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Heterogeneous Causes of Acute Respiratory Distress Syndrome Correlate With Distinct Peripheral Polyunsaturated Fatty Acid Metabolites.

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Title: Heterogeneous Causes of Acute Respiratory Distress Syndrome Correlate With Distinct Peripheral Polyunsaturated Fatty Acid Metabolites.
Authors: Leuenberger LA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Bednash JS; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Schott E; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Mikacenic C; Benaroya Institute, Seattle, Washington, USA., Morrell ED; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA., Richardson C; Center for Biostatistics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Fussner LA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Horowitz JC; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Mallampalli RK; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA., Shaikh SR; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Tighe RM; Department of Medicine, Duke University, Durham, North Carolina, USA., Gowdy KM; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2026 May 31; Vol. 40 (10), pp. e71850.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE
Imprint Name(s): Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley
Original Publication: [Bethesda, Md.] : The Federation, [c1987-
MeSH Terms: Respiratory Distress Syndrome*/metabolism , Respiratory Distress Syndrome*/etiology , Respiratory Distress Syndrome*/blood , Fatty Acids, Unsaturated*/metabolism , Fatty Acids, Unsaturated*/blood , Fatty Acids, Omega-3*/metabolism , Fatty Acids, Omega-3*/blood, Oxylipins/blood ; Oxylipins/metabolism ; Interleukin-6/blood ; Fatty Acids, Omega-6/blood ; Fatty Acids, Omega-6/metabolism ; Interleukin-8/blood ; Inflammation/metabolism ; Cytokines/blood ; Humans ; Female ; Male ; Middle Aged ; Aged ; Adult
Abstract: Acute Respiratory Distress Syndrome (ARDS), a heterogeneous syndrome of hypoxic respiratory failure secondary to dysregulated pulmonary inflammation, is caused by diverse insults. This heterogeneity presents challenges for mechanistic and therapeutic research, as evidenced by conflicting results from trials of n-3 polyunsaturated fatty acid (PUFA) supplementation for ARDS. 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, inflammation, and causes. To test this, PUFAs/oxylipins were measured by LC MS/MS in plasma samples from 90 patients with ARDS. Pro-inflammatory cytokines and chemokines IL-6 and IL-8 were measured by ELISA. Multivariable 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. As we observed that oxylipins varied by disease severity and underlying cause, these metabolites may function as biomarkers and suggest dysregulated mechanisms of lung repair. Furthermore, while oxylipins are derived from PUFAs, differences in PUFAs did not directly correlate with changes in oxylipins, suggesting altered lipid metabolism as a mechanism. Further consideration of differences in lipid metabolism in ARDS could identify subgroups with differential responses to n-3 PUFA supplementation or other therapies.
(© 2026 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Comments: Update of: bioRxiv. 2026 Jan 10:2026.01.09.698377. doi: 10.64898/2026.01.09.698377.. (PMID: 41542631)
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Grant Information: R01-HL081784 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01-HL097376 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01 HL171164 United States HL NHLBI NIH HHS; 2024 Young Investigator Grant CHEST Foundation (CHEST Philanthropy); R01-ES034350 HHS|National Institutes of Health (NIH); L70 HL175819 United States HL NHLBI NIH HHS; P30-DK056350 HHS|National Institutes of Health (NIH); S10OD032292 HHS|National Institutes of Health (NIH); S10RR027926 HHS|National Institutes of Health (NIH); R01-HL096376 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01-ES031378 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); K23-HL168328 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); T32-HL166132 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); RO1-HL171164 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); Research Grant in Critical Care CHEST Foundation (CHEST Philanthropy); R01-HL169265 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); UM1TR004548 HHS|NIH|National Center for Advancing Translational Sciences (NCATS); L30 HL175819 United States HL NHLBI NIH HHS; K08-HL169725 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); T32 HL166132 United States HL NHLBI NIH HHS; R01-HL149676 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI)
Contributed Indexing: Keywords: acute lung injury; acute respiratory distress syndrome; inflammation; lipidomics; lipids; lipids/oxidation; omega‐3 fatty acids; oxylipins; pulmonary inflammation
Substance Nomenclature: 0 (Fatty Acids, Unsaturated)
0 (Oxylipins)
0 (Interleukin-6)
0 (Fatty Acids, Omega-6)
0 (Interleukin-8)
0 (Fatty Acids, Omega-3)
0 (Cytokines)
Entry Date(s): Date Created: 20260513 Date Completed: 20260716 Latest Revision: 20260916
Update Code: 20260916
PubMed Central ID: PMC13170735
DOI: 10.1096/fj.202504787RR
PMID: 42126874
Database: MEDLINE
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  Data: Heterogeneous Causes of Acute Respiratory Distress Syndrome Correlate With Distinct Peripheral Polyunsaturated Fatty Acid Metabolites.
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  Data: <searchLink fieldCode="AU" term="%22Leuenberger+LA%22">Leuenberger LA</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Bednash+JS%22">Bednash JS</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Schott+E%22">Schott E</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Mikacenic+C%22">Mikacenic C</searchLink>; Benaroya Institute, Seattle, Washington, USA.<br /><searchLink fieldCode="AU" term="%22Morrell+ED%22">Morrell ED</searchLink>; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.<br /><searchLink fieldCode="AU" term="%22Richardson+C%22">Richardson C</searchLink>; Center for Biostatistics, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Fussner+LA%22">Fussner LA</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Horowitz+JC%22">Horowitz JC</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Mallampalli+RK%22">Mallampalli RK</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.<br /><searchLink fieldCode="AU" term="%22Shaikh+SR%22">Shaikh SR</searchLink>; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Tighe+RM%22">Tighe RM</searchLink>; Department of Medicine, Duke University, Durham, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Gowdy+KM%22">Gowdy KM</searchLink>; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine and The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
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  Data: <searchLink fieldCode="JN" term="%228804484%22">FASEB journal : official publication of the Federation of American Societies for Experimental Biology</searchLink> [FASEB J] 2026 May 31; Vol. 40 (10), pp. e71850.
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– Name: SubjectMESH
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  Data: <searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome%22">Respiratory Distress Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome%22">Respiratory Distress Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome+etiology%22">etiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome%22">Respiratory Distress Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Respiratory+Distress+Syndrome+blood%22">blood</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Unsaturated%22">Fatty Acids, Unsaturated*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Unsaturated+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Unsaturated%22">Fatty Acids, Unsaturated*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Unsaturated+blood%22">blood</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Omega-3%22">Fatty Acids, Omega-3*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Omega-3+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Omega-3%22">Fatty Acids, Omega-3*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids%2C+Omega-3+blood%22">blood</searchLink><br /><searchLink fieldCode="MH" term="%22Oxylipins%22">Oxylipins</searchLink>/<searchLink fieldCode="MH" term="%22Oxylipins+blood%22">blood</searchLink> ; <searchLink fieldCode="MH" term="%22Oxylipins%22">Oxylipins</searchLink>/<searchLink fieldCode="MH" term="%22Oxylipins+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Interleukin-6%22">Interleukin-6</searchLink>/<searchLink fieldCode="MH" term="%22Interleukin-6+blood%22">blood</searchLink> ; <searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Omega-6%22">Fatty Acids, Omega-6</searchLink>/<searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Omega-6+blood%22">blood</searchLink> ; <searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Omega-6%22">Fatty Acids, Omega-6</searchLink>/<searchLink fieldCode="MH" term="%22Fatty+Acids%2C+Omega-6+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Interleukin-8%22">Interleukin-8</searchLink>/<searchLink fieldCode="MH" term="%22Interleukin-8+blood%22">blood</searchLink> ; <searchLink fieldCode="MH" term="%22Inflammation%22">Inflammation</searchLink>/<searchLink fieldCode="MH" term="%22Inflammation+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Cytokines%22">Cytokines</searchLink>/<searchLink fieldCode="MH" term="%22Cytokines+blood%22">blood</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Middle+Aged%22">Middle Aged</searchLink> ; <searchLink fieldCode="MH" term="%22Aged%22">Aged</searchLink> ; <searchLink fieldCode="MH" term="%22Adult%22">Adult</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Acute Respiratory Distress Syndrome (ARDS), a heterogeneous syndrome of hypoxic respiratory failure secondary to dysregulated pulmonary inflammation, is caused by diverse insults. This heterogeneity presents challenges for mechanistic and therapeutic research, as evidenced by conflicting results from trials of n-3 polyunsaturated fatty acid (PUFA) supplementation for ARDS. 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, inflammation, and causes. To test this, PUFAs/oxylipins were measured by LC MS/MS in plasma samples from 90 patients with ARDS. Pro-inflammatory cytokines and chemokines IL-6 and IL-8 were measured by ELISA. Multivariable 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. As we observed that oxylipins varied by disease severity and underlying cause, these metabolites may function as biomarkers and suggest dysregulated mechanisms of lung repair. Furthermore, while oxylipins are derived from PUFAs, differences in PUFAs did not directly correlate with changes in oxylipins, suggesting altered lipid metabolism as a mechanism. Further consideration of differences in lipid metabolism in ARDS could identify subgroups with differential responses to n-3 PUFA supplementation or other therapies.<br /> (© 2026 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
– Name: Comment
  Label: Comments
  Group: Commnt
  Data: Update of: bioRxiv. 2026 Jan 10:2026.01.09.698377. doi: 10.64898/2026.01.09.698377.. (PMID: <searchLink fieldCode="PM" term="%2241542631%22">41542631)</searchLink>
– Name: Ref
  Label: References
  Group: RefInfo
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  Data: R01-HL081784 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01-HL097376 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01 HL171164 United States HL NHLBI NIH HHS; 2024 Young Investigator Grant CHEST Foundation (CHEST Philanthropy); R01-ES034350 HHS|National Institutes of Health (NIH); L70 HL175819 United States HL NHLBI NIH HHS; P30-DK056350 HHS|National Institutes of Health (NIH); S10OD032292 HHS|National Institutes of Health (NIH); S10RR027926 HHS|National Institutes of Health (NIH); R01-HL096376 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); R01-ES031378 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); K23-HL168328 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); T32-HL166132 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); RO1-HL171164 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); Research Grant in Critical Care CHEST Foundation (CHEST Philanthropy); R01-HL169265 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); UM1TR004548 HHS|NIH|National Center for Advancing Translational Sciences (NCATS); L30 HL175819 United States HL NHLBI NIH HHS; K08-HL169725 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI); T32 HL166132 United States HL NHLBI NIH HHS; R01-HL149676 HHS|NIH|National Heart, Lung, and Blood Institute (NHLBI)
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  Data: <i>Keywords: </i>acute lung injury; acute respiratory distress syndrome; inflammation; lipidomics; lipids; lipids/oxidation; omega‐3 fatty acids; oxylipins; pulmonary inflammation
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        Value: 10.1096/fj.202504787RR
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        Text: English
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        StartPage: e71850
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      – SubjectFull: Oxylipins blood
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      – SubjectFull: Fatty Acids, Omega-6 metabolism
        Type: general
      – SubjectFull: Interleukin-8 blood
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      – SubjectFull: Cytokines blood
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      – SubjectFull: Humans
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      – SubjectFull: Respiratory Distress Syndrome metabolism
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      – SubjectFull: Respiratory Distress Syndrome etiology
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      – SubjectFull: Respiratory Distress Syndrome blood
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      – TitleFull: Heterogeneous Causes of Acute Respiratory Distress Syndrome Correlate With Distinct Peripheral Polyunsaturated Fatty Acid Metabolites.
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              Text: 2026 May 31
              Type: published
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