Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Emphysema due to cigarette smoking is characterized by a loss of alveolar structures. We hypothesize that the disappearance of alveoli involves apoptosis of septal endothelial cells and a decreased expression of lung vascular endothelial growth factor (VEGF) and its receptor 2 (VEGF R2). By terminal transferase dUTP nick end labeling (TUNEL) in combination with immunohistochemistry, we found that the number of TUNEL+ septal epithelial and endothelial cells/lung tissue nucleic acid (microg) was increased in the alveolar septa of emphysema lungs (14.2 +/- 2.0/microg, n = 6) when compared with normal lungs (6.8 +/- 1.3/microg, n = 7) (p < 0.01) and with primary pulmonary hypertensive lungs (2.3 +/- 0.8/microg, n = 5) (p < 0.001). The cell death events were not significantly different between healthy nonsmoker (7.4 +/- 1.9/microg) and smoker (5.7 +/- 0.7/microg) control subjects. The TUNEL results were confirmed by single-stranded DNA and active caspase-3 immunohistochemistry, and by DNA ligation assay. Emphysema lungs (n = 12) had increased levels of oligonucleosomal-length DNA fragmentation when compared with normal lungs (n = 11). VEGF, VEGF R2 protein, and mRNA expression were significantly reduced in emphysema. We propose that epithelial and endothelial alveolar septal death due to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema.
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PMID:Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. 1125 33

The protective effects of retinoic acid on elastase-induced lung epithelial cell injury were studied using elastase extracted from purulent human sputum, the BEAS-2B human bronchial epithelial cell line, A549 human type II lung cell line, and primary cultures of human tracheal epithelial cells. Elastase decreased viability of BEAS-2B cells, A549 cells, and human tracheal epithelial cells in concentration- and time-dependent fashions. Elastase also induced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells detected with cell death detection enzyme-linked immunosorbent assay and terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) methods. Retinoic acid alone did not affect the viability of BEAS-2B cells, A549 cells, or the tracheal epithelial cells, and did not induce apoptosis of the cells. However, retinoic acid prevented the decreases in the viability and reduced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells induced by elastase. Likewise, retinoic acid inhibited caspase 3 activity in BEAS-2B cells and A549 cells induced by elastase, as well as proteolytic activity of elastase. Furthermore, caspase 3 inhibitor inhibited the elastase-induced apoptosis of the cells. These findings suggest that retinoic acid may inhibit elastase-induced lung epithelial cell injury partly through the inhibition of proteolytic activity of elastase and through the inhibition of caspase 3 activity by elastase. Retinoic acid may, therefore, have protective effects against the elastase-induced lung injury and subsequent development of pulmonary emphysema.
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PMID:Retinoic acid inhibits elastase-induced injury in human lung epithelial cell lines. 1259 52

Pulmonary emphysema is characterized by alveolar wall destruction and airspace enlargement. Recent evidence indicates that epithelial or endothelial apoptosis may be involved in the pathogenesis of emphysema. Here, we describe the induction of emphysematous changes, including airspace enlargement, alveolar wall destruction, and enhanced lung distensibility, in mice receiving a single intratracheal injection of active caspase-3 and Chariot, a newly developed protein transfection reagent. Epithelial apoptosis and enhanced elastolytic activity (optimal at pH 5.5) in bronchoalveolar lavage were noted. Emphysematous changes were also generated in mice receiving an intratracheal injection of nodularin, a proapoptotic serine/threonine kinase inhibitor. This murine model provides direct evidence that confirms that alveolar wall apoptosis causes emphysematous changes. Furthermore, this simple technique for protein transfection of lung tissue can be used in a variety of future applications.
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PMID:Alveolar wall apoptosis causes lung destruction and emphysematous changes. 1270 10

Emphysema is characterized by enlargement of the distal airspaces in the lungs due to destruction of alveolar walls. Alveolar endothelial and epithelial cell apoptosis induced by cigarette smoke is thought to be a possible mechanism for this cell loss. In contrast, our studies show that cigarette smoke condensate (CSC) induces necrosis in alveolar epithelial cells and human umbilical vein endothelial cells. Furthermore, study of the cell death pathway in a model system using Jurkat cells revealed that in addition to inducing necrosis, CSC inhibited apoptosis induced by staurosporine or Fas ligation, with both effects prevented by the antioxidants glutathione and dithiothreitol. Time course experiments revealed that CSC inhibited an early step in the caspase cascade, whereby caspase-3 was not activated. Moreover, cell-free reconstitution of the apoptosome in cytoplasmic extracts from CSC-treated cells, by addition of cytochrome-c and dATP, did not result in activation of caspases-3 or -9. Thus, smoke treatment may alter the levels of pro- and antiapoptogenic factors downstream of the mitochondria to inhibit active apoptosome formation. Therefore, unlike previous studies, cell death in response to cigarette smoke by necrosis and not apoptosis may be responsible for the loss of alveolar walls and inflammation observed in emphysema.
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PMID:Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. 1274 58

To test the hypothesis that VEGF is important for the maintenance of alveolar structure and elastic properties in adult mice, lung-targeted ablation of the VEGF gene was accomplished through intratracheal delivery of an adeno-associated cre recombinase virus (AAV/Cre) to VEGFloxP mice, and the effects were followed for 8 wk. Control mice were similarly treated with AAV/Cre. Pulmonary VEGF levels were reduced by 86% at 5 wk postinfection but returned to normal levels by 8 wk. VEGF receptor VEGFR-2 levels were also reduced at 5 wk (by 51%) and returned to control values by 8 wk. However, alveolar septal wall destruction (increased mean linear intercept) and loss of lung elastic recoil (increased compliance) persisted for 8 wk. No decrease in alveolar cell proliferation was detected by Western blot or immunohistochemical analysis of proliferating cell nuclear antigen. Increased alveolar septal cell and bronchial epithelial cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis at 5 wk. Total lung caspase-3 levels and enzyme activity were also increased at 5 wk. No obvious accumulation of inflammatory cells was observed at any time after tracheal instillation of AAV/Cre. Thus a transient decrease in pulmonary VEGF leads to increased alveolar and bronchial cell apoptosis, air space enlargement, and changes in lung elastic recoil (processes that are characteristic of emphysema) that persist for at least 8 wk.
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PMID:Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice. 1520 95

Pulmonary emphysema is associated with alterations in matrix proteins and protease activity. These alterations may be linked to programmed cell death by apoptosis, potentially influencing lung architecture and lung function. To evaluate apoptosis in emphysema, lung tissue was analysed from 10 emphysema patients and six individuals without emphysema (normal). Morphological analysis revealed alveolar cells in emphysematous lungs with convoluted nuclei characteristic of apoptosis. DNA fragmentation was detected using terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL) and gel electrophoresis. TUNEL revealed higher apoptosis in emphysematous than normal lungs. Markers of apoptosis, including active caspase-3, proteolytic fragment of poly (ADP-ribose) polymerase, Bax and Bad, were detected in emphysematous lungs. Linear regression showed that apoptosis was inversely correlated with surface area. Emphysematous lungs demonstrated lower surface areas and increased cell proliferation. There was no correlation between apoptosis and proliferation, suggesting that, although both events increase during emphysema, they are not in equilibrium, potentially contributing to reduced lung surface area. In summary, cell-based mechanisms associated with emphysematous parenchymal damage include increased apoptosis and cell proliferation. Apoptosis correlated with airspace enlargement, supporting epidemiological evidence of the progressive nature of emphysema. These data extend the understanding of cell dynamics and structural changes within the lung during emphysema pathogenesis.
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PMID:Correlation of lung surface area to apoptosis and proliferation in human emphysema. 1568 88

Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-gamma, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-gamma-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-gamma uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-gamma caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-gamma-induced emphysema. These interventions also ameliorated IFN-gamma-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-gamma-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-gamma-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.
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PMID:Role of cathepsin S-dependent epithelial cell apoptosis in IFN-gamma-induced alveolar remodeling and pulmonary emphysema. 1594 19

The senescence-accelerated mouse (SAM) is a naturally occurring animal model for accelerated aging after normal development and maturation. SAMP1 strain was reported to show age-related structural and functional changes in lung and to be a murine model of senile lung. We postulated that aging of lung is an important intrinsic process for development of emphysema and even in a short period of tobacco smoke exposure may be able to generate emphysema. At age 12 wk, SAMP1 inhaled air or 1.5% tobacco smoke (total particulate matter 23.9 mg/m3) through the nose for 30 min/day, 5 days/wk, and for 8 wk. The mean linear intercepts (MLI) and destructive index (DI) of lung were significantly increased [air vs. smoke (means+/-SE); MLI, 68.76+/-0.69 vs. 75.34+/-1.70 microm, P<0.05 and DI, 8.61+/-0.38 vs. 16.18+/-1.54%, P<0.05], whereas no significant changes were observed in SAMR1, control mice that show normal aging. In contrast, smoke-induced emphysema was completely prevented by concomitant ingestion of lycopene given as tomato juice [MLI: smoke with/without lycopene (mean+/-SE), 62.87+/-0.8 vs. 66.90+/-1.33 microm, P<0.05]. Smoke exposure increased apoptosis and active caspase-3 of airway and alveolar septal cells and reduced VEGF in lung tissues, but tomato juice ingestion significantly reduced apoptosis and increased tissue VEGF level. We conclude that SAMP1 is a useful model for tobacco smoke-induced emphysema and a valuable tool to explore both pathophysiological mechanisms and the effect of therapeutic intervention on smoke-induced emphysema.
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PMID:Tomato juice prevents senescence-accelerated mouse P1 strain from developing emphysema induced by chronic exposure to tobacco smoke. 1621 12

Th1 inflammation and remodeling characterized by tissue destruction frequently coexist in human diseases. To further understand the mechanisms of these responses, we defined the role(s) of CCR5 in the pathogenesis of IFN-gamma-induced inflammation and remodeling in a murine emphysema model. IFN-gamma was a potent stimulator of the CCR5 ligands macrophage inflammatory protein-1alpha/CCL-3 (MIP-1alpha/CCL-3), MIP-1beta/CCL-4, and RANTES/CCL-5, among others. Antibody neutralization or null mutation of CCR5 decreased IFN-gamma-induced inflammation, DNA injury, apoptosis, and alveolar remodeling. These interventions decreased the expression of select chemokines, including CCR5 ligands and MMP-9, and increased levels of secretory leukocyte protease inhibitor. They also decreased the expression and/or activation of Fas, FasL, TNF, caspase-3, -8, and -9, Bid, and Bax. In accordance with these findings, cigarette smoke induced pulmonary inflammation, DNA injury, apoptosis, and emphysema via an IFN-gamma-dependent pathway(s), and a null mutation of CCR5 decreased these responses. These studies demonstrate that IFN-gamma is a potent stimulator of CC and CXC chemokines and highlight the importance of CCR5 in the pathogenesis of IFN-gamma-induced and cigarette smoke-induced inflammation, tissue remodeling, and emphysema. They also demonstrate that CCR5 is required for optimal IFN-gamma stimulation of its own ligands, other chemokines, MMPs, caspases, and cell death regulators and the inhibition of antiproteases.
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PMID:Role of CCR5 in IFN-gamma-induced and cigarette smoke-induced emphysema. 1628 50

Lung disease is the leading and second-leading cause of death in women and men in Taiwan, respectively. Epidemiological studies conducted in Taiwan have shown that cigarette smoking is the principal risk factor of lung disease, but little is known about the association between apoptosis and cigarette smoke (CS)-induced lung pathogenesis. We designed an animal exposure system to study signal proteins involved in the process of apoptosis induced by smoking in rat terminal bronchiole. Rats were exposed to CS in doses of 5, 10, and 15 cigarettes, respectively, and the exposure lasted for 30 min, twice a day, 6 days a week for 1 month. Following which the rats were sacrificed and the lung tissues were analyzed by histopathological methods. The terminal bronchioles revealed mild to severe inflammation according to the doses of CS and marked lipid peroxidation, lymphocyte infiltration, congestion, and epithelial emphysema of alveolar spaces were also noted. Using an in situ cell death detection kit (TA300), the association of CS with apoptosis was determined in a concentration-dependent manner. Immunohistochemical evaluation showed that CS treatment produced an increase in the cellular levels of Bax, t-Bid, cleaved caspase-3, phospho-p53, phospho-JNK, and FasL but a decline in Bcl-2 and Mcl-1 (p<0.001 for all) in rat terminal bronchioles. The results provided evidences suggesting that exposure to CS not only induced apoptosis, but also involved p53/Bax and JNK/FasL cascade pathway.
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PMID:Immunohistochemical detection of apoptotic proteins, p53/Bax and JNK/FasL cascade, in the lung of rats exposed to cigarette smoke. 1634 95


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