Association of Forced Vital Capacity with the Developmental Gene NCOR2

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1.We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of Vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate

A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α

Remodeling in COPD has at least two dimensions: small airway wall thickening and destruction of alveolar walls. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal LPS instillation or local TNF expression (SPC-TNFalpha mice), were stained for elastin, collagen and hyaluronan. Furthermore TNFalpha, MMP2, 9 and 12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFalpha mice. Furthermore TNFalpha, and MMP2 and 9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFalpha mice. We show that only SPC-TNFalpha mice show changes in elastin remodeling which are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFalpha model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP2 and MMP9 in the breakdown of elastin in airways and alveoli of SPC-TNFalpha mice

Role of activin-A in cigarette smoke-induced inflammation and COPD

Pathogenesis and treatment of chronic pulmonary disease

Leptin as regulator of pulmonary immune responses: Involvement in respiratory diseases

Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia

Extrapulmonary manifestations of chronic obstructive pulmonary disease in a mouse model of chronic cigarette smoke exposure.

Rationale Cigarette smoking is the most commonly encountered risk factor for COPD, reflected by irreversible airflow limitation frequently associated with airspace enlargement and pulmonary inflammation. In addition, COPD has systemic consequences including systemic inflammation, muscle wasting and loss of muscle oxidative phenotype. However, the role of smoking in the development of these extrapulmonary manifestations remains rather unexplored. Methods Mice were exposed to cigarette smoke or control air for 6 months. Subsequently, emphysema was assessed by morphometry of lung tissue and blood cyto- and chemokine levels were determined by a multiplex assay. Soleus, plantaris, gastrocnemius and tibialis muscles were dissected and weighed. Muscle fiber typing was performed based on I, IIA, IIB, and IIX myosin heavy chain isoform composition. Results Lungs of the smoke exposed animals showed pulmonary inflammation and emphysema. Moreover, circulating levels of primarily pro-inflammatory proteins were elevated after smoke exposure, especially TNFalpha. Despite an attenuated body weight gain, only the soleus showed a tendency toward lower muscle weight after smoke exposure. Oxidative fiber type IIA proportion was significantly reduced in the soleus. Muscle oxidative enzyme activity was slightly reduced after smoke exposure, being most prominent for citrate synthase in the soleus and tibialis. Conclusions In this mouse model, chronic cigarette smoke exposure resulted in systemic features that closely resemble the early signs of the extrapulmonary manifestations observed in COPD patients. AD - Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, Netherlands. AU - Gosker HR AU - Langen RC AU - Bracke KR AU - Joos GF AU - Brusselle GG AU - Steele C AU - Ward KA AU - Wouters EF AU - Schols AM LA - ENG PT - JOURNAL ARTICLE DEP - 20081106 TA - Am J Respir Cell Mol Biol JT - American journal of respiratory cell and molecular biology JID - 891722