Alveolar epithelial and endothelial cell apoptosis in emphysema: What we know and what we need to know

Emphysema is mainly caused by cigarette smoking and is characterized by the loss of alveolar integrity and an enlargement of the alveolar space. However, mechanisms involved in its development are not fully understood. Alveolar cell apoptosis has been previously investigated in the lung of emphysematous subjects as a potential contributor to the loss of alveolar cell and has been found abnormally elevated. Though, mechanisms involved in the increased alveolar apoptosis that occurs in emphysema have now become a prolific field of research. Those mechanisms are reviewed here with special focus on how they affect cell viability and how they may be implicated in emphysema. Moreover, we suggest a model that integrates all those mechanisms to explain the increased alveolar apoptosis observed in emphysema. This review also includes some reflections and suggestions on the research to come

Differential requirement of a distal regulatory region for pre-initiation complex formation at globin gene promoters

Although distal regulatory regions are frequent throughout the genome, the molecular mechanisms by which they act in a promoter-specific manner remain to be elucidated. The human β-globin locus constitutes an extremely well-established multigenic model to investigate this issue. In erythroid cells, the β-globin locus control region (LCR) exerts distal regulatory function by influencing local chromatin organization and inducing high-level expression of individual β-like globin genes. Moreover, in transgenic mice expressing the entire human β-globin locus, deletion of LCR-hypersensitive site 2 (HS2) can alter β-like globin gene expression. Here, we show that abnormal expression of human β-like globin genes in the absence of HS2 is associated with decreased efficacy of pre-initiation complex formation at the human ɛ- and γ-promoters, but not at the β-promoter. This promoter-specific phenomenon is associated with reduced long-range interactions between the HS2-deleted LCR and human γ-promoters. We also find that HS2 is dispensable for high-level human β-gene transcription, whereas deletion of this hypersensitive site can alter locus chromatin organization; therefore the functions exerted by HS2 in transcriptional enhancement and locus chromatin organization are distinct. Overall, our data delineate one mechanism whereby a distal regulatory region provides promoter-specific transcriptional enhancement

The potential for aclidinium bromide, a new anticholinergic, in the management of chronic obstructive pulmonary disease

Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M 3 versus M 2 receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV 1 ) and other related lung function measurements. Improvements in peak FEV 1 on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema-2

<p><b>Copyright information:</b></p><p>Taken from "Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema"</p><p>http://respiratory-research.com/content/8/1/62</p><p>Respiratory Research 2007;8(1):62-62.</p><p>Published online 6 Sep 2007</p><p>PMCID:PMC2018693.</p><p></p>ted anti-CD56, CD4, CD8, or CD3, permeabilized, then labelled with fluorochrome-conjugated anti- A) granzyme B or B) perforin and analysed by flow cytometry. Columns represent mean ± SEM. Normal non-smokers (white), normal smokers (black), and emphysematous smokers (grey)

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema-1

<p><b>Copyright information:</b></p><p>Taken from "Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema"</p><p>http://respiratory-research.com/content/8/1/62</p><p>Respiratory Research 2007;8(1):62-62.</p><p>Published online 6 Sep 2007</p><p>PMCID:PMC2018693.</p><p></p>d cell count. B) PBMC were isolated from each subjects, double labelled with fluorochrome-conjugated antibodies (CD3/CD4 and CD3/CD8), and analysed by flow cytometry. For each subject, CD4/CD8 ratio was obtained by dividing the %CD3/CD4cells by the %CD3/CD8cells. Columns represent mean ± SEM. *p = 0.02. Normal non-smokers (white), normal smokers (black), and emphysematous smokers (grey)

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema-0

<p><b>Copyright information:</b></p><p>Taken from "Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema"</p><p>http://respiratory-research.com/content/8/1/62</p><p>Respiratory Research 2007;8(1):62-62.</p><p>Published online 6 Sep 2007</p><p>PMCID:PMC2018693.</p><p></p>RP levels were quantified by high sensitivity nephelometry. Columns represent mean ± SEM. *p = 0.002; **p = 0.0003. Normal non-smokers (white), normal smokers (black), and emphysematous smokers (grey)

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema-3

<p><b>Copyright information:</b></p><p>Taken from "Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema"</p><p>http://respiratory-research.com/content/8/1/62</p><p>Respiratory Research 2007;8(1):62-62.</p><p>Published online 6 Sep 2007</p><p>PMCID:PMC2018693.</p><p></p>expression of granzyme B, perforin, and FasL was assessed by real-time PCR, using 18S rRNA as housekeeping gene and compared using 2method. Columns represent mean ± SEM. *p = 0.02; **p = 0.05. Normal non-smokers (white), normal smokers (black), and emphysematous smokers (grey)