Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing Arginase 1 (ARG1) serves as a substrate for proline and collagen synthesis by lung fibroblasts.

Mechanisms of Lung Crosstalk with End-Organs: .

Session V of the inaugural biennual Research Symposium on Pulmonary Injury and Repair of the Endothelium (ReSPIRE) showcased cutting-edge research on pulmonary endothelial crosstalk with end-organs and its role in vascular disease. Growing evidence suggests that communication between injured organs and distal vascular beds plays a critical role in the pathogenesis of complex conditions such as sepsis, acute respiratory distress syndrome, pulmonary arterial hypertension, and heart failure with preserved ejection fraction. Circulating mediators-including heparan sulfate fragments, pro-inflammatory cytokines, mitochondrial damage-associated molecular patterns, bone morphogenetic protein 9, bile acids, and nitric oxide-have emerged as key factors linking pulmonary endothelial dysfunction to neural impairment, acute kidney injury, subclinical liver injury, and left-sided heart disease.

Heterogeneity in association of myocardial injury and mortality in sepsis or acute respiratory distress syndrome by subphenotype: a retrospective study.

Rationale: Myocardial injury is common in acute respiratory distress syndrome (ARDS) and sepsis and associated with increased mortality. Two latent class analysis derived subphenotypes are associated with differential risk of mortality in these populations, though the association of troponin-I with mortality within each subphenotype is unknown.

Methods: The derivation (n = 597 in EARLI) and validation (n = 452 in VALID) cohorts consisted of patients with sepsis or ARDS admitted to the ICU and enrolled in two separate prospective observational studies.

Host-Microbe Multiomic Profiling Predicts Mortality in Sepsis.

Rationale: Sepsis is a leading cause of mortality and involves a dysregulated host response to infection. Host and microbe have historically been considered independently in studies of sepsis, limiting our understanding of key relationships driving mortality.

Objectives: We sought to identify host and microbial factors associated with sepsis mortality and build prognostic classifiers.

Treatment with Allogenic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome: A Double-Blind, Placebo-controlled, Multi-Center, Phase 2b Clinical Trial (STAT).

Background: Prior clinical trials established the safety, but not the efficacy of bone marrow-derived mesenchymal stromal cells (MSCs) in the acute respiratory distress syndrome (ARDS).

Methods: We conducted a prospective, double-blind, multi-center randomized phase 2b clinical trial of one dose of intravenous MSCs (10 x 10/kg predicted body weight) versus placebo in 120 ventilated patients with ARDS (PaO/FiO < 250 mmHg). The primary endpoint was change in oxygenation index (OI) over 36 hours from baseline.

Approaches for establishing trust and alleviating stress during the surrogate informed consent process for critical care research.

Background: Trust with researchers is a consideration among surrogate decision makers (SDMs) who are approached to provide consent for research participation on behalf of critically ill patients. However, little is known about strategies that researchers can use to build trust with SDMs and alleviate stress when making these decisions.

Research Question: What are the best approaches to building trust and alleviating stress that can be used in the surrogate informed consent process?

Study Design And Methods: A convergent parallel mixed-methods study including surveys, focus groups, and semi-structured interviews with principal investigators (PIs), research coordinators (RCs), SDMs, and critically ill patients who were approached for participation in a critical care research clinical trial.

Biologic Mechanisms Underlying the Heterogeneous Response to Tight Glycemic Control among Differentially Inflamed Patients in the HALF-PINT Trial.

Tight glycemic control (TGC) with insulin has not consistently shown benefit in critically ill patients. We previously reported that the subset of children with a hyperinflammatory subphenotype benefited from TGC in the HALF-PINT (Heart and Lung Failure - Pediatric Insulin Titration) study of hyperglycemic children with heart and lung failure and the IIT-SBPP (Intensive Insulin Treatment - Severely Burned Pediatric Patients) study in severely burned pediatric patients. However, whether this effect was mediated through a reduction in inflammation or some other biologic process is not fully understood.

The lectin-like domain of TNF reduces pneumonia-induced injury in the perfused human lung.

Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection.

The Performance of the Surrogate Informed Consent Process for Critical Care Research: A Multi-Modal Study of Investigators, Coordinators, Surrogates, and Patients.

Background: Although surrogates are often required to participate in the informed consent process for critical care research, how to best engage surrogates in this process remains unclear.

Research Question: What are the best practices for conducting the surrogate informed consent processes for critical care research?

Study Design And Methods: This mixed-methods study was performed across academic medical centers located in the United States. It included quantitative surveys with open-ended questions, focus groups, and semi-structured interviews with principal investigators (PIs), research coordinators (RCs), and surrogate decision makers (SDMs) who were approached about a critical care research clinical trial and, when possible, the patient who had been critically ill.

Minimalistic Transcriptomic Signatures Permit Accurate Early Prediction of COVID-19 Mortality.

Background: Predicting mortality risk in patients with COVID-19 remains challenging, and accurate prognostic assays represent a persistent unmet clinical need. We aimed to identify and validate parsimonious transcriptomic signatures that accurately predict fatal outcomes within 48 hours of hospitalization.

Methods: We studied 894 patients hospitalized for COVID-19 across 20 US hospitals and enrolled in the prospective Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) with peripheral blood mononuclear cells (PBMC) and nasal swabs collected within 48 hours of admission.

Anti-CD14 treatment in patients with severe COVID-19: Clinical and biological effects in a Phase 2 randomized open-label adaptive platform clinical trial.

Background And Research Question: CD14-dependent innate immunity contributes to poor outcomes in COVID-19 pneumonia. We tested the clinical and biological efficacy of a blocking monoclonal antibody to CD14 (IC14) for treatment of severe COVID-19 pneumonia and the utility of a biomarker of CD14 pathway activation in predicting outcome.

Study Design And Methods: We report a preplanned secondary analysis of the I-SPY COVID Trial, which enrolled hospitalized patients with severe COVID-19 pneumonia at 19 medical centers in the U.

Plasma Soluble Intercellular Adhesion Molecule-1 Has a Central Role in Biomarker Network Analysis and Is Associated With Poor Outcomes in Two Distinct Pediatric Cohorts of Acute Respiratory Distress Syndrome and Acute Respiratory Failure.

Objectives: Intercellular adhesion molecule-1 (ICAM-1) is a glycoprotein expressed on immune, endothelial, and epithelial cells. In the setting of inflammation, it becomes upregulated and spliced into a soluble form (soluble ICAM-1 [sICAM-1]). This study examined the association of sICAM-1 with clinical outcomes in two large pediatric cohorts with acute respiratory distress syndrome (ARDS) and acute respiratory failure (ARF) and examined the relationships between sICAM-1 and other protein biomarkers utilizing network analysis to contextualize its role in ARDS pathophysiology.

Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury.

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear.

A randomized trial of open lung protective ventilation compared to conventional mechanical ventilation in deceased organ donors.

Background: We conducted a randomized trial of open lung protective ventilation (OLPV) compared to conventional ventilation (CV) in deceased donors. The primary outcome was lung utilization for transplantation.

Methods: Eligible donors were ≥13 years with PaO/FiO between 150 and 400 mmHg.

Elastance May Determine the Neuromuscular Blockade Effect on Mortality in Acute Respiratory Distress Syndrome.

Patients with acute respiratory distress syndrome (ARDS) have a reduction in functional lung volume that results in increased respiratory system elastance (Ers); however, the extent of this increase varies by patient. Patients with high Ers are at risk of excess lung-distending pressures and may derive greater clinical benefit from neuromuscular blockade (NMB). We sought to evaluate whether the effect of early NMB administration on mortality varies according to baseline physiological and biological biomarkers of lung injury, including Ers.

Acute respiratory distress vs healthy lung environments differently affect mesenchymal stromal cell extracellular vesicle miRNAs.

The acute respiratory distress syndrome (ARDS) inflammatory environment alters mesenchymal stromal cell (MSC) gene and protein expression but effects on microRNA (miRNA) content of MSC-extracellular vesicle (EVs) remain unknown. To assess this, sequencing analysis of EV-miRNAs prepared from human bone marrow-derived MSCs (hMSCs) exposed ex vivo to bronchoalveolar lavage fluid (BALF) from ARDS patients or healthy volunteers (HV) identified a number of differentially expressed miRNAs. Discriminant, differential expression, and functional enrichment analyses identified 14 miRNAs significantly changed following ARDS versus HV BALF exposure.

Temporal Transitions of the Hyperinflammatory and Hypoinflammatory Phenotypes in Critical Illness.

Systemic molecular phenotypes of critical illness are prognostically informative, yet their temporal kinetics and implications of changing phenotypes remain incompletely understood. To determine the temporal nature of the Hyperinflammatory and Hypoinflammatory phenotypes and assess the impact of transition between the phenotypes on mortality. We used data from one prospective observational cohort (MARS [Molecular Diagnosis and Risk Stratification of Sepsis]) and two randomized controlled trials in acute respiratory distress syndrome (ALVEOLI [Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury]) and sepsis (CLOVERS [Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis]).

Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia.

Secondary bacterial pneumonia (2°BP) is associated with significant morbidity following respiratory viral infection, yet remains incompletely understood. In a prospective cohort of 112 critically ill adults intubated for COVID-19, we comparatively assess longitudinal airway microbiome dynamics and the pulmonary transcriptome of patients who developed 2°BP versus controls who did not. We find that 2°BP is significantly associated with both mortality and corticosteroid treatment.

Pneumothoraces Associated With Vaping Cannabis Concentrate.

Vaping-associated spontaneous pneumothorax (VASP) is a new diagnosis created to describe spontaneous pneumothorax associated with the use of vape devices. We describe a case of bilateral VASP in a previously healthy 15-year-old male who was vaping cannabis concentrate. This is the first case report of VASP involving the sole usage of cannabis concentrate.