LOX (Lipoxygenase)-dependent Oxylipins Are Associated With Mortality in Viral Acute Respiratory Distress Syndrome

Rationale: Acute respiratory distress syndrome (ARDS) is an inflammatory lung injury defined by hypoxic respiratory failure. ARDS severity, which predicts mortality, is graded by the degree of hypoxemia and may reflect the extent of alveolar inflammation. However, mechanisms driving disease severity are not fully understood. Polyunsaturated fatty acids (PUFAs), integral components of the cellular membrane, impact inflammatory signaling via their downstream metabolites, called oxylipins. Classically, n-3 PUFAs and oxylipins are considered anti-inflammatory and pro-resolving, while n-6 PUFAs and oxylipins are inflammatory, but this paradigm is overly simplistic. PUFA metabolism to oxylipins can occur enzymatically via lipoxygenases (LOX). Specifically, LOX-dependent oxylipins of the n-6 PUFA Arachidonic Acid (AA) include hydroxyeicosatetraenoic acids (HETEs), while n-3 PUFA LOX-mediated metabolites include Eicosapentaenoic Acid (EPA)-derived hydroxyeicosapentaenoic acids (HEPEs), and Docosahexaenoic Acid (DHA)-derived hydroxydocosahexanoic acids (HDoHEs). While ARDS impacts LOX activity and oxylipin production, their role in ARDS severity is unknown. Therefore, we hypothesize that LOX-dependent oxylipin production is associated with ARDS severity and mortality. Methods: Using our institutional ICU biorepository of biospecimen, demographic, and clinical data, we performed a pilot analysis of patients with ARDS from plasma collected within 24 hours of ICU admission. For this analysis, we assessed n-3 and n-6 PUFAs as well as downstream oxylipins via LC-MS/MS in 20 ARDS patients, matched for age, sex, and BMI, and compared these to ARDS outcomes. Results: Our cohort had a mean age of 64.7 years, mean BMI of 28.2 kg/m2, 45% (9/20) were female, and 95% (19/20) had COVID-19 ARDS. Mortality and disease severity (PaO2/FiO2) were measured as outcomes variables. All patients had moderate to severe ARDS (mean PaO2/FiO2= 112) and a mortality rate of 50% (10/20). There were no differences in parent PUFAs between those who died or survived, including AA, EPA, and DHA. Interestingly, downstream LOX-dependent metabolites 12-HETE (p=0.038), 18-HETE (p=0.0027), and 17-HDoHE (p=0.02), were increased in patients who died compared to those who survived (analysis by unpaired t-test). Non-significant trends appeared in other LOX-mediated oxylipins. Conclusions: These data indicate that select LOX-dependent oxylipins are upregulated in the systemic circulation of patients who died from viral ARDS. Future studies will evaluate if these metabolites have a mechanistic role in ARDS outcomes by regulating systemic and pulmonary inflammation, and if these oxylipins are altered in respiratory biospecimens (such as bronchoalveolar lavage fluid). Ongoing work will also evaluate if this is unique to viral ARDS or is generalizable across other etiologies of ARDS.

Duke Scholars

Author Robert Matthew Tighe Medicine, Pulmonary, Allergy, and Critical Care Medicine