A lipid mediator hepoxilin A3 is a natural inducer of neutrophil extracellular traps in human neutrophils.

David N Douda,Nades Palaniyar,Hartmut Grasemann,Cecil Pace-Asciak

doi:10.1155/2015/520871

David N Douda, Nades Palaniyar + Show 2 more

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https://doi.org/10.1155/2015/520871

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Abstract

Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT-3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases.

Highlights

In infected and inflamed tissues, recruited neutrophils release neutrophil extracellular traps (NETs) [1]
It is known that NETs directly cause host cell death [5] and are directly linked to the pathogenesis of a number of lung disorders including transfusion related acute lung injury (TRALI) [6, 7], ventilator induced lung injury (VILI) [8], pneumonia [9, 10], and cystic fibrosis (CF) [11]
Using DPI (20 μM), a specific inhibitor of NADPH oxidase (NOX), we demonstrate that Hepoxilin A3 (HxA3)-induced NETosis is NOX-dependent at lower concentrations of HxA3 but becomes NOX-independent at higher doses of HxA3

Summary

Introduction

In infected and inflamed tissues, recruited neutrophils release neutrophil extracellular traps (NETs) [1]. It is known that NETs directly cause host cell death [5] and are directly linked to the pathogenesis of a number of lung disorders including transfusion related acute lung injury (TRALI) [6, 7], ventilator induced lung injury (VILI) [8], pneumonia [9, 10], and cystic fibrosis (CF) [11]. The precise mechanisms leading to the excess neutrophil recruitment, activation, and NET production are not clearly understood. The negative impact of NETs demonstrated in a variety of inflammatory disorders illustrates the need to better understand NETosis and its signaling pathways and physiological mechanisms in regulating NETosis in health

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