American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Nov 2019
Rare Protein-altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.
Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP). Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP. ⋯ Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011). Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.
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Am. J. Respir. Crit. Care Med. · Nov 2019
Role of Glucosylceramide in Lung Endothelial Cell Fate and Emphysema.
Rationale: The loss of pulmonary endothelial cells in emphysema is associated with increased lung ceramide. Ceramide perturbations may cause adaptive alterations in other bioactive sphingolipids, with pathogenic implications. We previously reported a negative correlation between emphysema and circulating glycosphingolipids (GSLs). ⋯ GCS inhibition in HLMVEC increased lysosomal pH, suppressed mTOR signaling, and triggered autophagy with impaired lysosomal degradation and apoptosis, recapitulating CS effects. In turn, increasing GlcCer by GCS overexpression in HLMVEC improved autophagic flux and attenuated CS-induced apoptosis. Conclusions: Decreased GSL production in response to CS may be involved in emphysema pathogenesis, associated with autophagy with impaired lysosomal degradation and lung endothelial cell apoptosis.
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Am. J. Respir. Crit. Care Med. · Nov 2019
Bacteriophages Improve Outcome in Experimental Staphylococcus Aureus Ventilator Associated Pneumonia.
Rationale: Infections caused by multidrug-resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy. Objectives: To evaluate the efficacy of intravenous phage therapy for the treatment of ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats. ⋯ IL-1β increased in all treatment groups over the course of therapy. Conclusions: Phage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant S. aureus. Combining antibiotics with phage therapy did not further improve outcomes.