Epigenetics and chromatin remodeling play a role in lung disease

Epigenetics is defined as heritable changes that affect gene expression without altering the DNA sequence. Epigenetic regulation of gene expression is facilitated through different mechanisms such as DNA methylation, histone modifications and RNA-associated silencing by small non-coding RNAs. All these mechanisms are crucial for normal development, differentiation and tissue-specific gene expression. These three systems interact and stabilize one another and can initiate and sustain epigenetic silencing, thus determining heritable changes in gene expression. Histone acetylation regulates diverse cellular functions including inflammatory gene expression, DNA repair and cell proliferation. Transcriptional coactivators possess intrinsic histone acetyltransferase activity and this activity drives inflammatory gene expression. Eleven classical histone deacetylases (HDACs) act to regulate the expression of distinct subsets of inflammatory/immune genes. Thus, loss of HDAC activity or the presence of HDAC inhibitors can further enhance inflammatory gene expression by producing a gene-specific change in HAT activity. For example, HDAC2 expression and activity are reduced in lung macrophages, biopsy specimens, and blood cells from patients with severe asthma and smoking asthmatics, as well as in patients with chronic obstructive pulmonary disease (COPD). This may account, at least in part, for the enhanced inflammation and reduced steroid responsiveness seen in these patients. Other proteins, particularly transcription factors, are also acetylated and are targets for deacetylation by HDACs and sirtuins, a related family of 7 predominantly protein deacetylases. Thus the acetylation/deacetylation status of NF-κB and the glucocorticoid receptor can also affect the overall expression pattern of inflammatory genes and regulate the inflammatory response. Understanding and targeting specific enzymes involved in this process might lead to new therapeutic agents, particularly in situations in which current anti-inflammatory therapies are suboptimal

On the Continuous Formation of Field Spheroidal Galaxies in Hierarchical Models of Structure Formation

We re-examine the assembly history of field spheroidals as a potentially powerful discriminant of galaxy formation models. Whereas monolithic collapse and hierarchical, merger-driven, models suggest radically different histories for these galaxies, neither the theoretical predictions nor the observational data for field galaxies have been sufficiently reliable for precise conclusions to be drawn. A major difficulty in interpreting the observations, reviewed here, concerns the taxonomic definition of spheroidals in merger-based models. Using quantitative measures of recent star formation activity drawn from the internal properties of a sample of distant field galaxies in the Hubble Deep Fields, we undertake a new analysis to assess the continuous formation of spheroidal galaxies. Whereas abundances and redshift distributions of modelled spheroidals are fairly insensitive to their formation path, we demonstrate that the distribution and amount of blue light arising from recent mergers provides a more sensitive approach. With the limited resolved data currently available, the rate of mass assembly implied by the observed colour inhomogeneities is compared to that expected in popular Lambda-dominated cold dark matter models of structure formation. These models produce as many highly inhomogeneous spheroidals as observed, but underpredict the proportion of homogeneous, passive objects. We conclude that colour inhomogeneities, particularly when combined with spectroscopic diagnostics for large, representative samples of field spheroidals, will be a more valuable test of their physical assembly history than basic source counts and redshift distributions. Securing such data should be a high priority for the Advanced Camera for Surveys on Hubble Space Telescope.Comment: 14 pages, 7 figures, submitted to MNRA

Formation and evolution of early-type galaxies. II. Models with quasi-cosmological initial conditions

In this study, with the aid of N-Body simulations based on quasi-cosmological initial conditions, we have followed the formation and evolution of two models of early-type galaxies, from their separation from global expansion of the Universe to their collapse to virialized structures, the formation of stars and subsequent nearly passive evolution. The cosmological background we have considered is the Standard CDM. The models have significantly different nitial total mass. Particular care has been paid to the star formation process, heating and cooling of gas, and chemical enrichment. In both models star formation is completed within the first Gyrs of evolution. The structural properties of the present-day models are in good agreement with current observations. The chemical properties, mean metallicity and metallicity gradients also agree with available observational data. Finally, conspicuous galactic winds are found to occur. The models conform to the so-called revised monolithic scheme, because mergers of substructures have occurred very early in the galaxy life. Our results agree with those obtained in other similar recent studies, thus strengthening the idea that the revised monolithic scheme is the right trail to follow in the forest of galaxy formation and evolution.Comment: 21 pages, 19 figures, 3 tables. To be published on Astronomy & Astrophysics (accepted April 12, 2006

How antimalarial drug resistance affects post-treatment prophylaxis

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base

Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E(2), due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE(2) production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE(2) production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4