American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Oct 2022
Opioid Use Disorder, Sleep Deficiency, and Ventilatory Control: Bidirectional Mechanisms and Therapeutic Targets.
Opioid use continues to rise globally. So too do the associated adverse consequences. Opioid use disorder (OUD) is a chronic and relapsing brain disease characterized by loss of control over opioid use and impairments in cognitive function, mood, pain perception, and autonomic activity. ⋯ The focus of this concise clinical review is to highlight the bidirectional mechanisms between OUD and sleep deficiency and the potential to target sleep deficiency with therapeutic interventions to promote long-term, healthy recovery among patients in OUD treatment. In addition, current knowledge on the effects of opioids on sleep quality, sleep architecture, sleep-disordered breathing, sleep apnea endotypes, ventilatory control, and implications for therapy and clinical practice are highlighted. Finally, an actionable research agenda is provided to evaluate the basic mechanisms of the relationship between sleep deficiency and OUD and the potential for behavioral, pharmacologic, and positive airway pressure treatments targeting sleep deficiency to improve OUD treatment outcomes.
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Am. J. Respir. Crit. Care Med. · Oct 2022
Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.
Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hypertension and control subjects. ⋯ Transfection of human endogenous retrovirus K envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and IFN genes, whereas vinculin is increased by human endogenous retrovirus K deoxyuridine triphosphate diphosphatase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus K envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.
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Am. J. Respir. Crit. Care Med. · Oct 2022
Impairment of the NKT-STAT1-CXCL9-axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Due to Lung Fibrosis.
Rationale: Pulmonary hypertension (PH) is a common, severe comorbidity in interstitial lung diseases such as pulmonary fibrosis (PF), and it has limited treatment options. Excessive vascular fibrosis and inflammation are often present in PH, but the underlying mechanisms are still not well understood. Objectives: To identify a novel functional link between natural killer T (NKT) cell activation and vascular fibrosis in PF-PH. ⋯ Secretome analysis of peripheral blood mononuclear cells identified CXCL9 and CXCL10 as indicators of NKT cell activation. Pharmacologically, CXCL9, but not CXCL10, potently inhibited collagen deposition in hPASMCs via the chemokine receptor CXCR3. Conclusions: Our results indicate that the absence of NKT cells impairs the STAT1-CXCL9-CXCR3 axis in PF-PH and that restoration of this axis by NKT cell activation may unravel a novel therapeutic strategy to target vascular fibrosis in interstitial lung disease.
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Am. J. Respir. Crit. Care Med. · Oct 2022
Editorial CommentInsights into Endotheliopathy in COVID-19.