A comprehensive overview of investigational elastase inhibitors for the treatment of acute respiratory distress syndrome

ABSTRACT

Introduction

Excessive activity of neutrophil elastase (NE), the main enzyme present in azurophil granules in the neutrophil cytoplasm, may cause tissue injury and remodeling in various lung diseases, including acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), in which it is crucial to the immune response and inflammatory process. Consequently, NE is a possible target for therapeutic intervention in ALI/ARDS.

Areas covered

The protective effects of several NE inhibitors in attenuating ALI/ARDS in several models of lung injury are described. Some of these NE inhibitors are currently in clinical development, but only sivelestat has been evaluated as a treatment for ALI/ARDS.

Expert opinion

Preclinical research has produced encouraging information about using NE inhibitors. Nevertheless, only sivelestat has been approved for this clinical indication, and only in Japan and South Korea because of the conflicting results of clinical trials and likely also because of the potential adverse events. Identifying subsets of patients with ARDS most likely to benefit from NE inhibitor treatment, such as the hyperinflammatory phenotype, and using a more advanced generation of NE inhibitors than sivelestat could enable better clinical results than those obtained with elastase inhibitors.

KEYWORDS:

• Acute respiratory distress syndrome
• acute lung injury
• neutrophil elastase
• neutrophil elastase inhibitors
• sivelestat

Article highlights

• The accumulation of activated and functionally distinct neutrophils with enhanced chemotaxis, enhanced metabolic activity, delayed apoptosis, and a novel transcriptional signature is clinically and pathologically important in ARDS.

• Neutrophils release an array of proteolytic enzymes, including NE, which is the main enzyme present in azurophil granules in the neutrophil cytoplasm, is crucial to the immune response and inflammatory process, and may cause tissue injury and remodeling in ALI/ARDS.

• The growing evidence of the essential contribution of NE in the development of ALI or ARDS has moved the attention of researchers and clinicians toward the possible use of NE inhibitors in the treatment of ALI/ARDS.

• The protective effects of NE inhibitors in attenuating ALI/ARDS have been described in several models of lung injury.

• Only sivelestat, a 2nd generation NE inhibitor, has been approved for this clinical indication, limited to Japan and South Korea, due to conflicting clinical trial results and potential adverse events.

• It is advisable to conduct trials with NE inhibitors of a more advanced generation, also considering possible subsets of patients with ARDS, such as the hyperinflammatory phenotype, who are most likely to benefit from such a pharmacological approach.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.