Acute Lung Injury Mechanisms and Models

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), result from direct pulmonary insults or systemic inflammatory triggers that disrupt the alveolar–capillary barrier, leading to pulmonary oedema, impaired gas exchange and refractory hypoxaemia. Central mechanisms include dysregulated activation of innate immune receptors, endothelial and epithelial barrier breakdown, excessive neutrophil recruitment and the release of pro-inflammatory mediators. Experimental models—ranging from lipopolysaccharide (LPS) instillation and acid aspiration to transfusion-related paradigms and “two-hit” combinations with mechanical ventilation—have been instrumental in delineating the temporal dynamics of injury, repair and fibrotic sequelae. These systems reveal how the balance between apoptosis and autophagy, the integrity of tight and adherens junctions, and angiogenic signalling converge to determine resolution or progression to chronic lung remodelling. A deeper mechanistic understanding of barrier failure, vascular permeability and inter-cellular cross-talk is essential for guiding the development of targeted interventions that restore homeostasis without compromising host defence.

Research from Nature Portfolio

Recent murine studies have characterised the long-term pulmonary consequences of LPS-induced injury, demonstrating that persistent downregulation of vascular endothelial growth factor (VEGF) and its receptor correlates with impaired alveolarisation, reduced exercise tolerance and altered lung compliance up to four weeks post-insult. These findings highlight angiogenic signalling as a therapeutic target for promoting tissue regeneration after ALI. Parallel work has compared intranasal and intratracheal routes of LPS administration in models of ARDS, finding that intranasal delivery elicits equivalent neutrophilic inflammation and alveolar permeability with reduced procedural variability and fewer artefacts in control animals. This non-invasive approach offers greater reproducibility and may refine preclinical screening of immunomodulatory therapies. Mechanistic investigations into eicosanoid biology have uncovered a pivotal role for thromboxane A2 in exacerbating vascular hyperpermeability via Ca2+- and Rho kinase-dependent disruption of endothelial adherens junctions, with blockade of the thromboxane receptor attenuating oedema formation without impairing neutrophil recruitment.

Acute Lung Injury Mechanisms and Models publication trend

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

Technical terms

Acute Lung Injury (ALI): A spectrum of lung damage characterised by increased alveolar–capillary permeability leading to non-cardiogenic pulmonary oedema and hypoxaemia.

Acute Respiratory Distress Syndrome (ARDS): The most severe form of ALI, defined by bilateral infiltrates, severe hypoxaemia and the need for mechanical ventilation.

Lipopolysaccharide (LPS): A component of Gram-negative bacterial cell walls used experimentally to elicit innate immune activation and lung inflammation.

Toll-like Receptor (TLR): A family of pattern recognition receptors that detect microbial components and initiate inflammatory signalling.

CD14: A co-receptor for TLR4 that binds LPS and facilitates its recognition by immune cells.

Apoptosis: Programmed cell death involving caspase activation, leading to controlled removal of damaged cells.

Autophagy: A cell-intrinsic degradation pathway that recycles cytoplasmic components and can modulate inflammatory responses.

Angiogenesis: The formation of new blood vessels, driven by factors such as VEGF, critical for tissue repair after injury.

Na/K-ATPase: A plasma-membrane ion pump that maintains electrochemical gradients and functions as a signalling receptor in lung epithelium.

Thromboxane A2 (TXA2): A lipid mediator that promotes vasoconstriction and increases vascular permeability through its receptor on endothelial cells.

References

1. Transfusion‐Related Acute Lung Injury: from Mechanistic Insights to Therapeutic Strategies. Advanced Science (2025).
2. ERRα protects against sepsis-induced acute lung injury in rats. Molecular Medicine (2023).
3. The Na/K-ATPase role as a signal transducer in lung inflammation. Frontiers in Immunology (2024).
4. Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways. Scientific Reports (2022).
5. Intranasal versus intratracheal exposure to lipopolysaccharides in a murine model of acute respiratory distress syndrome. Scientific Reports (2021).
6. Capturing the multifactorial nature of ARDS – “Two‐hit” approach to model murine acute lung injury. Physiological Reports (2018).
7. Thromboxane A2 exacerbates acute lung injury via promoting edema formation. Scientific Reports (2016).