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Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation

2023; Frontiers Media; Volume: 14; Linguagem: Inglês

10.3389/fimmu.2023.1274147

1664-3224

Olivia K. Favor, Lichchavi D. Rajasinghe, Kathryn A. Wierenga, Krishna Rao Maddipati, Kin Sing Stephen Lee, Andrew J. Olive, James J. Pestka,

Eicosanoids and Hypertension Pharmacology

Introduction Phagocytosis of inhaled crystalline silica (cSiO 2 ) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO 2 -triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO 2 -induced eicosanoids. Methods We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO 2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction. Results DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO 2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO 2 -induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO 2 elicited marked IL-1α, IL-1β, and TNF-α release after 1.5 and 4 h of cSiO 2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO 2 -triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs. Discussion FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO 2 -triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.