Lipoxin Generation Is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma

Abstract

Rationale: Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.Objectives: To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.Methods: Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.Measurements and Main Results: 8-Isoprostane levels in sputum supernatants were inversely related to LXA 4 in severe asthma (r = 20.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA 4 and 15-epi-LXA 4 biosynthesis by peripheral blood leukocytes. LXA 4 and 15-epi-LXA 4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA 4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited plateletactivating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA 4 100 nM], 78.3% inhibition [15-epi-LXA 4 100 nM]) and 15-epi-LXA 4 markedly inhibited tumor necrosis factora-induced increases in bronchial contraction.Conclusions: LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).

Pro-Resolving Effects of Resolvin D2 in LTD4 and TNF-α Pre-Treated Human Bronchi

“…In normal and tumoural mammary tissues, enzymes involved in lipoxin A 4 and RvD 2 synthesis are expressed, with these lipid mediators also reported to display a crucial role in oestrogen-dependent breast cancer progression [38]. In human bronchial explants, it has been demonstrated that LXA 4 mediates beneficial effects via formyl-peptide receptor 2 signalling [39]. This observation is correlated with the ability of LXA 4 to significantly inhibit the platelet-activating factor-induced increases in leukocyte-platelet aggregates and TNF-α-triggered AHR [39].…”

ALX receptor ligands define a biochemical endotype for severe asthma

“…Current anti-leukotriene drugs would not be expected to increase lipoxins in asthma. There are likely multiple factors responsible for the defective lipoxin production in SA; however, the increased oxidative stress in SA airways was recently determined to be a major cause of reduced lipoxin generation (11). In human studies, inhaled LXA 4 dampens bronchoprovocation in asthma (10) and lipoxins regulate cytokine-mediated increases in bronchial constriction induced by methacholine, histamine, and thromboxane (11).…”

“…There are likely multiple factors responsible for the defective lipoxin production in SA; however, the increased oxidative stress in SA airways was recently determined to be a major cause of reduced lipoxin generation (11). In human studies, inhaled LXA 4 dampens bronchoprovocation in asthma (10) and lipoxins regulate cytokine-mediated increases in bronchial constriction induced by methacholine, histamine, and thromboxane (11). Recently, a stable LXA 4 analog was shown to markedly decrease allergic inflammation and symptoms in patients with juvenile eczema (37).…”

“…9). Lipoxins also inhibit leukotriene-mediated prophlogistic actions, including in vivo in asthma (10), and decrease cytokine-induced human airway contractile responses (11). In peripheral blood, exhaled breath condensates, sputum, and bronchoalveolar lavage (BAL) fluid (BALF), LXA 4 levels are decreased in SA relative to non-SA (NSA) (12)(13)(14)(15), suggesting a link between defective resolution mechanisms and persistent airway inflammation in some asthma patients.…”

Future treatment for asthma

“…Recent findings have shown that the soluble epoxide hydrolase inhibitors would be of interest because they lead to the activation of endogenous pro-resolving mediators such as lipoxin A4 and epoxyeicosatrienoic acids, while at the same time inhibiting pro-inflammatory pathways [139].…”