Biology subjects

Morrell, E. D.

Publications and source records attributed to Morrell, E. D..

4 recordsLinked to original sources

bioRxiv2026

Airspace miR-146a levels in ventilated patients decrease with age and correlate with mortality

The acute respiratory distress syndrome is a heterogenous syndrome characterized by the rapid development of respiratory failure. Nearly 40% of patients who develop ARDS will die, and there is growing interest in identification of biomarkers to identify patients at risk of death and/or inform treatment decisions. Most prior work on biomarkers in ARDS has focused on the plasma compartment, but there is concern that circulating biomarkers may not reflect alveolar pathobiology. The anti-inflammatory microRNA-146a has been shown to be upregulated in inflammatory cells in human bronchoalveolar lavage fluid, but it is not known if these levels correspond with outcomes. We measured miR-146a expression by digital droplet PCR in human biospecimens from four different cohorts of patients with respiratory failure requiring mechanical ventilation - two plasma cohorts, one bronchoalveolar lavage cohort, and one heat moisture exchange (HME) filter fluid cohort. We found that miR-146a was detectible in plasma, bronchoalveolar lavage fluid, and HME fluid. However, only when measured in the alveolar space, was miR-146a expression significantly lower in older adults and those who died. It did not correlate with outcomes when measured in plasma. To our knowledge, this is the first report that nucleotides can be measured in HME fluid and builds upon expanding literature that circulating biomarkers may not reflect complex biology of the alveolar microenvironment during ARDS.

molecular biology↗

bioRxiv2026

Human lung γδ T cells maintain functionality during inflammatory lung disease

{gamma}{delta} T cells provide mucosal defense against infection while also contributing to tissue repair. However, data regarding the effect of the human lung environment on {gamma}{delta} T cell functionality remains limited. To address whether lung inflammation impacts {gamma}{delta} T cell functionality, we analyzed lung and matched hilar lymph node (LN) tissue from deceased donors and patients with interstitial lung disease (ILD). We performed high-parameter spectral flow cytometry to examine the expression pattern of phenotypic biomarkers and assess ex vivo function. We identified lung-specific enrichment of {gamma}{delta} T cells with an effector memory phenotype relative to matched regional LN. We then used an ex vivo stimulation approach to interrogate the capacity to protect against infection (granzyme B [GzmB], interferon-{gamma} [IFN{gamma}] and tumor necrosis factor [TNF]) and promote epithelial cell proliferation (amphiregulin [AREG]). We found that {gamma}{delta} T cells in lung and LN from deceased donors had similar functional properties. While {gamma}{delta} T cell populations from ILD lungs largely maintained cytokine production capacity, expression was diminished relative to LN counterparts. Importantly, lung {gamma}{delta} T cells maintained polyfunctional GzmB, IFN{gamma} and TNF expression across cohorts. Overall, we report human lung {gamma}{delta} T cells are regionally distinct with conserved functionality in a fibrotic environment.

immunology↗

bioRxiv2026

Heterogeneous causes of acute respiratory distress syndrome correlate with distinct peripheral polyunsaturated fatty acid metabolites

Acute Respiratory Distress Syndrome (ARDS), a heterogeneous syndrome of hypoxic respiratory failure secondary to dysregulated pulmonary inflammation, is caused by diverse insults. Because of this heterogeneity, mechanisms and treatments are difficult to study. As a treatment, n-3 polyunsaturated fatty acid (PUFA) supplementation has had mixed results. PUFAs and downstream oxylipins are important to pulmonary inflammation but are not well defined in ARDS. We hypothesized that differences in fatty acid metabolism, as measured by levels of n-3 and n-6 PUFAs and oxylipins, are associated with differences in ARDS outcomes, ARDS causes, and inflammation. To test this, PUFAs/oxylipins were measured by LC MS/MS in plasma samples from 90 patients with ARDS. Inflammatory cytokines (IL-6, IL-8) were measured by ELISA. Multivariate linear regressions modeled the relationship between PUFAs/oxylipins, inflammation, and ARDS mortality, severity and cause. Multiple n-3 and n-6 PUFA derived oxylipins were decreased in severe ARDS. We did not detect differences in PUFAs/oxylipins by mortality. PUFAs/oxylipins varied by cause of ARDS, especially between patients with sepsis and those with trauma. Furthermore, specific oxylipins were associated with IL-6 and IL-8. Based on our identification of oxylipins that vary by disease severity and injury, these metabolites should be considered as potential biomarkers and mechanisms of lung repair biomarkers. Furthermore, differences in PUFAs did not directly correlate with changes in oxylipins, suggesting differences in lipid metabolism by etiology of injury. Further consideration of differences in lipid metabolism in ARDS could identify potential subgroups that could benefit from n-3 PUFA supplementation or other therapies.

molecular biology↗

bioRxiv2024

Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis

OBJECTIVESWe aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. DESIGNIn two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes. SETTINGTwo tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center). PATIENTS186 patients with COVID-19 INTERVENTIONSNone MEASUREMENTS AND MAIN RESULTSNine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including in DOCK8 and in TMPRSS15, suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19. CONCLUSIONSBiomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19. Key PointsO_ST_ABSQUESTIONC_ST_ABSTo define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. FINDINGSIn two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects. MEANINGImmune related proteins and pathways are dysregulated in COVID-sHLH.

immunology↗