Neutrophil Extracellular Traps as Mediators of Acute Lung Injury: Bridging Clinical and Preclinical Evidence

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are multifaceted clinical conditions characterized by uncontrolled inflammatory responses and compromised integrity of the alveolar-capillary barrier. The lack of specific diagnostic tests and effective pharmacologic therapies for ARDS reflects its underlying biological heterogeneity. In sepsis, the excessive formation of neutrophil extracellular traps (NETs) contributes to ALI pathogenesis by inducing endothelial injury, increasing vascular permeability, and amplifying pulmonary inflammation. This meta-analysis integrates findings from clinical and preclinical studies to elucidate disease pathogenesis and inform diagnostic strategies.

A systematic search of PubMed, Google Scholar, and the Cochrane Library was conducted following predefined inclusion and exclusion criteria. The primary outcome measure was the standardized mean difference with a 95% confidence interval, assessed using a random-effects model.

We identified a significant upregulation of NETs and their related components, including myeloperoxidase (MPO), the MPO-DNA complex, neutrophils, citrullinated histone H3 (citH3), cell-free DNA (cfDNA), double-stranded DNA (dsDNA), and peptidylarginine deiminase 4 (PAD4) in preclinical models. Furthermore, we validated the elevated expression of NETs, cfDNA, dsDNA, and the MPO-DNA complex in patients with ALI/ARDS.

This meta-analysis identified key NET-associated biomarkers that are dysregulated in both patients with ALI and experimental models. These biomarkers are involved in disease pathophysiology and have the potential to serve as diagnostic indicators. These outcomes contribute to a deeper understanding of NET-mediated mechanisms in ALI and support the need for further research on NET-targeted diagnostic approaches and therapeutic strategies.