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, 9 (4), 370-377

Broncho-Vaxom® (OM-85 BV) Soluble Components Stimulate Sinonasal Innate Immunity

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Broncho-Vaxom® (OM-85 BV) Soluble Components Stimulate Sinonasal Innate Immunity

Vasiliki Triantafillou et al. Int Forum Allergy Rhinol.

Abstract

Background: Broncho-Vaxom® (OM-85 BV) is an extract of infectious respiratory bacteria that is used as an immunostimulant outside of the United States for the prevention and treatment of bronchitis and rhinosinusitis. Prior studies have shown that use of OM-85 BV is associated with reduction in frequency of respiratory infection and decreased duration of antibiotic usage. However, the effects of OM-85 BV on respiratory mucosal innate immunity are unknown.

Methods: Human sinonasal epithelial cells were grown at an air-liquid interface (ALI). Ciliary beat frequency (CBF) and nitric oxide (NO) production in response to stimulation with OM-85 BV was measured in vitro. Pharmacologic inhibitors of bitter taste receptor (T2R) signaling were used to determine if this pathway was taste-receptor-mediated.

Results: Apical application of OM-85 BV resulted in an NO-mediated increase in CBF (p < 0.05) and increased NO production (p < 0.0001) when compared to saline-stimulated control cultures. ALI pretreatment with taste receptor pathway inhibitors blocked OM-85 BV-induced increases in NO.

Conclusion: OM-85 BV has ciliostimulatory and immunogenic properties that may be partially responsible for its observed efficacy as a respiratory therapeutic. These responses were NO-dependent and consistent with T2R activation. Further work is necessary to elucidate specific component-receptor signaling relationships.

Keywords: ciliary motility; immunotherapy; innate immunity; rhinosinusitis; sinusitis; therapeutics.

Figures

Figure 1.
Figure 1.
OM-85BV stimulates CBF in a NO-dependent manner. A) CBF changes after addition of 30 μl of OM-85 BV supernatant (red) or PBS (blue) to the apical ciliated surface at t=0 minutes to ALIs or ALIs pre-treated with L-NAME (gold). Percentage change from baseline CBF is shown over 5 minutes with measurements every 30 seconds. B) Graph of change in CBF at 5 minutes after addition of PBS or OM-85 BV. Symbols and bars are means ± standard error of 3–5 cultures each. P-values relative to control. CBF= ciliary beat frequency; PBS= phosphate-buffered saline.
Figure 2.
Figure 2.
Apical Application of OM-85 BV Stimulates NO Production in Human Sinonasal ALI Cultures. A) Intracellular NO production measured by DAF-FM fluorescence following apical application of the soluble fraction OM-85 BV (red), PBS control (blue). Response is blocked by pre-incubating with the NOS inhibitor L-NAME (gold). B) NO release for each condition as the average DAF-FM fluorescence over last 30 seconds. Symbols and bars are means ± standard error of 3–5 cultures each. P-values relative to PBS control, by 1-way ANOVA with Dunnett’s post-test. L-NAME= L-NG-nitroarginine methyl ester, NO synthase inhibitor; NO= nitric oxide; PBS= phosphate-buffered saline.
Figure 3.
Figure 3.
OM-85 BV Stimulates NO Production in ALI Cultures in a Taste Receptor Dependent Manner. A) Intracellular NO responses to apical application of the soluble fraction of OM-85BV(red), PBS control (blue), or OM-85BV in the presence of TPPO (black; a TRPM5 inhibitor), active PLCβ2 blocker U73122 (green) and its inactive analogue U73343 (orange). B) NO release for each condition as the average DAF-FM fluorescence over last 30 seconds. Symbols and bars are means ± standard error of 3–5 cultures each. P-values relative to PBS control, by 1-way ANOVA with Dunnett’s post-test. NO= nitric oxide; PBS= phosphate-buffered saline; PLCβ2= phospholipase C isoform β2; TPPO= triphenylphosphine oxide; U73122= active PLCβ2 blocker; U73433= inactive PLCβ2 blocker.
Figure 4.
Figure 4.
All ALIs, regardless of T2R38 genotype, responded with increased NO production upon stimulation with OM-85BV. Cultures homozygous for the functional form of the T2R38 receptor (PAV/PAV) demonstrated a statistically significant greater increase of approximately 40 DAF-FM units compared to AVI/AVI cultures (n=2–3 cultures per condition). A) NO response to OM-85BV over a period of 5 min B) NO release for each condition as the average DAF-FM fluorescence over last 30 seconds.
Figure 5.
Figure 5.
Proposed OM-85BV stimulation of T2R taste receptors on ciliated sinonasal epithelium. Activation of taste-receptor signaling induces innate immune mechanisms including nitric oxide release which is directly bactericidal as well as stimulates ciliary beating. Ca2+= calcium ion; IP3= inositol trisphosphate; L-NAME= L-NG-nitroarginine methyl ester, NO synthase inhibitor; NO= nitric oxide; NOS=nitric oxide synthase; PLCβ2= phospholipase C isoform β2; T2R=bitter taste receptor; TPPO= triphenylphosphine oxide; U73122= active isoform of PLCβ2 blocker

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