Acute Respiratory Distress Syndrome Molecular Phenotypes Have Distinct Lower Respiratory Tract Transcriptomes

<b>Rationale:</b> Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and responses to therapy have been identified. Classification as "hyperinflammatory" or "hypoinflammatory" depends on plasma biomarker profiling. Limited data are available about the differences in the pulmonary biology of the molecular phenotypes. <b>Objectives:</b> To identify differences in the pulmonary biology of ARDS molecular phenotypes <b>Methods:</b> We compared tracheal aspirate gene expression between hyperinflammatory and hypoinflammatory phenotypes in bulk RNA sequencing (RNASeq) from coronavirus disease (COVID-19) and non-COVID-19 ARDS and single-cell RNASeq from non-COVID-19 ARDS. In a subset of subjects, we also compared plasma proteomic data. <b>Measurements and Main Results:</b> In bulk RNASeq analyses, 1,157 genes were differentially expressed (false discovery rate < 0.1) between phenotypes in non-COVID-19 ARDS, and 85 genes were differentially expressed between phenotypes in COVID-19 ARDS. Eighteen genes were reproducibly differentially expressed between phenotypes in both cohorts, including greater expression of <i>IL32</i>, <i>HSPA8</i>, and <i>PPP3CC</i> in hyperinflammatory ARDS. A total of 195 pathways were reproducibly enriched across the two cohorts by gene set enrichment analysis, including greater expression of granulopoiesis, T-cell and IFN signaling, and integrated stress response pathways in hyperinflammatory ARDS. Network analysis of single-cell RNASeq in a third group of patients identified greater T-cell signaling to other immune cells in hyperinflammatory ARDS. <b>Conclusions:</b> Hyperinflammatory and hypoinflammatory ARDS molecular phenotypes have distinct respiratory biology. Hyperinflammatory ARDS is characterized by an increased IFN-stimulated gene expression and T-cell activation in the lungs.

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Publication Details

Journal
American Journal of Respiratory and Critical Care Medicine
Published
2025-09-25
DOI
https://doi.org/10.1164/rccm.202407-1454oc
Citations
6
Primary Topic
Immune cells in cancer
Type
article
Field-Weighted Citation Impact
4.78
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article

Acute Respiratory Distress Syndrome Molecular Phenotypes Have Distinct Lower Respiratory Tract Transcriptomes

Charles Langelier, Stephanie A. Christenson, David J. Erle, Alejandra Jáuregui et al.
6 citations
American Journal of Respiratory and Critical Care Medicine
Immune cells in cancer
4.78
article

Acute Respiratory Distress Syndrome Molecular Phenotypes Have Distinct Lower Respiratory Tract Transcriptomes

Charles Langelier, Stephanie A. Christenson, David J. Erle, Alejandra Jáuregui, Lucile Neyton, Emily R. Siegel, Carolyn M. Hendrickson, Eran Mick, Matthew F. Krummel, Joseph L. DeRisi, Paula Hayakawa Serpa, Jennifer G. Wilson, Lieuwe D. J. Bos, Pratik Sinha, Michael A. Matthay, Christina Love, Manoj V. Maddali, Beth Shoshana Zha, Carolyn S. Calfee, Aleksandra Leligdowicz, Prescott G. Woodruff, Katrina Kalantar, Zoe M. Lyon, Thomas Deiss, Angela Oliveira Pisco, Rajani Ghale, Aartik Sarma, Farzad Moazed, Kirsten N. Kangelaris, Ashley Byrne, Saharai Caldera, Sidney C. Haller, Hanjing Zhuo
article en
6 citations

Abstract

<b>Rationale:</b> Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and responses to therapy have been identified. Classification as "hyperinflammatory" or "hypoinflammatory" depends on plasma biomarker profiling. Limited data are available about the differences in the pulmonary biology of the molecular phenotypes. <b>Objectives:</b> To identify differences in the pulmonary biology of ARDS molecular phenotypes <b>Methods:</b> We compared tracheal aspirate gene expression between hyperinflammatory and hypoinflammatory phenotypes in bulk RNA sequencing (RNASeq) from coronavirus disease (COVID-19) and non-COVID-19 ARDS and single-cell RNASeq from non-COVID-19 ARDS. In a subset of subjects, we also compared plasma proteomic data. <b>Measurements and Main Results:</b> In bulk RNASeq analyses, 1,157 genes were differentially expressed (false discovery rate < 0.1) between phenotypes in non-COVID-19 ARDS, and 85 genes were differentially expressed between phenotypes in COVID-19 ARDS. Eighteen genes were reproducibly differentially expressed between phenotypes in both cohorts, including greater expression of <i>IL32</i>, <i>HSPA8</i>, and <i>PPP3CC</i> in hyperinflammatory ARDS. A total of 195 pathways were reproducibly enriched across the two cohorts by gene set enrichment analysis, including greater expression of granulopoiesis, T-cell and IFN signaling, and integrated stress response pathways in hyperinflammatory ARDS. Network analysis of single-cell RNASeq in a third group of patients identified greater T-cell signaling to other immune cells in hyperinflammatory ARDS. <b>Conclusions:</b> Hyperinflammatory and hypoinflammatory ARDS molecular phenotypes have distinct respiratory biology. Hyperinflammatory ARDS is characterized by an increased IFN-stimulated gene expression and T-cell activation in the lungs.

American Journal of Respiratory and Critical Care MedicineVol. 211(12)
Western University (CA), San Francisco General Hospital (US), Berkeley College (US), City College of San Francisco (US), Palo Alto University (US), University of California, San Francisco (US), University of Toronto (CA), Washington University in St. Louis (US), Cardiovascular Institute Hospital (JP), Office of Infectious Diseases (US), University of California San Francisco Medical Center (US), Universidad Católica de Santa Fe (AR), Precision for Medicine (United States) (US), Advanced ENT and Allergy (US), Pulmonary and Allergy Associates (US), Chan Zuckerberg Initiative (United States) (US), Community Research Initiative (US), Amsterdam University Medical Centers (NL), Indiana University School of Medicine, University of San Francisco (US), University of Amsterdam (NL), University of California, Berkeley (US), Stanford University (US)
Openalex Percentile: Top 4%
Immune cells in cancer
4.78
DOIOpen Access PDFOpenAlex
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