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)

Chemokine receptors control several fundamental cellular processes in both hematopoietic and structural cells, including directed cell movement, i.e., chemotaxis, cell differentiation, and proliferation. We have previously demonstrated that CXCR3, the chemokine receptor expressed by Th1/Tc1 inflammatory cells present in the lung, is also expressed by human airway epithelial cells. In airway epithelial cells, activation of CXCR3 induces airway epithelial cell movement and proliferation, processes that underlie lung repair. The present study examined the expression and function of CXCR3 in human alveolar type II pneumocytes, whose destruction causes emphysema. CXCR3 was present in human fetal and adult type II pneumocytes as assessed by immunocytochemistry, immunohistochemistry, and Western blotting. CXCR3-A and -B splice variant mRNA was present constitutively in cultured type II cells, but levels of CXCR3-B greatly exceeded CXCR3-A mRNA. In cultured type II cells, I-TAC, IP-10, and Mig induced chemotaxis. Overexpression of CXCR3-A in the A549 pneumocyte cell line produced robust chemotactic responses to I-TAC and IP-10. In contrast, I-TAC did not induce chemotactic responses in CXCR3-B and mock-transfected cells. Finally, I-TAC increased cytosolic Ca(2+) and activated the extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B kinases only in CXCR3-A-transfected cells. These data indicate that the CXCR3 receptor is expressed by human type II pneumocytes, and the CXCR3-A splice variant mediates chemotactic responses possibly through Ca(2+) activation of both mitogen-activated protein kinase and PI 3-kinase signaling pathways. Expression of CXCR3 in alveolar epithelial cells may be important in pneumocyte repair from injury.
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PMID:Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A. 1837 41

Tobacco-related diseases are leading causes of death worldwide, and many are associated with expression of matrix metalloproteinase-1 (MMP-1). We have reported extracellular signal-regulated kinase (ERK)1/2-dependent induction of MMP-1 by cigarette smoke in lung epithelial cells. Our objectives were to define regions of the human MMP-1 promoter required for activation by smoke, to identify differences in responses of the 1G/2G -1607 polymorphic promoters to smoke, and to identify relevant transcription factors whose activity in airway epithelial cells is increased by smoke. The responses of deletion and mutant promoter constructs were measured in transfected cells during exposure to cigarette smoke extract (CSE). DNA oligonucleotide arrays were used to identify transcription factors activated after smoke exposure. CSE activated the MMP-1 promoter, and this induction was prevented by PD98059 blockade of ERK1/2 phosphorylation. Deletion studies revealed the distal 1kb promoter region (-4438 to -3280 upstream of the transcription start site) is essential for CSE induction of MMP-1, and confers activation of a minimal promoter. Studies of 1G and 2G MMP-1 polymorphic promoter variants revealed higher 2G allele basal and CSE-responsive activities than the 1G allele. Cotransfection, mithramycin, and electrophoretic mobility shift assay studies identified activating and repressive roles for Sp1 and PEA3 transcription factors, respectively. Oligonucleotide DNA arrays confirmed activation of Sp1 and PEA3 by CSE. These data demonstrate that the MMP-1 promoter is a direct target of cigarette smoke in lung epithelial cells. This characterization of a smoke response region in the distal MMP-1 promoter has implications for smoking-related diseases such as cancer, heart disease, and emphysema.
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PMID:Identification of a cigarette smoke-responsive region in the distal MMP-1 promoter. 1861 82

Homozygous mutant klotho (KL(-/-)) mice exhibit various characteristics resembling those of human aging, including emphysema. However, age-related changes of lungs have not been fully elucidated. Here, we investigated the structural, functional, biochemical, and cell kinetic alterations of lungs in KL(-/-) mice at 2-12 weeks of age. Homogeneous airspace enlargement and decreased lung elastic recoil were observed in KL(-/-) mice with aging. The apoptotic cells in airway walls in KL(-/-) mice were approximately 6 times greater than those in wild-type (KL(+/+)) mice at 2 weeks of age. However, lipid peroxidation and elastase activity of lungs were not increased in KL(-/-) mice. Western blotting suggested that protein levels of epidermal growth factor (EGF) and phosphorylated extracellular signal-regulated kinase were decreased in KL(-/-) mice. These data suggest that significantly increased apoptosis of airway cells via inhibition of the EGF-dependent pathway may be involved in the development of the aging lungs in KL(-/-) mice.
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PMID:Airspace enlargement with airway cell apoptosis in klotho mice: a model of aging lung. 1912 41

Reduced vascular endothelial growth factor (VEGF) has been reported in bronchoalveolar lavage fluid and lungs of severe emphysema patients. Airway epithelial cells (AEC) are exposed to various environmental insults like cigarette smoke and bacterial infections, but their direct effect on VEGF production in well-differentiated primary human AEC remains unclear. The current authors determined the effect of cigarette smoke extract (CSE) alone and in combination with Mycoplasma pneumoniae (Mp) on VEGF production in well-differentiated primary normal human bronchial epithelial (NHBE) and small airway epithelial cells (SAEC) in air-liquid interface cultures. Secretion and expression of VEGF were determined by ELISA and real-time RT-PCR, respectively. Cell growth, apoptosis, extracellular signal-regulated kinase (ERK)1/2 and protein kinase (PK)C signalling pathways were evaluated to further dissect VEGF regulation under CSE treatment. CSE significantly reduced VEGF secretion in NHBE and SAEC. In SAEC, Mp alone significantly increased the VEGF, while the presence of CSE attenuated Mp-induced VEGF production. While ERK inhibitor reduced VEGF secretion only in NHBE, a PKC inhibitor significantly decreased VEGF secretion in both NHBE and SAEC. In conclusion, direct cigarette smoke extract exposure significantly reduced vascular endothelial growth factor production in well-differentiated primary human airway epithelial cells, in part through modifying extracellular signal-regulated kinase 1/2 and protein kinase C signalling pathways.
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PMID:Cigarette smoke extract reduces VEGF in primary human airway epithelial cells. 1912 86

The protease-antiprotease imbalance in the lung plays an important role in the pathogenesis of smoke-induced emphysema. The aim of this study was to characterize the proteolytic responses leading to emphysema formation in the guinea pig smoke exposure model. Guinea pigs were exposed to cigarette smoke for 1, 2, 4, 8, and 12 weeks. Age-matched guinea pigs exposed to room air served as controls. Cigarette smoke induced inflammation after 4 weeks and generated emphysematous changes in the guinea pigs after 12 weeks of smoke exposure. Increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases was demonstrated post cigarette smoke exposure. A decrease in elastin and collagen and the loss of type III collagen were observed in the alveolar wall of smoke-exposed guinea pigs. Interestingly, no change was seen in the expression of collagenolytic matrix metalloproteinases. Furthermore, the authors observed a 3-fold increase in cathepsin K activity in the lungs of smoke-exposed guinea pigs. The significance of this finding was supported by human studies that demonstrate increased expression of cathepsin K in the lungs of patients with emphysema. Elevation of cathepsin K in guinea pig lungs after smoke exposure likely constitutes a critical event leading to the disruption of lung extracellular matrix in this model.
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PMID:Role for cathepsin K in emphysema in smoke-exposed guinea pigs. 1989 19

Cigarette smoke (CS), a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrated cigarette smoke extract (CSE) induced DISC formation in human lung fibroblasts (MRC-5). The aim of this study was to investigate the involvement of extracellular signal-regulated kinase (ERK) MAPK activation in CSE induced DISC formation. Immunoprecipitation (IP) for Fas and Western Immunoblot (IB) analysis for caspase 8 were then performed to show DISC. Lactate dehydrogenase (LDH) release was measured using a cytotoxicity detection kit. MTT assay was used as a measure of cell viability. We demonstrated that CSE induces DISC formation in MRC-5 using IP for Fas and IB for caspase 8. ERK was expressed in MRC-5 exposed to CSE. MEK-1 inhibitor (PD98059) decreased DISC formation in MRC-5 exposed to 20% CSE at 1 hr, and cell viability, as assessed by colorimetric MTT assay, was increased in MEK-1 inhibitor treated MRC-5 cells after 24 hr CSE exposure compared to the control. Inhibiting ERK significantly decreased the caspase-3,-8 activity in MEK-1 inhibitor treated MRC-5 cells compared to the control.The DISC formation, initial event of extrinsic apoptotic pathway, is a primary component of CSE- induced death in MRC-5, and ERK activation plays an active role in the DISC formation and downstream pathway. These results suggest that modulation of ERK may have therapeutic potential in the prevention of smoke-related lung injury.
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PMID:Extracellular signal-regulated kinase (ERK) inhibition attenuates cigarette smoke extract (CSE) induced-death inducing signaling complex (DISC) formation in human lung fibroblasts (MRC-5) cells. 2011 22