Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma

Abstract

Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (5-LO) inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes, and epithelial cells, and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated in part by inhibition of eosinophil-derived LTB4. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, including those with isolated eosinophilic inflammation, and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC, and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all, stimuli. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.

Pathogenetic profiling of COVID-19 and SARS-like viruses

“…Another gene Abl2 is important for cell entry and replication of SARS-like viruses [ 47 , 48 ]. Furthermore, LTB4 is highly prevalent in type 1 diabetic patients, and overexpression of this gene triggers acute asthma attacks in SARS-related diseases [ 61 , 62 ]. This also explains the increased susceptibility of diabetic patients to COVID-19.…”

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…Interestingly, a recent report by Pal et al clearly describes that, even though LTB 4 production has traditionally been attributed to neutrophils and alveolar macrophages, eosinophils are actually a major source of LTB 4 . The authors demonstrate that human eosinophils isolated from patients with severe asthma express the enzyme LTA 4 hydrolase and produce LTB 4 in response to stimuli [ 175 ].…”

The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders

“…For example, both levels of 5-LO and LTA 4 H in the airways and the number of circulating neutrophils are higher in patients with asthma than in those without [55,56]. Increased levels of LTB 4 are detected in the blood, BAL fluid [57], and exhaled breath condensate (EBC) [58,59] from children and adolescents with asthma. In contrast to CysLTs, which are potent mediators of bronchoconstriction [48], LTB 4 is a proinflammatory mediator that has a major effect on recruitment, activation, and survival of myeloid leukocytes [60].…”