepsin G of the azurophil granule is a potent activator of this latent collagenase once the collagenase is released from its membrane dependent latency. Thus latency of enzymes, the nature of the latency and accessibility of the latent enzymes to activating mechanisms must all be taken into account in any analysis of their contribution to pathogenesis of local lung disease. Equally important is that fact that polys are not a prominent cellular component of normal lung. Polys must be attracted to the lung by chemotactic peptides. These peptides must be released by the interaction of inflammatory stimuli, such as smoke particles, with complement components or they must be provided by other sources. The hypothesis that lung damage in panacinar emphysema is mediated by polys and their proteases is attractive and suggestive evidence supporting this is available. However, more evidence that takes into full account the cell biology of the proteases any poly turnover in the lung are needed to extend the hypothesis and to form a rational basis for therapeutic and prophylactic measures.
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PMID:Neutral proteases of human polymorphonuclear granulocytes: putative mediators of pulmonary damage. 625 Aug 11

Hydrolytic enzymes are major constituents of alveolar macrophages, which in recent years have been shown to be involved in many aspects of the inflammatory response in addition to their better-known role in bactericidal processes. This review summarizes the general properties, physiologic function, cellular physiology, and clinical associations of four important hydrolytic enzymes of alveolar macrophages--lysozyme, elastase, plasminogen activator, and collagenase--with particular attention to the relationship of these enzymes to the pathophysiology of lung disease. The information reviewed shows that much is known about the biochemistry of these enzymes, that each is produced in greater quantity when alveolar macrophages are stimulated, that each has a distinctive physiologic role in the inflammatory process, and that they function as part of the overall pulmonary antibacterial defense system. Studies of the pathophysiologic effects consequent to the elaboration of excess quantities of these enzymes by stimulated macrophages show that some hydrolytic enzymes injure the lung by attacking normal as well as inflammatory tissue sites that are susceptible to degradation. Such damage is normally limited by enzymatic inhibitors, like alpha-antitrypsin, but the inactivating capacity of the inhibitors can be overwhelmed and in these instances excess enzyme contributes to the development of emphysema. This newer understanding of the pathophysiologic role of hydrolytic enzymes may lead to therapeutically beneficial methods for modulating the pulmonary inflammatory response.
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PMID:Hydrolytic enzymes of alveolar macrophages. 631 90

The normal structure and function of the human lung is dependent on the maintenance of the connective tissue matrix. These structural macromolecules provide the template for normal parenchymal cell architecture on which efficient gas exchange depends. In addition, the organization and amount of this extracellular matrix accounts for much of the mechanical behavior of the lung parenchyma during the respiratory cycle. The preservation of this intricate connective tissue scaffold depends on the lung's capacity to prevent enzymatic disruption of the component matrix proteins. Specifically, the integrity of the normal connective tissue skeleton of the lung is determined by the maintenance of a balance between proteases capable of cleaving these structural elements and the specific protease inhibitors. The normal extracellular matrix is preserved when the local concentrations of protease inhibitors prohibits expression of active connective tissue proteases within the lung parenchyma. Conversely, the disruption of lung structure during the course of acute and chronic inflammatory diseases of the lung is often associated with an imbalance of protease-antiprotease activity. The consequence is the expression of unimpeded proteolytic attack on the connective tissue matrix of the lung. In this context, the nature of the pulmonary lesion and its physiologic consequences, reflect the specificity of the expressed proteases for the individual connective tissue components. Experimental evidence suggests that the differential expression of collagenase and elastase, prototypes of connective tissue proteases, may determine whether the pathologic outcome is fibrosis (e.g., idiopathic pulmonary fibrosis) or destruction (e.g., emphysema) of the alveolar structures.
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PMID:Role of connective tissue proteases in the pathogenesis of chronic inflammatory lung disease. 632 73

We examined the expression of interstitial collagenase and its enzymatic activity in lung damage induced by tobacco smoke. Guinea pigs were exposed to the smoke of 20 cigarettes per day from 1-8 wk. Age-matched guinea pigs were used as controls. At 6 and 8 wk of smoke exposure, lungs exhibited interstitial and peribronchiolar inflammation and moderate emphysematous changes. In situ hybridization of injured lungs revealed patchy expression of collagenase mRNA mainly in macrophages but also in alveolar epithelial and interstitial cells. Immunoreactive protein was detected in alveolar macrophages and in the alveolar walls and interstitium. Collagenolytic activity increased beginning in the 4th wk of exposure (0.7 +/- 0.43 micrograms collagen degraded/mg collagen incubated relative to 0.23 +/- 0.14 in controls; P < 0.05). At 6 and 8 wk, values were 0.85 +/- 0.34 and 0.98 +/- 0.33 compared with 0.25 +/- 0.11 and 0.26 +/- 13 in controls (P < 0.005 and 0.001). Collagen concentration decreased from 50.7 +/- 8.5 mg/g dry wt in control lungs to 40.2 +/- 5.0 and 42.9 +/- 6.0 at 6 and 8 wk of exposure, respectively (P < 0.05). These results strongly suggest that increased interstitial collagen degradation plays a role in the development of lung emphysema.
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PMID:Tobacco smoke-induced lung emphysema in guinea pigs is associated with increased interstitial collagenase. 894 16

The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.
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PMID:Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. 1021 97

The lung is the major site expressing plasma phospholipid transfer protein (PLTP) mRNA in humans and mice, suggesting that this protein might have an important role in maintaining normal function of this organ. In the lung of human collagenase transgenic mice, an emphysematous animal model, PLTP mRNA was 3-fold higher than in control mice. However, the mRNA in other tissues was not changed. To further assess the expression and function of PLTP, we measured PLTP mRNA level in lung tissue of two emphysematous patients and found that the mRNA was 4-fold higher than in control subjects. In situ hybridization on mouse lung suggested positive staining in alveolar type II epithelial cells. In addition, immortalized rat alveolar pre-type II epithelial cells and freshly isolated mature rat alveolar type II epithelial cells both highly expressed PLTP mRNA, and the former cells actively secreted PLTP activity into the medium. To examine the possible mechanisms leading to high levels of PLTP expression in vivo, we exposed the pre-type II cells to hypoxia and demonstrated induction of PLTP mRNA and a coordinate increase in secreted PLTP activity. Thus, the PLTP gene is highly expressed in alveolar type II epithelial cells and is induced during hypoxia and in emphysema. These observations suggest that a hypoxic stimulus occurring in emphysema may be a novel mechanism that contributes to enhanced expression of PLTP.
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PMID:Expression of plasma phospholipid transfer protein mRNA in normal and emphysematous lungs and regulation by hypoxia. 962 68

The aim of this study was to compare the time course of neutrophil and macrophage elastinolytic potentials in the lungs of rats exposed daily to cigarette smoke inhalation for 1-6 mo in relation to the onset and progression of cigarette smoke-induced emphysema. Normal room air-exposed rats served as controls. Morphometric data of lung histological sections showed evidence of emphysema lesions in the lungs of smoke-exposed rats at month 2 and continuing to month 6. Data of total and differential cell counts in bronchoalveolar lavage fluid and collagenase-dissociated lung showed an increased number of lung neutrophils at month 1 of smoke exposure, but this was reduced to control levels at months 2-6. In contrast, an increased number of lung macrophages was evident in the smoke-exposed rats at month 2 of exposure and continued to month 6. Data of the elastinolytic activities of the neutrophils and macrophages, determined in [3H]elastin-coated culture wells, showed that the elastinolytic activity of lung neutrophils in the smoke-exposed rats was similar to that of the control air-exposed rats at months 1-6 of exposure. In contrast, the elastinolytic activity of lung macrophages in the smoke-exposed rats was increased at month 2 of exposure and remained increased at month 6. Excessive in vivo lung elastin breakdown (judged by increased levels of elastin-derived peptides and desmosine in lavage fluid, determined immunologically) was observed in the smoke-exposed rats at months 2-6 of exposure. These data indicate that the time course of increased macrophage-directed elastinolytic activity in the lung, not that of neutrophils, is more closely associated with the evolution of cigarette smoke-induced emphysema.
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PMID:Time course of neutrophil and macrophage elastinolytic activities in cigarette smoke-induced emphysema. 984 51

The aim of this study was to ascertain the putative roles of neutrophils or macrophages in the pathogenesis of cigarette smoking-induced emphysema on the basis of effects of anti-neutrophil (anti-PMN) antibody or anti-monocyte/macrophage (anti-MoMac) antibody on the development of emphysema in cigarette smoke-exposed rats. Rats were treated with rabbit anti-PMN or anti-MoMac antibody and exposed 7 days/wk for 2 mo to cigarette smoke inhalation; rats treated with nonimmunized rabbit IgG (control antibody) and exposed to cigarette smoke or normal room air served as controls. Antibody treatments began 24 h before the start of smoke or air exposure and was continued with 1 treatment/wk. Total and differential cell counts in bronchoalveolar lavage fluid and collagenase-dissociated lung and determinations of the elastinolytic activity of lung neutrophils or macrophages in [(3)H]elastin-coated wells indicated specific suppression of neutrophil accumulation and neutrophil-related elastinolytic burden in the lungs of the anti-PMN antibody-treated smoke-exposed rats, in contrast to specific suppression of macrophage accumulation and macrophage-related elastinolytic burden in the lungs of the anti-MoMac antibody-treated smoke-exposed rats. Cigarette smoke exposure-induced lung elastin breakdown (quantitated by immunologic assay of levels of elastin-derived peptides and desmosine in lavage fluid) and emphysema in the lungs (based on morphometric analysis of alveolar mean linear intercepts and alveolar tissue density in fixed lungs) were not prevented in the lungs of anti-PMN antibody-treated smoke-exposed rats but was clearly prevented in lungs of the anti-MoMac antibody-treated smoke-exposed rats. These findings implicate macrophages rather than neutrophils as the critical pathogenic factor in cigarette smoke-induced emphysema.
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PMID:Effects of depletion of neutrophils or macrophages on development of cigarette smoke-induced emphysema. 1040 35


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