Inflammation-driven mitochondrial dysfunction and ROS accumulation orchestrate pulmonary fibrotic remodeling in sepsis.

Summary

Using integrated multi-omics, animal models, and single-cell/bulk transcriptomics, the authors show that the lung undergoes pronounced immune amplification and mitochondrial dysfunction during early inflammation, activating profibrotic signaling in sepsis. Six ROS-regulatory mitochondrial genes correlate with clinical outcomes, and sustained TNF-α/IL-1β drives ROS overload that reprograms fibroblasts.

Key Findings

• Lung shows stronger immune amplification and more severe mitochondrial dysfunction than other organs during early inflammation, initiating fibrotic signaling in the acute phase.
• Six mitochondrial ROS-regulatory genes (Bcl2l1, Gsr, Msrb3, AA467197, Stom, Sod2) correlate with clinical outcomes in sepsis.
• Persistent TNF-α/IL-1β overexpression drives ROS activation; ROS overload directly damages cells and reprograms fibroblasts in vitro.
• Single-cell and bulk transcriptomics reveal altered immune–parenchymal intercellular communication in septic lungs.

Clinical Implications

Early modulation of ROS and upstream cytokines (TNF-α/IL-1β), and monitoring of identified mitochondrial genes, could enable prevention or attenuation of post-sepsis pulmonary fibrosis.

Limitations

• Preclinical design without interventional human validation limits direct clinical translation.
• Potential species and model (inflammation/sepsis) differences; therapeutic efficacy not tested in vivo.

Future Directions

Validate mitochondrial-ROS and cytokine axes in human sepsis cohorts; test ROS/mitochondria-targeted and anti-cytokine interventions to prevent post-sepsis pulmonary fibrosis.