Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Studies from our laboratory have shown that chronic cigarette smoke exposure causes a neutrophilia associated with a shortening of the mean transit time of polymorphonuclear leukocytes (PMN) though the postmitotic pool of the marrow. The present study was designed to test the hypothesis that PMN newly released from bone marrow by smoke exposure preferentially sequestered in pulmonary microvessels. The thymidine analogue 5'-bromo-2'-deoxyuridine (BrdU) was used to label dividing PMN in the marrow of rabbits; their appearance in the circulation was measured using immunocytochemistry, and their sequestration in lung tissue was determined using standard morphometric techniques. Animals exposed to 11 d of cigarette smoke (n = 6) compared with sham-exposed control animals (n = 4) showed no increase in circulating PMN counts but showed an increase in both the percentage of band cells (smoking, 9.8 +/- 1.1% versus control, 5.5 +/- 0.9%; P < 0.05) and BrdU-labeled PMN (PMNBrdU) in the circulation (smoking, 10.8 +/- 0.6% versus control, 7.5 +/- 0.3%; P < 0.05). There were more PMN sequestered in the lungs of smoke-exposed animals (51.7 +/- 3.4 x 10(7)/ml tissue) than in those of control animals (25.1 +/- 1.8 x 10(7)/ ml tissue) (P < 0.05) and a higher percentage of these cells were PMNBrdU (smoking, 16.9 +/- 2. 3% versus control, 9.6 +/- 0.4%; P < 0.05). The percentage of PMNBrdU in the gravity-independent regions (11.7 +/- 1.9%) of the lung was higher than gravity-dependent regions (7.8 +/- 1.8%) in the smoke-exposure group (P < 0.05). Transmission electron microscopy showed pulmonary capillary endothelial damage with adherent PMN in the smoke-exposure group. We conclude that younger PMN released from the bone marrow by cigarette smoking preferentially sequestered in pulmonary microvessels and speculate that these PMN may contribute to the alveolar wall damage associated with smoke-induced lung emphysema.
Am J Respir Cell Mol Biol 1999 Jan
PMID:Cigarette smoking causes sequestration of polymorphonuclear leukocytes released from the bone marrow in lung microvessels. 987 Sep 31

The beige mouse is currently used as a model of elastase and cathepsin G deficiency to demonstrate or exclude the role of these proteases in a variety of pathologic conditions. We recently demonstrated that beige cathepsin G is tightly bound to neutrophil lysosomal membranes but is released in near normal quantities during exocytosis. Also, beige neutrophils contain a latent form of elastase that undergoes spontaneous activation when released under in vitro or in vivo conditions. However, the pathogenic potential of this enzyme in matrix degradation has not been ascertained previously. The possibility that in beige mice elastolytic proteases from neutrophils recruited into the lung have the capability to damage alveolar septa was investigated following an intratracheal instillation of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (200 microg). Neutrophil influx was followed by a decrease in lung elastin content (-18%) and by a significant increase of the mean linear intercept (+30%) and of morphologic emphysema. The onset of pulmonary lesion was preceded by a marked increase of neutrophil elastase burden on the alveolar interstitium. The appearance of emphysema was prevented by administration of the serine protease inhibitor 4-(2-aminoetyl)-benzenesulfonyl fluoride hydrochloride (2. 4 microg/ml saline). These results demonstrate that the lung elastin degradation and emphysema can occur in beige lungs. The fact that the beige mouse does develop lung elastolytic changes after neutrophil recruitment indicates that this mutant cannot be considered a model of neutrophil function deficiency and used as a model of elastase deficiency.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Neutrophil influx into the lungs of beige mice is followed by elastolytic damage and emphysema. 992 17

Alpha1-antitrypsin (alpha1AT) therapy is used as a treatment for alpha1AT deficiency. It has also been proposed as a therapy for cigarette smoke-induced emphysema, although the efficacy of such therapy is as yet unproven. Moreover, the optimal route of delivery of alpha1AT to the lung interstitium, the crucial locus of action, is unknown. We created transgenic mice with expression of the human alpha1AT gene directed by a human surfactant protein C (SpC) promoter fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to examine the ability of pulmonary epithelial cell expression of alpha1AT to deliver protein to the interstitium, and to produce a model that would allow studies on the efficacy of alpha1AT in preventing lung damage after cigarette smoke exposure. Four transgenic lines were studied. In situ hybridization and light microscopic immunohistochemistry showed that two CC10 driven lines expressed human alpha1AT in type 11 alveolar cells and airway epithelial cells; alpha1AT expression was seen in the alveolar parenchyma in two SpC driven lines, and in small airway epithelium in one of the SpC lines. Electron microscopic immunochemistry showed the presence of the human alpha1AT protein in the interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9 microg/g lung protein and serum levels from 0.72 to 1.3 microg/ml, compared to normal human serum alpha1AT levels of 2-5 mg/ml. We conclude that transgene-mediated expression of alpha1AT in pulmonary epithelial cells results in diffuse expression of the transgene in the alveolar parenchyma and reproducibly leads to transfer of protein to the interstitium. The present model is, however, limited by low levels of protein production; limited protein production may be a problem in other forms of gene therapy in which relatively large amounts of extracellular protein are needed in the lung for a therapeutic effect.
J Mol Med (Berl) 1999 Apr
PMID:Pulmonary epithelial expression of human alpha1-antitrypsin in transgenic mice results in delivery of alpha1-antitrypsin protein to the interstitium. 1035 39

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.
Am J Respir Cell Mol Biol 2000 Jan
PMID:Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. 1061 62

Recent studies have suggested that macrophage-derived metalloproteases are the critical mediators of cigarette smoke-induced emphysema, in contrast to earlier hypotheses that this process was mediated by neutrophil elastase. To determine whether smoke can acutely induce connective tissue breakdown in the lung and to examine the mediators of this process, we exposed C57-BL/6 mice to whole cigarette smoke and used high-performance liquid chromatography to examine lavage fluid levels of desmosine (DES), a marker of elastin breakdown, and hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose-response increase in lavage neutrophils, DES, and HP, but not lavage macrophages (MACs). This effect was evident by 6 h after exposure to two cigarettes. Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced lavage PMNs to undetectable levels after smoke exposure, did not affect MAC numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection of a commercial human alpha1-antitrypsin (alpha1AT) 24 h before smoke exposure increased serum alpha1AT levels approximately 3-fold and completely abolished smoke-induced connective tissue breakdown as well as the increase in lavage PMNs, again without affecting MAC numbers. We conclude that in this model cigarette smoke can acutely induce connective tissue breakdown and that this effect is mediated by neutrophil-derived serine proteases, most likely neutrophil elastase. Exogenous alpha1AT is protective and appears to inhibit both matrix degradation and PMN influx, suggesting that alpha1AT has anti-inflammatory as well as antiproteolytic effects in this system.
Am J Respir Cell Mol Biol 2000 Feb
PMID:Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. 1065 46

Understanding the sources of variation in airway reactivity and airflow is important for unraveling the pathophysiology of asthma, obstructive lung disease, and other pulmonary disorders. Transgenic expression of two closely related cytokines in the mouse lung produced opposite effects on these parameters. Interleukin (IL)-6 did not alter basal airways resistance and decreased methacholine responsiveness, whereas IL-11 caused airways obstruction and increased airway responses to methacholine. To clarify these differences we examined histologic sections and used morphometry to compare bronchiolar and parenchymal dimensions in 1- to 2-mo-old transgenic mice expressing IL-6 or IL-11 and littermate control mice. Both transgenic strains showed similar emphysema-like airspace enlargement, nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis. When compared with littermate control mice, the IL-6 mice showed an approximately 50% increase in the caliber of their bronchioles and an increase in airway wall thickness that was in proportion to the increase in the size of their airways. In contrast, the remodeling response was more robust in the IL-11 transgenic mice. It was also seen in airways with normal external and luminal diameters and thus was out of proportion to the caliber of their airways. These results support the hypothesis that structural alterations and resulting caliber changes of respiratory airways can have important effects on airway physiology and reactivity.
Am J Respir Cell Mol Biol 2000 Mar
PMID:Airway hyperresponsiveness and airway obstruction in transgenic mice. Morphologic correlates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung. 1069 65

Emphysema is a slowly progressive degenerative lung disease involving fragmentation and depletion of elastic fibers, loss of lung elastance, and architectural destruction with ectasia, tortuosity, and loss of bronchioles irrespective of localization or morphological type. Occurring under physiological conditions, predominantly in geriatrics, matrix laxity and destructive parenchymal lesions are indicative of a pathological loss of tissue tensile strength attributable to bioengineering or structural fatigue in repetitively stressed tissues. The occurrence of severe premature emphysema in inherited connective tissue diseases and under some experimental and iatrogenic conditions is supportive evidence. Experiments advocating unrestrained proteolysis as a cause or pathogenic factor are invalid, being based on a false premise and assumed causality.
Exp Mol Pathol 2000 Aug
PMID:Proteinase imbalance versus biomechanical stress in pulmonary emphysema. 1089 Dec 92

alpha1-Antitrypsin (AAT) deficiency is a common inherited cause of emphysema and cirrhotic liver disease. Current laboratory diagnosis of Pi (proteinase inhibitor) status by protein analysis depends on the availability of blood samples and has a limited accuracy. Single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing can be performed from blood cells or from tissue samples, but it is a time-consuming procedure not suitable for screening purposes. We used a Light-Cycler assisted PCR approach to identify the PiZ mutation and to determine hetero- and homozygous carrier status from whole blood and from paraffin-embedded archival tissue specimens. The results were compared to those obtained by standard PCR amplification followed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR identified heterozygous PiZ mutations in 16 samples, a homozygous PiZ status in three cases, and wild-type PiM in five control samples. In all cases the results were confirmed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR has a high detection rate for the PiZ mutation. It can be performed from blood or from fixed archival tissues, requires only small amounts of DNA, and allows a rapid diagnosis on a high output level.
J Mol Med (Berl) 2000
PMID:Rapid analysis of alpha1-antitrypsin PiZ genotype by a real-time PCR approach. 1093 83

Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.
Am J Respir Cell Mol Biol 2000 Sep
PMID:Impaired distal airway development in mice lacking elastin. 1097 Aug 22

Human neutrophil elastase (HNE, IEC 3. 4. 21. 37) is a causative factor of inflammatory diseases, including emphysema and rheumatoid arthritis. Enzymatic characterization is important for the development of new drugs involved in the regulation of this enzyme. In this study, we investigated the enzymatic and biochemical properties of five different elastolytic enzymes, with a molecular mass between 24 kDa and 72 kDa. Three elastases, molecular masses of 27, 29, 31 kDa, might be elastase isozymes that have the same NH2-terminal amino acid sequences of Ile-Val-Gly-Gly-Arg-Arg-Ala. The 24-kDa enzyme, which showed the identical NH2-terminal amino acid sequences to elastase, was a degraded fragment of native elastase. The elastolytic activity was conserved at the 6/7 domain of the NH2-terminal region. The inhibitory characteristics of PMSF, DipF were the same as those of native elastases. The 72-kDa molecule, which showed elastolytic activity, might be a trimer formed between native elastases (31 kDa and 29 kDa) and a cathepsin G-like enzyme, which did not show elastolytic activity but enhanced the elastolytic activity of neutrophil elastase. Although this cathepsin G-like enzyme showed weak cathepsin G activity, it has distinguishable NH2-terminal sequences of Ile-Val-Gly-Gly-Ser-Arg-Ala- from those of elastase or cathepsin G. The potentiation of elastolytic activity could be a result of the trimerization of native elastase with a cathepsin G-like enzyme, and was then weakly inhibited by serine protease inhibitors, such as PMSF, DipF. Therefore, we suggest the cathepsin G-like enzyme to be a novel enzyme, which has an important role in the development of inflammation.
Mol Cells 2000 Oct 31
PMID:Enzymatic and molecular biochemical characterizations of human neutrophil elastases and a cathepsin G-like enzyme. 1110 Nov 39


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