Inulabritanoid U (Compound 6) from Inula britannica inhibits `NF-κB` and `MAPK/AP-1` pathways, reducing LPS-induced pneumonia inflammation.

Pneumonia remains a highly prevalent acute respiratory infection globally, causing significant morbidity and mortality. Current treatments often face challenges such as antibiotic resistance and insufficient anti-inflammatory effects, highlighting the urgent need for novel therapeutic agents. Natural products, particularly those with traditional medicinal uses like Inula britannica, are a rich source for discovering new bioactive compounds. This study explores the anti-pneumonia potential of constituents from I. britannica, focusing on their ability to modulate inflammatory pathways relevant to acute respiratory distress and inflammation.

Researchers isolated twenty compounds from Inula britannica, including seven newly discovered compounds (inulabritanoids P-U, 1-6, and inulabritanoid V, 7), along with thirteen known compounds (8-20). Structural elucidation was performed using 1D and 2D NMR and HR-MS data. The anti-pneumonia activities of all isolated compounds were assessed using a lipopolysaccharide (LPS)-induced pneumonia model in MH-S alveolar macrophages. The primary endpoint was the inhibition of inflammatory markers, with a focus on nitric oxide (NO) production and cytokine expression.

Five compounds (3, 5, 6, 12, and 18) demonstrated potent anti-pneumonia activities in LPS-exposed MH-S cells. Compound 6, named inulabritanoid U, exhibited the most potent bioactivity among all tested compounds. It significantly inhibited nitric oxide (NO) production, a key mediator of inflammation. Furthermore, compound 6 effectively downregulated the expression levels of several critical inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-6, and chemokine (C-C motif) ligand 5 (CCL5). These findings highlight its broad anti-inflammatory action. Further mechanistic investigations revealed that the anti-pneumonia effect of compound 6 was dependent on inhibiting two major inflammatory signaling pathways: NF-κB and MAPK/AP-1.