cyclin-d1 and Pulmonary-Disease--Chronic-Obstructive

T cell adequate function is critical for defense against pathogens. Transient disruption of T cell homeostasis occurs when primarily naive cells undergo antigen-driven expansion and acquire effector functions. Effector T cells then either undergo programmed cell death (PCD, it occurs usually as massive apoptosis during the contraction phase of the immune response) or survive to become memory cells. Two main pathways of effector T cell PCD are discussed in the review: activation induced cell death (AICD), which is a form of extrinsic apoptosis, and neglect-induced death (NID), which is an intrinsic one. Initial studies using in vitro models supported a role of AICD, mostly initiated by TCR receptor triggering in immune contraction. However, it was not finally supported by either recent in vivo experiments or current review authors' clinical studies concerning primed T cell apoptosis in chronic inflammatory lower airway diseases. Actually, Bcl-2 family members seem to be critical for the culling of T cell responses. The antiapoptotic molecule Bcl-2 and its proapoptotic antagonist Bcl-2, both under upstream control of autocrine interleukin-2, are the most probable candidates for regulators of T cell contraction. Other possible mechanisms regulating the process of contraction such as death receptor ligation, the impact of cytokines, as well as the importance of transcription factor NF-κB, are discussed. Additionally, attention is turned to the potential role of T cell survival/apoptosis regulation in future therapies of some diseases, including tumors and lung fibrosis.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Death; Cyclin D1; Humans; Interleukin-2; Lung Neoplasms; NF-kappa B; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Signal Transduction; T-Lymphocytes

Cigarette smoking contributes to the development of pulmonary hypertension (PH) complicated with chronic obstructive pulmonary disease (COPD), and the pulmonary vascular remodeling, the structural basis of PH, could be attributed to abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs).In this study, morphometrical analysis showed that the pulmonary vessel wall thickness in smoker group and COPD group was significantly greater than in nonsmokers. In addition, we determined the expression patterns of connective tissue growth factor (CTGF) and cyclin D1 in PASMCs harvested from smokers with normal lung function or mild to moderate COPD, finding that the expression levels of CTGF and cyclin D1 were significantly increased in smoker group and COPD group. In vitro experiment showed that the expression of CTGF, cyclin D1 and E2F were significantly increased in human PASMCs (HPASMCs) treated with 2% cigarette smoke extract (CSE), and two CTGF siRNAs with different mRNA hits successfully attenuated the upregulated cyclin D1 and E2F, and significantly restored the CSE-induced proliferation of HPASMCs by causing cell cycle arrest in G0. These findings suggest that CTGF may contribute to the pathogenesis of abnormal proliferation of HPASMCs by promoting the expression of its downstream effectors in smokers with or without COPD.

Topics: Aged; Cell Cycle Checkpoints; Cell Proliferation; Cells, Cultured; Connective Tissue Growth Factor; Cyclin D1; Down-Regulation; E2F Transcription Factors; Humans; Lung; Middle Aged; Myocytes, Smooth Muscle; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Messenger; RNA, Small Interfering; Smoking; Up-Regulation

The purpose of this study was to investigate the changes of protein kinase Calpha (PKCalpha) and cyclin D1 expressions in pulmonary arteries from smokers with normal lung function and smokers with mild to moderate chronic obstructive pulmonary disease (COPD). The peripheral lung tissues were obtained from 10 non-smokers with normal lung function (non-smoker group), 14 smokers with normal lung function (smoker group), 11 smokers with mild to moderate COPD (COPD group). The morphological changes of pulmonary arteries were observed by HE-staining. The expressions of alpha-smooth muscle actin (alpha-SMA), proliferating cell nuclear antigen (PCNA), PKCalpha and cyclin D1 proteins in pulmonary artery smooth muscle cells (PASMCs) were immunohistochemically determined. The percentages of PCNA-positive cells were taken as the smooth muscle cells proliferation index (PI). The mRNA expressions of PKCalpha and cyclin D1 in PASMCs were evaluated by real-time fluorescence PCR. Morphometrical analysis showed that the ratio of pulmonary artery wall area to total area (WA%) in smoker group and COPD group was significantly greater than that in non-smoker group (P<0.01). The PASMCs proliferation index in smoker group and COPD group was significantly higher than that in nonsmoker group (P<0.01). The protein levels of PKCalpha and cyclin D1 in PASMCs were significantly increased in smoker group and COPD group as compared with non-smoker group (P<0.01). The mRNA expressions of PKCalpha and cyclin D1 in PASMCs were significantly elevated in smoker group and COPD group as compared with non-smoker group (P<0.01). Significant correlations were found between PKCalpha protein and WA% or PI (P<0.01). Correlations between cyclin D1 protein and WA% or PI also existed (P<0.01). The expression of PKCalpha was positively correlated with the expression of cyclin D1 at both protein and mRNA levels (P<0.01). In conclusion, increased expressions of PKCalpha and cyclin D1 might be involved in the pathogenesis of abnormal proliferation of PASMCs in smokers with normal lung function and smokers with mild to moderate COPD.

Topics: Aged; Case-Control Studies; Cyclin D1; Female; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Protein Kinase C-alpha; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; RNA, Messenger; Smoking

A major feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, which includes an increased airway smooth muscle (ASM) mass. The mechanisms underlying ASM remodelling in COPD are currently unknown. We hypothesized that cigarette smoke (CS) and/or lipopolysaccharide (LPS), a major constituent of CS, organic dust and gram-negative bacteria, that may be involved in recurrent airway infections and exacerbations in COPD patients, would induce phenotype changes of ASM.. To this aim, using cultured bovine tracheal smooth muscle (BTSM) cells and tissue, we investigated the direct effects of CS extract (CSE) and LPS on ASM proliferation and contractility.. Both CSE and LPS induced a profound and concentration-dependent increase in DNA synthesis in BTSM cells. CSE and LPS also induced a significant increase in BTSM cell number, which was associated with increased cyclin D1 expression and dependent on activation of ERK 1/2 and p38 MAP kinase. Consistent with a shift to a more proliferative phenotype, prolonged treatment of BTSM strips with CSE or LPS significantly decreased maximal methacholine- and KCl-induced contraction.. Direct exposure of ASM to CSE or LPS causes the induction of a proliferative, hypocontractile ASM phenotype, which may be involved in airway remodelling in COPD.

Topics: Airway Remodeling; Animals; Cattle; Cell Proliferation; Cells, Cultured; Cyclin D1; DNA Replication; Dose-Response Relationship, Drug; Flavonoids; Imidazoles; Isometric Contraction; Lipopolysaccharides; Methacholine Chloride; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Phenotype; Phosphorylation; Potassium Chloride; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Smoke; Smoking; Time Factors; Tissue Culture Techniques; Trachea

Glucocorticoids seem to mediate the effect of stimulant drugs such as nicotine. Several studies have pointed to an association between the BclI polymorphism in the glucocorticoid receptor gene and increased glucocorticoid effects. We analysed the association of smoking behaviour and the BclI polymorphism using a case-control design within the framework of a larger pharmacogenetic study. A total of 327 Caucasian patients with asthma or chronic obstructive pulmonary disease from 39 German general practices gave informed consent to take part in the study. They filled in questionnaires concerning their smoking behaviour and were genotyped for the BclI polymorphism. The genotype frequencies for non-smokers (n = 251; CC, 0.42; CG, 0.46; GG, 0.12) as well as for smokers (n = 76; CC, 0.29; CG, 0.55; GG, 0.16) were consistent with the Hardy-Weinberg equilibrium. The proportion of smokers was significantly lower among carriers of the CC-genotype (22/127 = 17%) compared with carriers of the G-allele (54/200 = 27%; chi2 = 4.08; P = 0.04). Within the group of smokers, the proportion of heavy smokers (> 19 cigarettes/day; median) was reduced in C-homozygous patients when compared with carriers of the G-allele (7/22 = 32% versus 31/54 = 57%; chi2 = 4.09; P = 0.04). Stepwise logistic regression analysis also pointed to an association between the CC-genotype and a reduced probability of being a smoker (odds ratio = 0.55; 95% confidence interval = 0.30-1.00; P = 0.05) controlling for other predictors. In summary, this study provides evidence that the BclI polymorphism might play a role in the maintenance and severity of nicotine dependence.

Topics: Aged; Alleles; Asthma; Cyclin D1; Female; Gene Frequency; Genetic Carrier Screening; Genotype; Germany; Homozygote; Humans; Male; Middle Aged; Polymorphism, Genetic; Pulmonary Disease, Chronic Obstructive; Receptors, Glucocorticoid; Smoking; Tobacco Use Disorder