American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Jul 2014
Multicenter Study Observational StudyClinical Mechanism of the CFTR Potentiator Ivacaftor in G551D-Mediated Cystic Fibrosis.
Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. ⋯ Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.
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FEV1, measured using spirometry, provides a straightforward, widely available, and inexpensive global measurement of airflow limitation and lung function. For decades, FEV1 has remained the main intermediate endpoint used in research studies and for the development of new chronic obstructive pulmonary disease (COPD) therapies. Not surprisingly, treatments that acutely improve FEV1 dominate as COPD therapies. ⋯ In individual patients and in COPD cohort studies, thoracic imaging using X-ray computed tomography, and magnetic resonance imaging (conventional (1)H as well as hyperpolarized noble gases such as (129)Xe, (3)He, and inhaled O2 and (19)F) can be used to directly visualize the structural and functional consequences of COPD and thus provide a clearer picture of COPD mechanisms, disease progression, and response to therapy. We briefly describe pulmonary imaging methods that provide a way to visualize and quantify, with high spatial and temporal resolution, regional ventilation abnormalities, gas trapping, emphysema, and airway remodeling in COPD. Finally, we discuss the implications of recent imaging findings and their impact on future biomarker and therapy research aimed at improving COPD outcomes.
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Am. J. Respir. Crit. Care Med. · Jul 2014
Randomized Controlled TrialBosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia (BPHIT).
Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. ⋯ This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).
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Am. J. Respir. Crit. Care Med. · Jul 2014
Wnt Co-receptor Lrp5 is a Driver of Idiopathic Pulmonary Fibrosis.
Wnt/β-catenin signaling has been implicated in lung fibrosis, but how this occurs and whether expression changes in Wnt pathway components predict disease progression is unknown. ⋯ We show that the Wnt coreceptor, Lrp5, is a genetic driver of lung fibrosis in mice and a marker of disease progression and severity in humans with IPF. Evidence that TGF-β signaling can override a loss in Lrp5 has implications for patient selection and timing of Wnt pathway inhibitors in lung fibrosis.