Candidate genetic and multi-omics determinants potentially contributing to Macklin effect development in acute respiratory distress syndrome: A narrative review.

BACKGROUND

Acute respiratory distress syndrome (ARDS) is a complex and heterogeneous clinical syndrome characterized by diffuse alveolar damage, severe hypoxemia, and a high risk of respiratory complications. Among these, the Macklin effect has emerged as an early radiological sign associated with the subsequent development of barotrauma. Although several genetic and molecular factors have been implicated in ARDS susceptibility and progression, their potential contribution to the biological processes underlying Macklin effect development remains largely unexplored.

OBJECTIVE

This review aims to examine current evidence on genetic susceptibility factors, molecular biomarkers, and multi-omics signatures involved in ARDS pathophysiology, with particular attention to mechanisms that may increase alveolar fragility and predispose to the development of the Macklin effect.

METHODS

A narrative review of the literature was conducted, focusing on studies investigating genetic polymorphisms, inflammatory pathways, transcriptomic profiles, proteomic biomarkers, and metabolomic alterations associated with ARDS severity, tissue injury, and pulmonary complications.

RESULTS

Available evidence indicates that genetic variants involved in innate immunity, inflammatory signaling, and endothelial barrier regulation, including polymorphisms in TLRs, IL-1B, TNF-α, and S1PR3, contribute to interindividual variability in ARDS susceptibility and clinical outcomes. Multi-omics studies have identified several biomarkers, including TIMP1, MMP8, PTX3, and CCL2, that are consistently associated with dysregulated inflammation, extracellular matrix remodeling, immune cell recruitment, and epithelial-endothelial barrier dysfunction. These mechanisms are biologically plausible contributors to progressive alveolar injury and increased susceptibility to air leak syndromes. In parallel, molecular profiling studies have identified distinct ARDS subphenotypes associated with differences in disease severity, ventilator dependence, and mortality.

CONCLUSIONS

To date, no genetic or molecular biomarkers have been specifically validated as predictors of Macklin effect development. Nevertheless, the available literature supports the existence of molecular pathways linking inflammation, tissue remodeling, and barrier dysfunction to processes that may facilitate alveolar rupture and air dissection. Further prospective studies integrating molecular profiling, radiological findings, and clinical outcomes are needed to determine whether these candidate biomarkers can improve risk stratification and prediction of barotrauma in patients with ARDS.