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RATIONALE: We developed an evidence-based decision aid for patients with advanced cystic fibrosis considering referral for lung transplantation. OBJECTIVES: To prospectively evaluate whether use of the decision aid increased knowledge about the options, improved realistic expectations, and decreased decisional conflict in adult patients. METHODS: We performed a single-blind randomized controlled trial involving 149 adult patients with cystic fibrosis with an FEV(1)

Rationale: Different sensitivities to profibrotic compounds such as bleomycin are observed among mouse strains. Objectives: To identify genetic factors contributing to the outcome of lung injury. Methods: Physiological comparison of C57BL/6 (sensitive) and BALB/c (resistant) mice challenged by intratracheal bleomycin instillation revealed several early differences: global gene expression profiles were thus established from lungs derived from the two strains, in the absence of any bleomycin administration. Measurements and Main Results: Expression of 25 genes differed between the two strains. Among them, two molecules, not previously associated with pulmonary fibrosis, were identified. The first corresponded to dipeptidyl-peptidase I (DPPI), a cysteine peptidase (also known as cathepsin C) essential for the activation of serine proteinases produced by immune/inflammatory cells. The second corresponded to tissue inhibitor of matrix metalloproteinase-3, which also inhibits members of the ADAM (a disintegrin and metalloproteinase) family, such as the tumor necrosis factor-converting enzyme. In functional studies performed in the bleomycin-induced lung fibrosis model, the level of expression of these two genes was closely correlated with specific early events associated with lung fibrosis, namely activation of polymorphonuclear neutrophil-derived serine proteases and tumor necrosis factor-alpha-dependent inflammatory syndrome. Surprisingly, genetic deletion of DPPI in the context of a C57BL/6 genetic background did not protect against bleomycin-mediated fibrosis, suggesting additional function(s) for this key enzyme. Conclusions: This study highlights the importance of the early inflammatory events that follow bleomycin instillation in the development of lung fibrosis, and describes for the first time the roles that DPPI and tissue inhibitor of matrix metalloproteinase-3 may play in this process. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neutrophil elastase in the cystic fibrosis airways inhibits opsonophagocytosis and induces the expression of interleukin-8, a neutrophil chemoattractant. Prolastin is a therapeutic preparation of alpha-1 proteinase inhibitor (alpha1,-PI), a neutrophil elastase inhibitor. The objective of this study was to determine the effects of Prolastin aerosol therapy on airway inflammation in cystic fibrosis. METHODS: The primary endpoint of this study was sputum taurine, an amino-acid present in high concentrations in neutrophils. Sputum taurine correlates with respiratory exacerbations of cystic fibrosis. Seventeen patients with cystic fibrosis were each assigned to three sequential 10-day periods including first, aerosol therapy of 5 ml saline solution bid; second, aerosol therapy of 250 mg Prolastin bid; third, no aerosol therapy. On days 8, 9 and 10 of each period, early morning sputum was collected for the quantification of alpha1-PI, neutrophil elastase activity, IL-8 and taurine. RESULTS: During Prolastin therapy, a 3-fold increase in sputum alpha1-PI was observed (P = 0.002). Baseline values of sputum alpha1-PI correlated with the values obtained after Prolastin aerosol (R = 0.77, P < 0.01). Sputum neutrophil elastase activity remained unchanged but taurine decreased after Prolastin therapy (during therapy P = 0.052, after therapy P = 0.026). Prolastin aerosol therapy had no adverse effect on pulmonary function. CONCLUSIONS: Aerosol therapy with Prolastin in patients with cystic fibrosis leads to a progressive decrease in sputum taurine. This suggests that even in the absence of sustained elastase inhibition, Prolastin aerosol therapy may have a beneficial effect on airway inflammation in patients with cystic fibrosis. [ABSTRACT FROM AUTHOR]

Resolution of pulmonary oedema is mediated by active absorption of liquid across the alveolar epithelium. A key component of this process is the sodium-potassium ATPase (Na[sup +] K[sup +]-ATPase) enzyme located on the basolateral surface of epithelial cells and up-regulated during oedema resolution. We hypothesised that lung liquid clearance could be further up-regulated by lipid-mediated transfer and expression of exogenous Na[sup +]K[sup +]-ATPase cDNA. We demonstrate proof of this principle in a model of high permeability pulmonary oedema induced by intraperitoneal injection of thiourea (2.5 mg/kg) in C57/BL6 mice. Pretreatment of mice (24 h before thiourea) by nasal sniffing of cationic liposome (lipid #67)-DNA complexes encoding the α and β subunits of Na[sup +]K[sup +]-ATPase (160 µg per mouse), significantly (P < 0.01) decreased the wet:dry weight ratios measured 2 h after thiourea injection compared with control animals, pretreated with an equivalent dose of an irrelevant gene. Whole lung Na[sup +]K[sup +]-ATPase activity was significantly (P < 0.05) increased in mice pretreated with Na[sup +]K[sup +]-ATPase cDNA compared both with untreated control animals as well as animals pretreated with the irrelevant gene. Nested RT-PCR on whole lung homogenates confirmed gene transfer by detection of vector-specific mRNA in three of four mice studied 24 h after gene transfer. This demonstration of a significant reduction in pulmonary oedema following in vivo gene transfer raises the possibility of gene therapy as a novel, localised approach for pulmonary oedema in clinical settings such as ARDS and lung transplantation. [ABSTRACT FROM AUTHOR]