American journal of respiratory and critical care medicine
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Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. ⋯ To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis.
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Am. J. Respir. Crit. Care Med. · Sep 2019
Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement.
Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. ⋯ Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.
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Am. J. Respir. Crit. Care Med. · Sep 2019
Comparative StudyAlveolar Macrophage Transcriptional Programs Are Associated with Outcomes in Acute Respiratory Distress Syndrome.
Rationale: Serial measurements of alveolar macrophage (AM) transcriptional changes in patients with acute respiratory distress syndrome (ARDS) could identify cell-specific biological programs that are associated with clinical outcomes. Objectives: To determine whether AM transcriptional programs are associated with prolonged mechanical ventilation and 28-day mortality in individuals with ARDS. Methods: We performed genome-wide transcriptional profiling of AMs purified from BAL fluid collected from 35 subjects with ARDS. ⋯ Dead/intubatedDay28 subjects exhibited an opposite pattern, characterized by progressive upregulation of proinflammatory programs over the course of ARDS. The relationship between AM expression profiles and 28-day clinical status was distinct in subjects with direct (pulmonary) versus indirect (extrapulmonary) ARDS. Conclusions: Clinical outcomes in ARDS are associated with highly distinct AM transcriptional programs.