Pretreatment with Kahweol Attenuates Sepsis-Induced Acute Lung Injury via Improving Mitochondrial Homeostasis in a CaMKKII/AMPK-Dependent Pathway

Scope: It is well-established that dysregulated mitochondrial homeostasis in macrophages leads to inflammation, oxidative stress, and tissue damage, which are essential in the pathogenesis of sepsis-induced acute lung injury (ALI). Kahweol, a natural diterpene extracted from coffee beans, reportedly possesses anti-inflammatory and mitochondrial protective properties. Herein, the study investigates whether Kahweol can alleviate sepsis-induced ALI and explore the underlying mechanisms.

Methods and results: C57BL/6J mice are intraperitoneally injected with lipopolysaccharide (LPS) for 12 h to induce ALI. Pretreatment with kahweol by gavage for 5 days significantly alleviates lung pathological injury, inflammation, and oxidative stress, accompanied by shifting the dynamic process of mitochondria from fission to fusion, enhancing Mitophagy, and activating AMPK. To investigate the underlying molecular mechanisms, differentiated THP-1 cells are cultured in a medium containing Kahweol for 12 h prior to LPS exposure, yielding consistent findings with the in vivo results. Moreover, AMPK inhibitors abrogate the above effects, indicating Kahweol acts in an AMPK-dependent manner. Furthermore, the study explores how Kahweol activates AMPK and finds that this process is mediated by CamKK II.

Conclusion: Pretreatment with Kahweol attenuates sepsis-induced acute lung injury via improving mitochondrial homeostasis in a CaMKKII/AMPK-dependent pathway and may be a potential candidate to prevent sepsis-induced ALI.

AMPK, Kahweol; acute lung injury; mitochondrial dynamics; mitophagy.