Myeloid Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus.

Hypercapnia, elevation of the partial pressure of CO in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that elevated CO increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMØs).

Efzofitimod for the Treatment of Pulmonary Sarcoidosis.

Background: Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation.

Research Question: What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis?

Study Design And Methods: In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16.

A Novel MIP-1-Expressing Macrophage Subtype in BAL Fluid from Healthy Volunteers.

Tissue availability remains an important limitation of single-cell genomic technologies for investigating cellular heterogeneity in human health and disease. BAL represents a minimally invasive approach to assessing an individual's lung cellular environment for diagnosis and research. However, the lack of high-quality, healthy lung reference data is a major obstacle to using single-cell approaches to study a plethora of lung diseases.

Comparing Racial Differences in Emphysema Prevalence Among Adults With Normal Spirometry: A Secondary Data Analysis of the CARDIA Lung Study.

Background: Computed tomography (CT) imaging complements spirometry and may provide insight into racial disparities in respiratory health.

Objective: To determine the difference in emphysema prevalence between Black and White adults with different measures of normal spirometry results.

Design: Observational study using clinical data and spirometry from the CARDIA (Coronary Artery Risk Development in Young Adults) study obtained in 2015 to 2016 and CT scans done in 2010 to 2011.

Hypercapnia selectively modulates LPS-induced changes in innate immune and DNA replication-related gene transcription in the macrophage.

Hypercapnia, the elevation of CO in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases and is associated with increased risk of death. Recent studies have shown that hypercapnia inhibits expression of select innate immune genes and suppresses host defence against bacterial and viral pneumonia in mice. In the current study, we evaluated the effect of culture under conditions of hypercapnia (20% CO) versus normocapnia (5% CO), both with normoxia, on global gene transcription in human THP-1 and mouse RAW 264.

Epithelial cell-specific loss of function of causes a spontaneous COPD-like phenotype and up-regulates expression in mice.

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of , which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of , the receptor for SARS-CoV-2.

Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1.

Hypercapnia (HC), elevation of the partial pressure of CO in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that HC inhibits multiple macrophage and neutrophil antimicrobial functions and increases the mortality of bacterial pneumonia in mice. In this study, we show that normoxic HC increases viral replication, lung injury, and mortality in mice infected with influenza A virus (IAV).

Elevated CO regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans.

Carbon dioxide (CO) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster).

Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells.

Hypercapnia, the elevation of CO in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown.

A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression.

Hypercapnia, elevated levels of CO in the blood, is a known marker for poor clinical prognosis and is associated with increased mortality in patients hospitalized with both bacterial and viral pneumonias. Although studies have established a connection between elevated CO levels and poor pneumonia outcomes, a mechanistic basis of this association has not yet been established. We previously reported that hypercapnia inhibits expression of key NF-κB-regulated, innate immune cytokines, TNF-α, and IL-6, in LPS-stimulated macrophages in vitro and in mice during Pseudomonas pneumonia.

Dimensions and Role-Specific Mediators of Surrogate Trust in the ICU.

Objective: In the ICU, discussions between clinicians and surrogate decision makers are often accompanied by conflict about a patient's prognosis or care plan. Trust plays a role in limiting conflict, but little is known about the determinants of trust in the ICU. We sought to identify the dimensions of trust and clinician behaviors conducive to trust formation in the ICU.

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.

Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription.

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression.

Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells.

Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen.

Hypercapnia, elevated partial pressure of CO2 in blood and tissue, develops in many patients with chronic severe obstructive pulmonary disease and other advanced lung disorders. Patients with advanced disease frequently develop bacterial lung infections, and hypercapnia is a risk factor for mortality in such individuals. We previously demonstrated that hypercapnia suppresses induction of NF-κB-regulated innate immune response genes required for host defense in human, mouse, and Drosophila cells, and it increases mortality from bacterial infections in both mice and Drosophila.

Pleural Hypercarbia After Lung Surgery Is Associated With Persistent Alveolopleural Fistulae.

Background: Persistent air leak (PAL) > 5 days due to alveolopleural fistulae is a leading cause of morbidity following surgical resection. Elevated CO2 levels reportedly inhibit alveolar epithelial cell proliferation and impair wound healing in vitro. Because the injured lung surface is in direct communication with the pleural cavity, we investigated whether the pleural gaseous milieu affected lung healing.

Decreased CXCL12 is associated with impaired alveolar epithelial cell migration and poor lung healing after lung resection.

Background: Prolonged air leak (PAL) is an important cause of morbidity and mortality after lung resection, but its pathogenesis has not been elucidated. Migration of alveolar type II epithelial cells is essential for lung wound repair. Here we determined the role of C-X-C motif chemokine 12 (CXCL12) on alveolar epithelial cell migration and lung wound healing.

Pleural Gas Analysis for Detection of Alveolopleural Fistulae.

Purpose: Visual inspection (VI) of bubbles in the chest drainage unit does not differentiate a true leak of alveolopleural fistula (APF) from a false leak. We hypothesized that detection of elevated levels of carbon dioxide, increase in oxygen content, or both, in pleural gas upon the administration of supplemental oxygen would accurately identify APF.

Description: Prospective study comparing pleural gas analysis (GA) with VI to detect APF after surgical lobectomy (n = 50).