Mechanisms and therapeutics of immunometabolic reprogramming driving macrophage-ECs interactions in sepsis-associated ARDS from the gut-lung axis perspective.

Acute respiratory distress (ARDS) caused by sepsis is a critical inflammatory condition with high mortality rates in clinical settings. The gut-lung axis plays a crucial role in regulating the immune response in both the intestinal and pulmonary environments, significantly impacting the development of ARDS. Immunometabolic reprogramming, a fundamental regulator of immune cell function, has recently been shown to profoundly affect the activity of macrophages and endothelial cells (ECs), as well as their crosstalk, thereby shaping the pathogenesis of ARDS. While a great deal has been learned about the potential inflammatory pathways involved, few clinically actionable therapies are available in part due to an incomplete understanding of gut-lung crosstalk in their shared ecosystem of cells and molecules. The current review systematically advances novel insights into the immunometabolic reprogramming that influences macrophage-ECs interactions via sepsis-induced ARDS, with a specific regard to the gut-lung axis. Here, we summarize the key biochemical pathways that control immune cell phenotypes and endothelial function, review the latest experimental evidence for their intercellular crosstalk, and describe the molecular targets that might be targeted to inform therapeutic strategies. Integrating the current evidence, this review seeks to provide a comprehensive theoretical framework and novel methods for the precise treatment of sepsis-associated ARDS, which could be beneficial to clinical practices and patients' prognoses.