American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Dec 2022
Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U. S. ⋯ Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial-mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
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Am. J. Respir. Crit. Care Med. · Dec 2022
Randomized Controlled Trial Multicenter StudyHigh-Flow Versus VenturiMask Oxygen Therapy to Prevent Re-Intubation in Hypoxemic Patients After Extubation: A Multicenter, Randomized Clinical Trial.
Rationale: When compared with VenturiMask after extubation, high-flow nasal oxygen provides physiological advantages. Objectives: To establish whether high-flow oxygen prevents endotracheal reintubation in hypoxemic patients after extubation, compared with VenturiMask. Methods: In this multicenter randomized trial, 494 patients exhibiting PaO2:FiO2 ratio ⩽ 300 mm Hg after extubation were randomly assigned to receive high-flow or VenturiMask oxygen, with the possibility to apply rescue noninvasive ventilation before reintubation. ⋯ Conclusions: Reintubation rate did not significantly differ between patients treated with VenturiMask or high-flow oxygen after extubation. High-flow oxygen yielded less frequent use of rescue noninvasive ventilation. Clinical trial registered with www.clinicaltrials.gov (NCT02107183).
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Am. J. Respir. Crit. Care Med. · Dec 2022
Multicenter StudyFirst Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease.
Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. ⋯ Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.