Association of innate defense proteins BPIFA1 and BPIFB1 with disease severity in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal inflammatory response in the lungs caused by the inhalation of noxious particles and gases. The airway epithelium has a protective function against these harmful agents by maintaining a physical barrier and by secreting defensive proteins, such as bactericidal/permeability-increasing fold-containing (BPIF) proteins, BPIFA1 and BPIFB1. However, inconsistent data regarding BPIFA1 expression in smokers and COPD patients have been reported to date. Therefore, we investigated the expression of BPIFA1 and BPIFB1 in a large cohort of never-smokers and smokers with and without COPD, both on the messenger RNA (mRNA) level in lung tissue and on the protein level in airway epithelium. Furthermore, we examined the correlation between BPIFA1 and BPIFB1 levels, goblet cell hyperplasia, and lung function measurements. BPIFA1 and BPIFB1 mRNA expressions were significantly increased in stage III-IV COPD patients compared with stage II COPD patients and subjects without COPD. In addition, protein levels in COPD patients were significantly increased in comparison with subjects without COPD. BPIFA1 and BPIFB1 levels were inversely correlated with measurements of airflow limitation and positively correlated with goblet cell hyperplasia. In addition, by the use of immunofluorescence double staining, we demonstrated the expression of BPIFB1 in goblet cells. In conclusion, we show that BPIFA1 and BPIFB1 levels are elevated in COPD patients and correlate with disease severity

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

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

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

Activation of the WNT/β-catenin pathway attenuates experimental emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/β-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/β-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative RT-PCR, immunohistochemistry, and Western blotting. The role of WNT/β-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/β-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear !-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/β-catenin signaling was downregulated in both experimental emphysema models. Preventive, as well as therapeutic, WNT/β-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSION: Decreased WNT/β-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/β-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/β-catenin activation as a future therapeutic approach for emphysema