Pulmonary hypertension associated with COPD

Although the prevalence of pulmonary hypertension (PH) in individuals with chronic obstructive pulmonary disease (COPD) is not known precisely, approximately 10%–30% of patients with moderate to severe COPD have elevated pulmonary pressures. The vast majority of PH associated with COPD is mild to moderate and severe PH occurs in <5% of patients. When COPD is associated with PH, both mortality and morbidity are increased. There are no clinical or physical examination findings that accurately identify patients with underlying PH. Radiographic imaging findings are specific but not sensitive indicators of PH. Echocardiography is the principle noninvasive diagnostic test but may be technically limited in a significant proportion of patients with COPD. Right heart catheterization is required for accurate measurement of pulmonary pressures. The combined effects of inflammation, endothelial cell dysfunction, and angiogenesis appear to contribute to the development of PH associated with COPD. Systemic vasodilators have not been found to be effective therapy. Selective pulmonary vasodilators including inhaled nitric oxide and phosphodiesterase inhibitors are promising treatments for patients with COPD associated PH but further evaluation of these medications is needed prior to their routine use

Health care utilization history, GOLD guidelines, and respiratory medication prescriptions in patients with COPD

Joseph Seaman1,2, Anthony C Leonard3, Ralph J Panos1,21Pulmonary, Critical Care, and Sleep Division, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH, USA; 2Pulmonary, Critical Care, and Sleep Division, University of Cincinnati School of Medicine, Cincinnati, OH, USA; 3Department of Public Health Sciences, University of Cincinnati School of Medicine, Cincinnati, OH, USABackground: The relationship between prior health care utilization and respiratory medication prescriptions in an unselected population of patients with COPD is not known.Methods: We determined the prescribed respiratory medications and respiratory and nonrespiratory health care encounters in 523 Veterans with COPD at the Cincinnati Veterans Affairs Medical Center between 2000 and 2005. Prescribed treatments were compared with the GOLD guidelines and each patient was classified as receiving less medications than recommended in the guidelines (&amp;lt;G), medications according to the guidelines (=G), or more medications than recommended (&amp;gt;G).Results: Respiratory medications were &amp;lt;G for 54%, =G in 33%, and &amp;gt;G for 14% of the patients studied. For GOLD stages 1 and 2, &amp;lt;G patients had the fewest and &amp;gt;G patients the most prior respiratory encounters during a 12 month period (0.31 &amp;plusmn; 0.073 (0.21, 0.47), 0.75 &amp;plusmn; 0.5 (0.37, 1.5), 1.1 &amp;plusmn; 0.27 (0.74, 1.6) visits/person/year, &amp;lt;G, =G, &amp;gt;G, respectively, mean + standard error of mean (SEM) (95% confidence limits) 2 degrees of freedom (df) ANOVA P &amp;lt; 0.001 for prescription effect). For GOLD stages 3 and 4, &amp;lt;G was associated with significantly fewer prior respiratory visits than was =G (0.78 &amp;plusmn; 0.11 (0.6, 1.0) and 2.4 &amp;plusmn; 0.47 (1.9, 3.1) visits/person/year, respectively, P &amp;lt; 0.001). There were no differences in nonrespiratory health care visits for GOLD stages 1 and 2 by prescription level (3.1 &amp;plusmn; 0.24 (2.6, 3.5), 3.1 &amp;plusmn; 0.46 (2.1, 4.6) and 4.1 &amp;plusmn; 0.55 (3.3, 5.1) visits/person/year, &amp;lt;G, =G, &amp;gt;G respectively, 2 df ANOVA P = 0.096) or for GOLD stages 3 and 4 (3.6 &amp;plusmn; 0.25 (3.2, 4.1) and 4.0 &amp;plusmn; 0.44 (3.3, 4.9) visits/ person/year, &amp;lt;G and =G, respectively, P = 0.36).Conclusions: Respiratory medications prescribed for an unselected population with a broad range of COPD severity complied poorly with the GOLD pharmacologic treatment guidelines but correlated with the number of prior respiratory health care visits.Keywords: health care, COPD, respiratory visits, GOLD guidelines, prescriptio

Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function

9 pages, 6 figures, 1 table.Keratinocyte growth factor (KGF), also called fibroblast growth factor-7, is widely known as a paracrine growth and differentiation factor that is produced by mesenchymal cells and has been thought to act specifically on epithelial cells. Here it is shown to affect a new cell type, the microvascular endothelial cell. At subnanomolar concentrations KGF induced in vivo neovascularization in the rat cornea. In vitro it was not effective against endothelial cells cultured from large vessels, but did act directly on those cultured from small vessels, inducing chemotaxis with an ED50 of 0.02-0.05 ng/ml, stimulating proliferation and activating mitogen activated protein kinase (MAPK). KGF also helped to maintain the barrier function of monolayers of capillary but not aortic endothelial cells, protecting against hydrogen peroxide and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) induced increases in permeability with an ED50 of 0.2-0.5 ng/ml. These newfound abilities of KGF to induce angiogenesis and to stabilize endothelial barriers suggest that it functions in microvascular tissue as it does in epithelial tissues to protect them against mild insults and to speed their repair after major damage.Peer reviewe

The Anti-Sigma Factor MucA of Pseudomonas aeruginosa: Dramatic Differences of a mucA22 vs. a ΔmucA Mutant in Anaerobic Acidified Nitrite Sensitivity of Planktonic and Biofilm Bacteria in vitro and During Chronic Murine Lung Infection

Mucoid mucA22 Pseudomonas aeruginosa (PA) is an opportunistic lung pathogen of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients that is highly sensitive to acidified nitrite (A-NO2-). In this study, we first screened PA mutant strains for sensitivity or resistance to 20 mM A-NO2- under anaerobic conditions that represent the chronic stages of the aforementioned diseases. Mutants found to be sensitive to A-NO2- included PA0964 (pmpR, PQS biosynthesis), PA4455 (probable ABC transporter permease), katA (major catalase, KatA) and rhlR (quorum sensing regulator). In contrast, mutants lacking PA0450 (a putative phosphate transporter) and PA1505 (moaA2) were A-NO2- resistant. However, we were puzzled when we discovered that mucA22 mutant bacteria, a frequently isolated mucA allele in CF and to a lesser extent COPD, were more sensitive to A-NO2- than a truncated ΔmucA deletion (Δ157–194) mutant in planktonic and biofilm culture, as well as during a chronic murine lung infection. Subsequent transcriptional profiling of anaerobic, A-NO2--treated bacteria revealed restoration of near wild-type transcript levels of protective NO2- and nitric oxide (NO) reductase (nirS and norCB, respectively) in the ΔmucA mutant in contrast to extremely low levels in the A-NO2--sensitive mucA22 mutant. Proteins that were S-nitrosylated by NO derived from A-NO2- reduction in the sensitive mucA22 strain were those involved in anaerobic respiration (NirQ, NirS), pyruvate fermentation (UspK), global gene regulation (Vfr), the TCA cycle (succinate dehydrogenase, SdhB) and several double mutants were even more sensitive to A-NO2-. Bioinformatic-based data point to future studies designed to elucidate potential cellular binding partners for MucA and MucA22. Given that A-NO2- is a potentially viable treatment strategy to combat PA and other infections, this study offers novel developments as to how clinicians might better treat problematic PA infections in COPD and CF airway diseases

Undifferentiated Connective Tissue Disease-Associated Interstitial Lung Disease: Changes in Lung Function

Undifferentiated connective tissue disease (UCTD) is a distinct clinical entity that may be accompanied by interstitial lung disease (ILD). The natural history of UCTD-ILD is unknown. We hypothesized that patients with UCTD-ILD would be more likely to have improvement in lung function than those with idiopathic pulmonary fibrosis (IPF) during longitudinal follow-up. We identified subjects enrolled in the UCSF ILD cohort study with a diagnosis of IPF or UCTD. The primary outcome compared the presence or absence of a ≥5% increase in percent predicted forced vital capacity (FVC) in IPF and UCTD. Regression models were used to account for potential confounding variables. Ninety subjects were identified; 59 subjects (30 IPF, 29 UCTD) had longitudinal pulmonary function data for inclusion in the analysis. After accounting for baseline pulmonary function tests, treatment, and duration between studies, UCTD was associated with substantial improvement in FVC (odds ratio = 8.23, 95% confidence interval, 1.27–53.2; p = 0.03) during follow-up (median, 8 months) compared with IPF. Patients with UCTD-ILD are more likely to have improved pulmonary function during follow-up than those with IPF. These findings demonstrate the clinical importance of identifying UCTD in patients presenting with an “idiopathic” interstitial pneumonia

Association of warfarin dose with genes involved in its action and metabolism

We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00439-006-0260-8 and is accessible for authorized users