Expression of neutral endopeptidase activity during clinical and experimental acute lung injury

Abstract

BackgroundNeutral endopeptidase (NEP), an enzyme that cleaves inflammatory bioactive peptides, may play a protective role in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, its low extracellular activity hinders the precise measurement of changes that take place during ALI/ARDS. The main objective of this study was to clarify the regulation of NEP activity and its expression during ALI/ARDS.MethodsIn a clinical study, we measured plasma NEP activity in patients who developed postoperative ALI/ARDS, using a HPLC fluorometric system. In an experimental study, we induced ALI by intratracheal instillation of hydrochloric acid (HCl) or lipopolysaccharide (LPS) in mice, and similarly measured NEP activity in plasma, lung tissue, and broncho-alveolar lavage fluid (BALF). We also studied the distribution and measured the amounts of NEP protein, using immuno-histochemical and immunoblot analyses, and measured the levels of NEP mRNA, using real-time reverse transcription-polymerase chain reaction, in the lungs of mice with ALI.ResultsThe plasma NEP activity was significantly lower in patients presenting with ALI/ARDS than in controls. Similarly, the NEP activity in plasma and lung tissue was markedly lower, and lung injuries more severe in LPS- than in HCl-treated mice. In contrast, the activity of NEP in the BALF of LPS-treated mice was increased. The intratracheal instillation of LPS decreased the gene expression of NEP in the lung. Immuno-histochemical and Western immunoblot studies in mice confirmed a) the presence of NEP in the alveolar wall, a critical target in ALI/ARDS, and b) a decrease in its expression in HCl- and LPS-induced ALI.ConclusionIn this experimental and clinical study of ALI/ARDS, the activity of NEP was significantly decreased in plasma and increased in the alveolar air space.

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial

“…NEP is a membrane bound zinc metallopeptidase responsible for the metabolism and inactivation of an array of vasodilator (e.g., natriuretic peptides, adrenomedullin, vasoactive intestinal peptide) and vasoconstrictor (e.g., angiotensin II, endothelin-1 [ET-1]) peptides (Erdos & Skidgel, 1989;Kenny & Stephenson, 1988). These observations fit with the up-regulation of NEP in the pulmonary circulation during acute lung injury and heart failure (Abassi, Kotob, Golomb, Pieruzzi, & Keiser, 1995;Hashimoto, Amaya, Oh-Hashi, Kiuchi, & Hashimoto, 2010). These observations fit with the up-regulation of NEP in the pulmonary circulation during acute lung injury and heart failure (Abassi, Kotob, Golomb, Pieruzzi, & Keiser, 1995;Hashimoto, Amaya, Oh-Hashi, Kiuchi, & Hashimoto, 2010).…”

“…Indeed, preclinical evidence indicates that NEP −/− mice are less susceptible to hypoxiainduced pulmonary oedema (Irwin, Patot, Tucker, & Bowen, 2005) and that inhibition of NEP attenuates hypoxia-induced PH by potentiating the action of natriuretic peptides Thompson, Sheedy, & Morice, 1994;Winter, Zhao, Krausz, & Hughes, 1991). These observations fit with the up-regulation of NEP in the pulmonary circulation during acute lung injury and heart failure (Abassi, Kotob, Golomb, Pieruzzi, & Keiser, 1995;Hashimoto, Amaya, Oh-Hashi, Kiuchi, & Hashimoto, 2010).…”

The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19

“…In an experimental and clinical study of ARDS, the activity of NEP was significantly increased in the alveolar air space, thereby suggesting a pivotal role of this enzyme in acute lung injury [ 66 ]. In fact, it has been demonstrated that several cytokines, including IL-1α, TNF-α, transforming growth factor, IL-6, and granulocyte macrophage colony-stimulating factor, enhance activity of NEP on the surface of intact lung fibroblasts [ 67 ].…”

Study on mechanism of the Hanshi Zufei syndrome formula for COVID-19 based on network pharmacology

“…In ammation causes disease through uid transfer across cell membranes and cell layers, which leads to changes in muscle function and pain, and changes in ion channels have been detected in ALI [39]. Neutral endopeptidase is an enzyme that cleaves in ammatory bioactive peptides and plays a protective role in the pathogeneses of ALI and ARDS [40].…”