American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Nov 2020
Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-Mediated Regulation of PDGFRβ.
Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored. Objectives: To elucidate the role of TYKRIL (tyrosine kinase receptor-inducing lncRNA) as a regulator of p53/ PDGFRβ (platelet-derived growth factor receptor β) signaling pathway and to investigate its role in PAH. ⋯ RNA immunoprecipitation using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay revealed that TYKRIL interferes with the p53-p300 interaction (n = 3) and regulates p53 nuclear translocation. Conclusions: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis.
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Am. J. Respir. Crit. Care Med. · Nov 2020
Multicenter StudyRelative Hypotension and Adverse Kidney-related Outcomes Among Critically Ill Patients with Shock- A Multicenter Prospective Cohort Study.
Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidney-related outcomes among critically ill patients with shock. Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation. Methods: At seven multidisciplinary ICUs, 302 patients, aged ≥40 years and requiring ≥4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled. ⋯ Likewise, for every one-unit increase in the percentage of time points with an MPP deficit > 20%, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 1.2% (0.3-2.2; P = 0.008) and 1.4% (0.4-2.4; P = 0.004), respectively. Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes. Study registered with Australian New Zealand Clinical Trial Registry (ACTRN 12613001368729).
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Am. J. Respir. Crit. Care Med. · Nov 2020
Case ReportsSingle Cell Transcriptomic Analysis Identifies a Unique Pulmonary Lymphangioleiomyomatosis Cell.
Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. ⋯ Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. Conclusions: A unique population of LAMCORE cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.
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Am. J. Respir. Crit. Care Med. · Nov 2020
Chronic Hypersensitivity Pneumonitis, an Interstitial Lung Disease with Distinct Molecular Signatures.
Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF). Objectives: To determine the common and unique molecular features of CHP and IPF. ⋯ MUC5B expression was also associated with lung fibrosis and honeycombing. Conclusions: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP.