Introduction Eicosanoids are bioactive lipids with roles in airway remodeling, smooth muscle hypertrophy, emphysema and pulmonary fibrosis via inflammatory pathways. Specific eicosanoids have been associated with diseases like asthma and pulmonary fibrosis, yet their broader associations with lung function remain unclear. We investigated associations of eicosanoids and related metabolites with early changes in lung function and structure.

Methods We comprehensively profiled >250 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study with independent validation in the Framingham Heart Study (FHS). We performed cross-sectional analysis of associations between metabolites and lung function as assessed by spirometry and quantitative computed tomography (CT) measures.

Results Among 3384 MESA Lung participants (mean age 63±10 years, 51% women), 51 metabolites were associated with lung function (22 with % predicted FEV1, 18 with % predicted FVC, and 25 with FEV1/FVC), with 24 validated in FHS. Of these, 27 were associated with obstructive physiology, including linoleic acid derivatives (9-HODE) and other long-chain fatty acids (LCFAs, hydroxyhexadecanoic and hydroxyoctadecanoic acids) associated with higher odds. Fourteen metabolites were associated with restrictive physiology, including LTB3 and its analog associated with lower odds, and omega-3 fatty acids (EPA, stearidonic acid) associated with higher odds.

Conclusions Specific eicosanoids and eicosanoid-related metabolites including linoleic acid derivatives and LCFAs were associated with obstructive, and leukotrienes and omega-3 fatty acids with restrictive physiology. These findings highlight bioactive lipids involved in pro- and anti-inflammatory pathways as potential influencers of lung function and may be future therapeutic targets.

Take Home Message We identified eicosanoid metabolites associated with pulmonary function testing measurements and several that are associated with altered odds of obstructive and restrictive lung physiologies in a cohort MESA participants, with validation in FHS.

M. Jain currently holds equity and a leadership position at Sapient Bioanalytics, LLC, and is engaged in research related to the current study. All other authors have nothing to disclose.

Dr. Ho was supported by grants from the NIH (R01 HL140224, R01 HL160003, R01 HL168889, K24 HL153669). Dr. Alotaibi was supported by grant K08HL166950. This work was partially supported by the National Heart, Lung, and Blood Institute (NHLBI) (Framingham Heart Study: contract N01-HC25195 and HHSN268201500001I; Multi-Ethnic Study of Atherosclerosis: contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169; MESA Lung R01-HL130506, R01-HL077612, RC1-HL100543, R01-HL093081, and R01-HL121270). The Multi-Ethnic Study of Atherosclerosis was also supported by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). A full list of participating Multi-Ethnic Study of Atherosclerosis investigators and institutions can be found at https://www.mesa-nhlbi.org. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRBs of Multi-Ethnic Study of Atherosclerosis, Framingham Heart Study, and Beth Israel Deaconess Medical Center gave ethical approval for this work.

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Funding: Dr. Ho was supported by grants from the NIH (R01 HL140224, R01 HL160003, R01 HL168889, K24 HL153669). Dr. Alotaibi was supported by grant K08HL166950.

This work was partially supported by the National Heart, Lung, and Blood Institute (NHLBI) (Framingham Heart Study: contract N01-HC25195 and HHSN268201500001I; Multi-Ethnic Study of Atherosclerosis: contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169; MESA Lung R01-HL130506, R01-HL077612, RC1-HL100543, R01-HL093081, and R01-HL121270). The Multi-Ethnic Study of Atherosclerosis was also supported by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). A full list of participating Multi-Ethnic Study of Atherosclerosis investigators and institutions can be found at https://www.mesa-nhlbi.org. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions.

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services.

Conflict of Interest: M. Jain currently holds equity and a leadership position at Sapient Bioanalytics, LLC, and is engaged in research related to the current study. All other authors have nothing to disclose.

All data produced in the present study are available upon reasonable request to the authors.