Cigarette smoke–induced lung inflammation is a central contributor to multiple pulmonary diseases, and current anti-inflammatory therapies have limited effectiveness. The authors investigate a structurally distinct botanical-derived formulation, AB-free kava (a Piper methysticum extract depleted of flavokavains A/B) that contains six major kavalactones, as a potential source of new anti-inflammatory agents for smoke-related lung injury. Prior work demonstrated that this AB-free kava formulation suppressed cigarette smoke–induced lung inflammation in mice; the present study aimed to identify the bioactive constituent(s) and define underlying mechanisms.
The study evaluated the six major kavalactones present in the AB-free kava formulation for their ability to suppress inflammatory responses. A clear structure–activity relationship was reported: desmethoxyyangonin (DMY) emerged as the most potent suppressor of inflammatory prostaglandin production in vitro, whereas dihydrokavain (DHK)—a structurally similar analog—displayed minimal activity. Another kavalactone, dihydromethysticin (DHM), demonstrated notable in vivo efficacy despite only moderate in vitro potency, an observation the authors attributed to differences in bioavailability.
Using lipopolysaccharide (LPS)–stimulated macrophage assays, several kavalactones were tested for inhibition of prostaglandin E2 (PGE2) production. DMY showed the strongest suppression of LPS-stimulated PGE2, and also reduced LPS-induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). In contrast, DHK lacked significant activity in these assays. The pattern of activity in the macrophage system supported a structure–activity relationship among the kavalactones.
Mechanistic experiments indicated that DMY, but not DHK, attenuated induction of cyclooxygenase-2 (COX-2) and reduced phosphorylation of cAMP response element–binding protein (CREB). Pharmacological inhibition of protein kinase A (PKA) produced similar reductions in p-CREB, COX-2, and PGE2, supporting a model in which a PKA-dependent CREB/COX-2 signaling axis mediates suppression of PGE2 by active kavalactones. The authors reported these effects occurred independently of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) signaling pathways in their assays.
When proinflammatory pathways were triggered by cigarette smoke condensate in vitro, DMY and DHK produced results consistent with their LPS findings: DMY attenuated smoke condensate–induced proinflammatory signaling and PGE2 production, while DHK showed minimal effect. This concordance between LPS and cigarette smoke condensate models supported the relevance of the identified signaling axis to smoke-related inflammatory stimuli.
In mouse models, DMY demonstrated significant efficacy in suppressing cigarette smoke–induced lung inflammation, whereas DHK was ineffective. Interestingly, DHM exhibited the greatest in vivo anti-inflammatory efficacy despite only moderate in vitro potency; the authors attribute this discrepancy to DHM’s apparently superior bioavailability compared with DMY. Consistent with mechanistic findings, cigarette smoke exposure increased p-CREB and COX-2 expression in mouse lungs, and treatment with AB-free kava and its bioactive kavalactones attenuated these increases. The degree of p-CREB and COX-2 suppression correlated with the compounds’ in vivo anti-inflammatory efficacy. Additionally, DHM suppressed LPS-induced neutrophil accumulation in mouse lungs in the reported experiments.
The reported structure–activity relationship distinguished DMY as a potent in vitro inhibitor of PGE2 and proinflammatory cytokines, while DHK was inactive under the same conditions. The superior in vivo performance of DHM relative to its in vitro potency was interpreted by the authors as likely due to differences in pharmacokinetics and bioavailability among the kavalactones, suggesting that both intrinsic activity and systemic exposure determine in vivo efficacy.
Collectively, the data as presented identify bioactive kavalactones within AB-free kava that suppress cigarette smoke– and LPS-induced lung inflammation through modulation of a PKA/CREB/COX-2 signaling axis. The findings support further development of structurally distinct anti-inflammatory agents derived from kavalactones for smoke-induced pulmonary inflammation. The abstract does not report specific experimental doses, detailed exposure regimens, full pharmacokinetic data, or comprehensive safety assessments; those details were not available in the provided source text.
The authors declared a competing financial interest: the AB-free kava product evaluated is based on intellectual property owned by Kuality Herbceutics, and one author holds a 75% ownership interest in that company. Funding was declared from the Florida Department of Health. No other competing interests were reported in the provided text.