22 research outputs found
Upregulation of pirin expression by chronic cigarette smoking is associated with bronchial epithelial cell apoptosis
BACKGROUND: Cigarette smoke disrupts the protective barrier established by the airway epithelium through direct damage to the epithelial cells, leading to cell death. Since the morphology of the airway epithelium of smokers does not typically demonstrate necrosis, the most likely mechanism for epithelial cell death in response to cigarette smoke is apoptosis. We hypothesized that cigarette smoke directly up-regulates expression of apoptotic genes, which could play a role in airway epithelial apoptosis. METHODS: Microarray analysis of airway epithelium obtained by bronchoscopy on matched cohorts of 13 phenotypically normal smokers and 9 non-smokers was used to identify specific genes modulated by smoking that were associated with apoptosis. Among the up-regulated apoptotic genes was pirin (3.1-fold, p < 0.002), an iron-binding nuclear protein and transcription cofactor. In vitro studies using human bronchial cells exposed to cigarette smoke extract (CSE) and an adenovirus vector encoding the pirin cDNA (AdPirin) were performed to test the direct effect of cigarette smoke on pirin expression and the effect of pirin expression on apoptosis. RESULTS: Quantitative TaqMan RT-PCR confirmed a 2-fold increase in pirin expression in the airway epithelium of smokers compared to non-smokers (p < 0.02). CSE applied to primary human bronchial epithelial cell cultures demonstrated that pirin mRNA levels increase in a time-and concentration-dependent manner (p < 0.03, all conditions compared to controls). Overexpression of pirin, using the vector AdPirin, in human bronchial epithelial cells was associated with an increase in the number of apoptotic cells assessed by both TUNEL assay (5-fold, p < 0.01) and ELISA for cytoplasmic nucleosomes (19.3-fold, p < 0.01) compared to control adenovirus vector. CONCLUSION: These observations suggest that up-regulation of pirin may represent one mechanism by which cigarette smoke induces apoptosis in the airway epithelium, an observation that has implications for the pathogenesis of cigarette smoke-induced diseases
Percutaneous treatment of patients with heart diseases: selection, guidance and follow-up. A review
Aortic stenosis and mitral regurgitation, patent foramen ovale, interatrial septal defect, atrial fibrillation and perivalvular leak, are now amenable to percutaneous treatment. These percutaneous procedures require the use of Transthoracic (TTE), Transesophageal (TEE) and/or Intracardiac echocardiography (ICE). This paper provides an overview of the different percutaneous interventions, trying to provide a systematic and comprehensive approach for selection, guidance and follow-up of patients undergoing these procedures, illustrating the key role of 2D echocardiography
A self-avoidance mechanism in patterning of the urinary collecting duct tree
BACKGROUND: Glandular organs require the development of a correctly patterned epithelial tree. These arise by iterative branching: early branches have a stereotyped anatomy, while subsequent branching is more flexible, branches spacing out to avoid entanglement. Previous studies have suggested different genetic programs are responsible for these two classes of branches. RESULTS: Here, working with the urinary collecting duct tree of mouse kidneys, we show that the transition from the initial, stereotyped, wide branching to narrower later branching is independent from previous branching events but depends instead on the proximity of other branch tips. A simple computer model suggests that a repelling molecule secreted by branches can in principle generate a well-spaced tree that switches automatically from wide initial branch angles to narrower subsequent ones, and that co-cultured trees would distort their normal shapes rather than colliding. We confirm this collision-avoidance experimentally using organ cultures, and identify BMP7 as the repelling molecule. CONCLUSIONS: We propose that self-avoidance, an intrinsically error-correcting mechanism, may be an important patterning mechanism in collecting duct branching, operating along with already-known mesenchyme-derived paracrine factors
Matrilysin (MMP-7) Inhibition of BMP-7 Induced Renal Tubular Branching Morphogenesis Suggests a Role in the Pathogenesis of Human Renal Dysplasia
Ureteric branching morphogenesis in BMP4 heterozygous mutant mice
Exogenous bone morphogenetic protein 4 (BMP4) inhibits ureteric branching morphogenesis and amplifies the already existing branching asymmetry in the developing mouse kidney in vitro. In the present study we examined ureteric branching morphogenesis in BMP4/lacZ heterozygous (BMP4+/–) mice in vitro under control conditions and in the presence of exogenous BMP4 using three-dimensional image analysis software. The relative expression of BMP4 mRNA was determined in BMP4+/– and wildtype urogenital ridges using real-time PCR. Embryonic day 12.5 (E12.5) BMP4+/– and wildtype mouse metanephroi were cultured for 48 h with or without 260 ng mL−1 recombinant human BMP4 (rhBMP4) and were then wholemount immunostained in order to identify the ureteric epithelium, which was quantified in three dimensions. Despite a significant reduction in BMP4 mRNA in BMP4+/– mice, qualitative and quantitative studies identified no differences in ureteric branching morphogenesis between phenotypically normal BMP4+/– and wildtype metanephroi in either BMP4-treated or control cultures. Both BMP4+/– and wildtype metanephroi cultured in the presence of BMP4 showed a decrease in total ureteric length, branch number and ureteric volume, and increased average branch length compared with control cultures. A marked anterior–posterior asymmetry in both ureteric length, branch number and average branch length was observed in BMP4-treated metanephroi from both genotypes. A similar asymmetry was revealed in control metanephroi from both genotypes. This asymmetry is the result of reduced ureteric branching morphogenesis but not elongation in the posterior region of the kidney. These results suggest that despite reduced endogenous BMP4 mRNA levels, most BMP4+/– embryos can still facilitate normal ureteric branching morphogenesis during development. In addition, reduced endogenous levels of BMP4 do not alter the inhibitory effects of exogenous BMP4 on ureteric branching or amplification of normal renal asymmetry