Neutrophil Function and Acute Lung Injury Mechanisms

Neutrophils are frontline effectors of the innate immune system, rapidly recruited to pulmonary tissue in response to infection, injury or sterile inflammation. Upon activation, they release reactive oxygen species (ROS), proteolytic enzymes such as neutrophil elastase and myeloperoxidase, and form neutrophil extracellular traps (NETs). These mechanisms instigate microbial killing but also contribute to endothelial and epithelial injury when dysregulated. In acute lung injury (ALI), excessive neutrophil activation drives capillary–alveolar barrier disruption, proteinaceous oedema, surfactant dysfunction and impaired gas exchange. Chemokine cascades, adhesion molecules and complement fragments govern neutrophil trafficking, while intracellular signalling pathways such as Src family kinases, MAP kinases and calcium flux regulate degranulation and oxidative burst.

Systemic or local insults—from sepsis and aspiration to viral pneumonitis—can trigger an overwhelming neutrophilic response that amplifies pulmonary inflammation. NETosis, characterised by chromatin extrusion, further augments tissue damage through procoagulant activity and endothelial toxicity. The protease–antiprotease balance is overturned by elastase and cathepsin G, contributing to matrix degradation and alveolar collapse. Mitochondrial ROS generation and inflammasome activation potentiate cytokine release, sustaining the inflammatory milieu. Understanding these intersecting pathways is critical for devising targeted therapies that preserve host defence while limiting collateral damage.

Despite advances in supportive care, specific pharmacological interventions remain limited. Emerging strategies aim to modulate neutrophil recruitment, inhibit key proteases or ROS production, stabilise mitochondrial function and attenuate NET formation. Such approaches hold promise for reducing the global burden of ALI and its severe form, acute respiratory distress syndrome (ARDS).

Research from Nature Portfolio

Recent studies have demonstrated that small-molecule inhibitors of neutrophil elastase can restore protease–antiprotease equilibrium and reduce pulmonary oedema in lipopolysaccharide-induced lung injury models. By directly targeting elastase activity, these compounds attenuate myeloperoxidase release, lower neutrophil infiltration and improve alveolar fluid clearance, highlighting the therapeutic potential of selective protease inhibition.

Investigations into botanical-derived agents have identified an extract that suppresses superoxide anion generation and elastase release by human neutrophils through dual inhibition of Src family kinases and calcium mobilisation. This extract effectively reduces neutrophil adhesion and chemotaxis, offering a complementary anti-inflammatory approach that preserves core antimicrobial functions.

Neutrophil Function and Acute Lung Injury Mechanisms publication trend

The graph below shows the total number of articles in neutrophil function and acute lung injury mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Neutrophil extracellular traps (NETs): Web-like networks of chromatin and granular proteins expelled by activated neutrophils to ensnare pathogens.

Protease–antiprotease imbalance: Disruption of the equilibrium between proteolytic enzymes (eg, elastase) and endogenous inhibitors, leading to tissue degradation.

Reactive oxygen species (ROS): Chemically reactive molecules (eg, superoxide, hydrogen peroxide) produced by neutrophils to kill microbes but capable of inducing oxidative damage.

NADPH oxidase: Multicomponent enzyme complex that generates superoxide radicals during the respiratory burst in neutrophils.

Src family kinases: Non-receptor tyrosine kinases that regulate neutrophil degranulation, adhesion and ROS production.

Alveolar–capillary barrier: Functional interface of alveolar epithelium and capillary endothelium whose integrity is critical for fluid homeostasis and gas exchange.

References

1. GPR84 regulates pulmonary inflammation by modulating neutrophil functions. Acta Pharmacologica Sinica (2023).
2. NMDARs antagonist MK801 suppresses LPS-induced apoptosis and mitochondrial dysfunction by regulating subunits of NMDARs via the CaM/CaMKII/ERK pathway. Cell Death Discovery (2023).
3. Sirtinol Inhibits Neutrophil Elastase Activity and Attenuates Lipopolysaccharide-Mediated Acute Lung Injury in Mice. Scientific Reports (2015).
4. Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation During Infection. Frontiers in Immunology (2020).
5. Anti-inflammatory effects of Perilla frutescens in activated human neutrophils through two independent pathways: Src family kinases and Calcium. Scientific Reports (2015).