Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammation and impaired airway immunity, providing an opportunistic platform for nontypeable Haemophilus influenzae (NTHi) infection. In this context, therapies targeting not only overactive inflammation without significant adverse effects, but also infection are of interest. Increasing evidence suggests that polyphenols, plant secondary metabolites with anti-inflammatory and antimicrobial properties, may be protective. Here, a Cistus salviifolius plant extract containing quercetin, myricetin, and punicalagin was shown to reduce NTHi viability. Analysis of these polyphenols revealed that quercetin has a bactericidal effect on NTHi, does not display synergies, and that bacteria do not seem to develop resistance. Moreover, quercetin lowered NTHi airway epithelial invasion through a mechanism likely involving inhibition of Akt phosphorylation, and reduced the expression of bacterially-induced proinflammatory markers il-8, cxcl-1, il-6, pde4b, and tnfα. We further tested quercetin’s effect on NTHi murine pulmonary infection, showing a moderate reduction in bacterial counts and significantly reduced expression of proinflammatory genes, compared to untreated mice. Quercetin administration during NTHi infection on a zebrafish septicemia infection model system showed a bacterial clearing effect without signs of host toxicity. In conclusion, this study highlights the therapeutic potential of the xenohormetic molecule quercetin against NTHi infection.
Highlights
Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease, typically caused by cigarette smoking [1]
Genomic heterogeneity is a known feature for nontypeable Haemophilus influenzae (NTHi) [44,45,46], which may lead to variable polyphenol susceptibility among strains, as is shown for other antimicrobials [33]
We evaluated the effect of quercetin, myricetin, and punicalagin on three NTHi clinical strains isolated from COPD sputum samples and belonging to different clonal types [45]; their viability decreased when exposed to polyphenols, with some minimal inhibitory concentrations (MIC) variations among them (Table S2)
Summary
Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease, typically caused by cigarette smoking [1]. Airflow limitation in COPD associates with chronic inflammation of the respiratory tract, a result of repeated insult by noxious components of cigarette smoke [2,3]. ICS are the mainstay of anti-inflammatory therapy, but their usefulness in COPD has been questioned due to potential side effects such as an increased risk of pneumonia [10,11,12] and corticosteroid insensitivity due to oxidative stress from cigarette smoke and chronic inflammation [13]. Excessive anti-inflammatory effects may dampen immune responses, facilitating infectious processes In this context, therapies targeting overactive inflammation without significant adverse effects, and infection are of particular translational significance. High quality randomized controlled trials confirm that long-term azithromycin treatment decreases the risk of COPD exacerbations, careful attention needs to be paid to the potential risks of hearing decrements, cardiac toxicity, and development of microbial resistance patterns [14,15,16]
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