Dendrobine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Mitochondrial-ER Crosstalk and NLRP3 Inflammasome Activation

Sepsis, a severe systemic response to infection, frequently leads to acute lung injury (ALI), significantly increasing morbidity and mortality. Current treatments often fall short in effectively controlling the excessive macrophage-mediated inflammation central to ALI pathogenesis. Emerging research highlights mitochondria-endoplasmic reticulum (ER) crosstalk as a critical driver of inflammatory injury, presenting a novel therapeutic target. Modulating this interaction could offer a new strategy to mitigate sepsis-induced organ damage.

Researchers investigated dendrobine, a bioactive alkaloid, using LPS-stimulated THP-1 macrophages in vitro and a murine model of LPS-induced sepsis in vivo. The study evaluated dendrobine's anti-inflammatory and organ-protective effects. Key endpoints included circulating cytokine levels (IL-1β, IL-18), reactive oxygen species production, mitochondrial DNA release, and expression of inflammasome components (NLRP3, cleaved caspase-1). Mechanistic studies focused on glycolysis-related factors like HIF-1α and HK2, and the IP3R-GRP75-VDAC1 complex. No specific dose or duration for dendrobine administration was detailed in the abstract.

Dendrobine consistently suppressed glycolysis-induced mitochondria-ER crosstalk, significantly reducing macrophage-driven inflammation and tissue injury in both in vitro and in vivo models. In septic mice, dendrobine lowered circulating levels of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18, and effectively alleviated ALI. > Mechanistically, dendrobine decreased reactive oxygen species production and mitochondrial DNA (mtDNA) release, leading to a downregulation of NLRP3 and cleaved caspase-1. These protective effects stemmed from dendrobine's inhibition of hypoxia-inducible factor-1α (HIF-1α) and hexokinase 2 (HK2)-mediated glycolysis. This inhibition prevented HK2 dissociation from voltage-dependent anion channel 1 (VDAC1) and disrupted the formation of the IP3R-GRP75-VDAC1 complex, a key regulator of mitochondrial-ER communication.