Fisetin and Lung Health

Epidemiological studies have noted for some time that a relationship exists between lung function and diet. A meta-analysis published in 2015 found that an unhealthy, western-style diet was associated with increased risk for chronic obstructive pulmonary disease (COPD). Conversely, healthy dietary patterns were associated with reduced risk for COPD. These findings suggested that diet could have a protective impact on COPD pathophysiology, most likely through modulating inflammatory pathways and oxidative stress, which are two factors implicated in COPD onset.¹

Higher dietary intake of flavonoids is known to be positively associated with parameters of lung function in general. To examine whether a specific association existed between dietary flavonoid intake and the risk of smoking-related COPD, a large prospective cohort study followed 55,413 men and women, who were aged 50–65 and without COPD at the time of recruitment, for a period of 23 years. Participants with the highest total flavonoid intake had a 20% lower risk of COPD when compared to participants with the lowest intake. On an absolute scale, the study found that both current and former smokers had a considerably higher risk of COPD than non-smokers regardless of flavonoid intake, but current smokers with low flavonoid intake had the highest risk.²

Aging is another major factor that affects lung function. In fact, aging is the single greatest risk factor for several non-communicable chronic lung conditions, such as COPD, idiopathic pulmonary fibrosis (IPF), and many types of lung cancer.³ The link between IPF and aging is so robust that some researchers have coined the term “senescence-associated pulmonary fibrosis” to refer to this chronic, progressive condition in which extracellular collagen accumulates in the lung parenchyma leading to severe decline in lung function.⁴ In animal and experimental models of IPF, the polyphenol flavonoid, fisetin, was found to reduce collagen accumulation in lung cells.⁵

Fisetin has also been shown to decrease airway hyperreactivity in an animal model of allergic asthma.⁶In a recent experimental study that investigated its mechanisms of action with regard to asthma, fisetin was found to reduce oxidative stress in lung cells and bronchial epithelial cells by inhibiting COX-2 expression. It was also shown to reduce inflammatory chemokine and cytokine expression in tracheal epithelial cells through a number of mechanisms, including inhibiting transcription and downstream activity of nuclear factor kappa B (NF-κB) via inhibition of TNF-α, which resulted in significantly reduced levels of IL-8, a pro-inflammatory cytokine that plays a key role in lung inflammation.⁷

The TNF-α/NF-κB/IL-8 molecular signaling pathway is also involved in COPD. High levels of IL-8 have been found in the respiratory epithelium of COPD patients during periods of disease exacerbation, and increased NF-κB activity is associated with worsening COPD symptoms.⁸ Fisetin was shown in an experimental study of COPD to inhibit the TNF-α/NF-κB/IL-8 signaling pathways, suggesting it could potentially have a therapeutic benefit for inflammatory lung conditions.⁹

Clinical Implications

Inflammation, oxidative stress, and impaired autophagy are known to be involved in the aging process. Research is also discovering the crucial impact of the gut microbiome on both immunosenescence (decline in immune efficacy), and the chronic pro-inflammatory state associated with aging.¹⁰ Naturally occurring polyphenols, such as fisetin, have been shown to have a positive effect on this complex array of interconnected signaling mechanisms – inflammation, oxidative stress, autophagy, and the gut microbiome – that play a key role in regulating aging and health.¹¹ In this regard, polyphenols, derived from both the diet and as dietary supplements, can be viewed as significant allies in modulating two of the major risk factors for lung health: nutrition and aging.

References

1. https://www.tandfonline.com/doi/full/10.3109/15412555.2015.1098606
2. https://erj.ersjournals.com/content/early/2022/01/13/13993003.02604-2021
3. https://erj.ersjournals.com/content/45/3/807
4. https://www.nature.com/articles/s12276-019-0371-7
5. https://www.frontiersin.org/articles/10.3389/fphar.2020.553690/full
6. http://bmrat.org/index.php/BMRAT/article/view/731
7. https://www.mdpi.com/2072-6643/14/9/1841
8. https://synapse.koreamed.org/articles/1000749
9. https://www.sciencedirect.com/science/article/abs/pii/S1043466618300048
10. https://www.tandfonline.com/doi/full/10.1080/10408398.2020.1867054?src=recsys
11. https://www.tandfonline.com/doi/abs/10.1080/10408398.2020.1773390