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The following is a summary of “Heme-induced lung injury in human precision-cut lung slices: a new model for acute lung injury,” published in the April 2025 issue of Respiratory Research by Kewalramani et al.

Acute respiratory distress syndrome (ARDS) remains a life-threatening condition characterized by high morbidity and mortality, with no targeted pharmacological therapy currently available. One major barrier to drug development for ARDS is the lack of reliable and physiologically relevant human models that accurately replicate the pathophysiological features of the syndrome. Emerging evidence has implicated elevated levels of circulating heme—a pro-oxidant molecule released during hemolysis—as a potential contributor to ARDS severity and outcome. This study sought to investigate the pathological role of free heme in ARDS and to establish a human-based ex vivo model using precision-cut lung slices (PCLS) exposed to heme, thereby enabling deeper mechanistic insights and potential therapeutic screening. 

Serum samples from patients diagnosed with COVID-19-associated ARDS were compared to those of healthy controls to quantify heme levels, expression of its catabolic enzyme heme oxygenase-1 (HO-1), and circulating pro-inflammatory cytokines. Subsequently, human PCLS were exposed to varying concentrations of heme, and responses were analyzed through assessments of cell viability, membrane integrity, gene expression profiling, and proteomic analyses via ELISA and mass spectrometry. To mimic bacterial co-infection, PCLS were also co-treated with lipopolysaccharide (LPS) to evaluate any additive effects on cytotoxicity. Clinical data revealed that patients with COVID-19 and ARDS exhibited significantly elevated circulating heme and HO-1 levels relative to controls, alongside increased systemic inflammatory cytokines. 

In the ex vivo model, heme exposure led to dose-dependent cell death, activation of pro-inflammatory signaling pathways, and remodeling of the extracellular matrix. Transcriptomic and proteomic analyses identified 27 overlapping biomarkers significantly upregulated in response to heme (log2 fold change > 1, adjusted p < 0.05), the majority of which were associated with inflammation. These same inflammatory mediators were also found to be elevated in patient blood samples, establishing a strong parallel between the ex vivo model and clinical observations. Interestingly, the addition of LPS did not exacerbate heme-induced cytotoxicity, suggesting that heme alone is a potent mediator of lung injury. Overall, this study demonstrates that heme-induced inflammation and cytotoxicity in human PCLS faithfully recapitulates key aspects of ARDS pathogenesis observed in patients, particularly those with viral-induced lung injury such as COVID-19. 

These findings support the use of heme-stimulated PCLS as a novel and physiologically relevant ex vivo model for acute lung injury, providing a valuable tool for mechanistic studies and preclinical evaluation of candidate therapeutics targeting ARDS.

Source: respiratory-research.biomedcentral.com/articles/10.1186/s12931-025-03191-z