Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To examine the role of placenta growth factor (PlGF) in the pathogenesis of pulmonary emphysema, we generated PlGF-transgenic (TG) mice using a phosphoglycerate kinase promoter. This resulted in constitutive overexpression of PlGF. In these TG mice, pulmonary emphysema, with enlarged air spaces and enhanced pulmonary compliance, first appeared at 6 months of age and became prominent at 12 months. Increased alveolar septal cell apoptosis was noted in their lungs. Fluorescence-activated cell sorter analysis suggests that these apoptotic septal cells are type II pneumocytes. At the same time, the messenger RNA of vascular endothelial growth factor and platelet-endothelial cell adhesion molecule-1, an endothelial cell marker, were downregulated indicating a reduced number of endothelial cells and its survival factor VEGF. In vitro, exogenous PlGF can inhibit the proliferation and promote the cell death of mouse type II pneumocytes. In normal newborn mice, abundant expression of PlGF messenger RNA was detected in the lungs during saccular division but was rapidly downregulated after alveolarization was complete. Thus, a persistently elevated PlGF was detrimental to the developed lung and causes the emphysematous change seen in our TG mice. Our study suggests that PlGF plays an important role in the pathogenesis of pulmonary emphysema via its action on type II pneumocytes.
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PMID:Overexpression of placenta growth factor contributes to the pathogenesis of pulmonary emphysema. 1464 31

Vascular endothelial growth factor (VEGF), a survival factor for endothelial cells and a promoter of angiogenesis, is reportedly expressed in alveolar macrophages (AMs). To investigate whether long-term smoking with age affects VEGF expression in AMs, bronchoalveolar lavage (BAL) was performed on 18 young and 23 older volunteers with various smoking histories. The expressions of VEGF and its functional receptor, fms-like tyrosine kinase (Flt)-1, were quantified in AMs by real-time RT-PCR and, further, the level of VEGF in BAL fluid was determined by ELISA. VEGF mRNA in AMs demonstrated a 1.8-fold reduction in current smokers compared with nonsmokers in older subjects and, furthermore, a 1.5-fold downregulation in those with emphysema, although there was no difference between current smokers and nonsmokers among the young subjects. The downregulation in total VEGF mRNA was supported by the substantial reduction of VEGF121 and VEGF165 isoforms. However, in contrast, Flt-1 mRNA did not differ within the older groups, whereas it was upregulated in young current smokers compared with age-matched nonsmokers. VEGF in BAL fluid is significantly decreased in current smokers compared with nonsmokers, regardless of their age. In conclusion, these data imply that the biological availability of vascular endothelial growth factor in alveolar macrophages is impaired in older current smokers with long-term smoking histories.
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PMID:Decrease of vascular endothelial growth factor in macrophages from long-term smokers. 1580 35

Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix, and we believe this "altered" matrix has the ability to promote lung carcinoma cell growth. One extracellular matrix molecule shown to be altered in these lung diseases is fibronectin (Fn). We previously reported increased growth and survival of non-small cell lung carcinoma (NSCLC) cells exposed to Fn. Thus Fn may serve as a mitogen/survival factor for NSCLC and therefore represents a novel target for anti-cancer strategies. To this end, we studied the effects of the PPARgamma ligands 15d-PGJ(2), rosiglitazone (BRL49653), and troglitazone on Fn expression in NSCLC cells and found that they were able to inhibit Fn gene transcription. Inhibition of Fn expression by BRL49653 and troglitazone, but not by 15d-PGJ(2), was prevented by the specific PPARgamma antagonist GW-9662 and by PPARgamma small interfering RNA. Working with Fn deletion and mutated promoter constructs, we found that the region between -170 and -50 bp downstream from the transcriptional start site of the promoter was involved in PPARgamma ligand inhibition. PPARgamma ligands also diminished the phosphorylation of CREB, diminished Sp1 nuclear protein expression, and prevented the binding of these transcription factors to CRE and Sp1 sites, respectively, within the Fn promoter. In summary, our results demonstrate that PPARgamma ligands inhibit Fn gene expression in NSCLC cells through PPARgamma-dependent and -independent pathways that affect both CREB and Sp1.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. 1590 79

The pulmonary vascular endothelial cell plays a crucial role in the regulation of the pulmonary vascular tone and in the maintenance of the barrier function and integrity of the alveolar-capillary membrane. It also plays a major role in coagulation, fibrinolysis, and angiogenesis and participates in inflammatory reactions. Vascular endothelial growth factor (VEGF) is a central growth and survival factor for the endothelial cell. Particularly high levels of VEGF are expressed in the lungs, reflecting the critical role of VEGF for lung development and structural integrity of the adult lung. Vascular endothelial growth factor exerts a variety of physiological and pathophysiological actions in the lung. Recent evidence suggests its involvement in the pathogenesis of lung diseases such as bronchopulmonary dysplasia, acute lung injury, emphysema, and pulmonary hypertension. To summarize the critical effects of VEGF on the pulmonary endothelial cell in the pathogenesis of these diseases, the purposes of this review are to (1) discuss the biological activities and intracellular signaling pathways of VEGF in the lung; (2) summarize the regulatory mechanisms involved in VEGF expression; (3)address the effects of VEGF on endothelial cells in hyperoxia-induced and other forms of lung injury; (4) highlight the endothelial effects of VEGF in the pathogenesis of emphysema; and (5) explore the role of VEGF in the pathogenesis of pulmonary arterial hypertension.
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PMID:The critical role of vascular endothelial growth factor in pulmonary vascular remodeling after lung injury. 1751 May 98

COPD is a leading cause of morbidity and mortality, characterized by a chronic abnormal inflammatory response to noxious agents. Apoptosis is a physiologic process, critical to cellular homeostasis, in which cell death follows a programmed sequence of events. Apoptosis has been recognized to play an important role in clinical and experimental models of lung diseases. Abnormal apoptotic events in smokers' and in emphysematous lungs have been shown in epithelial and endotheliallung cells, neutrophils, lymphocytes, and myocytes. Many factors associated with COPD, including cigarette smoke, have the potential to cause apoptosis of alveolar epithelial cells, the main sites of vascular endothelial growth factor (VEGF) production. The decreased expression of VEGF, a known survival factor for endothelial cells, and its receptor, results in lung septal endothelial cell death, leading perhaps to the emphysema observed in COPD. In smokers who develop COPD there is an activation of adaptive immunity, with an infiltration of CD4+ and, especially, CD8 + cells. CD8 + cells are cytotoxic to epithelial cells through the release of granzymes and perforin, which can further induce apoptosis of alveolar cells. Moreover, any reduction in neutrophil apoptosis or dysregulation of macrophage uptake of apoptotic neutrophils could lead to chronic inflammation and tissue injury. Increased rates of T-cell apoptosis may lead to a defective immune response to infective organisms, contributing to the high frequency of infections seen in COPD. Increased apoptosis of skeletal muscle could be responsible for the skeletal muscle atrophy, the main cause of unexplained weight loss in patients with COPD. This paper is a review of the current knowledge on the apoptotic pathways involved in COPD pathogenesis and their interaction with other known contributing factors.
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PMID:Apoptotic mechanisms in the pathogenesis of COPD. 1804 93