American journal of respiratory and critical care medicine
-
Am. J. Respir. Crit. Care Med. · Jan 2020
Platelet Extracellular Vesicles Drive Inflammasome-IL-1β-Dependent Lung Injury in Sickle Cell Disease.
Rationale: Intraerythrocytic polymerization of Hb S promotes hemolysis and vasoocclusive events in the microvasculature of patients with sickle cell disease (SCD). Although platelet-neutrophil aggregate-dependent vasoocclusion is known to occur in the lung and contribute to acute chest syndrome, the etiological mechanisms that trigger acute chest syndrome are largely unknown. Objectives: To identify the innate immune mechanism that promotes platelet-neutrophil aggregate-dependent lung vasoocclusion and injury in SCD. ⋯ Inhibition of the inflammasome effector caspase-1 or IL-1β pathway attenuated platelet EV generation, prevented platelet-neutrophil aggregation, and restored microvascular blood flow in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. Conclusions: These results are the first to identify that platelet-inflammasome-dependent shedding of IL-1β and caspase-1-carrying platelet EVs promote lung vasoocclusion in SCD. The current findings also highlight the therapeutic potential of targeting the platelet-inflammasome-dependent innate immune pathway to prevent acute chest syndrome.
-
Am. J. Respir. Crit. Care Med. · Jan 2020
Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies.
Rationale: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (COPD). IFN-β is a key component of the innate immune response to viral infection. To date, studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations. ⋯ IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs. Conclusions:In vitro modeling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.
-
Am. J. Respir. Crit. Care Med. · Jan 2020
Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.
Rationale: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux. Objectives: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations. ⋯ We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations. Conclusions: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.