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. 2015 Aug;153(2):291-7.
doi: 10.1177/0194599815586720. Epub 2015 May 27.

Chlorogenic Acid Activates CFTR-Mediated Cl- Secretion in Mice and Humans: Therapeutic Implications for Chronic Rhinosinusitis

Elisa A Illing  1 , Do-Yeon Cho  1 , Shaoyan Zhang  1 , Daniel F Skinner  1 , Quinn A Dunlap  1 , Eric J Sorscher  1 , Bradford A Woodworth  2
Affiliations

Chlorogenic Acid Activates CFTR-Mediated Cl- Secretion in Mice and Humans: Therapeutic Implications for Chronic Rhinosinusitis

Elisa A Illing et al. Otolaryngol Head Neck Surg. 2015 Aug.

Abstract

Objectives: Salubrious effects of the green coffee bean are purportedly secondary to high concentrations of chlorogenic acid. Chlorogenic acid has a molecular structure similar to bioflavonoids that activate transepithelial Cl(-) transport in sinonasal epithelia. In contrast to flavonoids, the drug is freely soluble in water. The objective of this study is to evaluate the Cl(-) secretory capability of chlorogenic acid and its potential as a therapeutic activator of mucus clearance in sinus disease.

Study design: Basic research.

Setting: Laboratory.

Subjects and methods: Chlorogenic acid was tested on primary murine nasal septal epithelial (MNSE) (CFTR(+/+) and transgenic CFTR(-/-)) and human sinonasal epithelial (HSNE) (CFTR(+/+) and F508del/F508del) cultures under pharmacologic conditions in Ussing chambers to evaluate effects on transepithelial Cl(-) transport. Cellular cyclic adenosine monophosphate (cAMP), phosphorylation of the CFTR regulatory domain (R-D), and CFTR mRNA transcription were also measured.

Results: Chlorogenic acid stimulated transepithelial Cl(-) secretion (change in short-circuit current [ΔISC = µA/cm(2)]) in MNSE (13.1 ± 0.9 vs 0.1 ± 0.1; P < .05) and HSNE (34.3 ± 0.9 vs 0.0 ± 0.1; P < .05). The drug had a long duration until peak effect at 15 to 30 minutes after application. Significant inhibition with INH-172 as well as absent stimulation in cultures lacking functional CFTR suggest effects are dependent on CFTR-mediated pathways. However, the absence of elevated cellular cAMP and phosphorylation the CFTR R-D indicates chlorogenic acid does not work through a PKA-dependent mechanism.

Conclusion: Chlorogenic acid is a water-soluble agent that promotes CFTR-mediated Cl(-) transport in mouse and human sinonasal epithelium. Translating activators of mucociliary transport to clinical use provides a new therapeutic approach to sinus disease. Further in vivo evaluation is planned.

Keywords: CFTR; chloride secretion; chlorogenic acid; chronic sinusitis; mucociliary clearance; murine nasal culture; sinus epithelium; transepithelial ion transport.

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Conflict of interest statement

Conflict of Interest: Eric Sorscher, MD, and Bradford Woodworth, MD are inventors on a patent pending regarding the use of chloride secretagogues for therapy of sinus disease (35 U.S.C. n111(b) and 37 C.F.R n.53 (c)) in the United States Patent and Trademark Office.

Figures

Figure 1
Figure 1
A - Representative Ussing chamber tracings show pharmacologic manipulation of ion transport in murine nasal septal epithelial cultures. B - Summary data reveals marked activation of Cl− secretion by chlorogenic acid (*p<0.05). Chlorogenic acid-stimulated ΔISC is also greater than water control when CFTR is maximally activated with forskolin in both sets of cultures (*p<0.05). INH-172 also significantly inhibited ΔISC in chlorogenic acid treated monolayers (*p<0.05). C - CFTR−/− cultures tested with the drug reveal its effects are dependent on CFTR-mediated pathways.
Figure 1
Figure 1
A - Representative Ussing chamber tracings show pharmacologic manipulation of ion transport in murine nasal septal epithelial cultures. B - Summary data reveals marked activation of Cl− secretion by chlorogenic acid (*p<0.05). Chlorogenic acid-stimulated ΔISC is also greater than water control when CFTR is maximally activated with forskolin in both sets of cultures (*p<0.05). INH-172 also significantly inhibited ΔISC in chlorogenic acid treated monolayers (*p<0.05). C - CFTR−/− cultures tested with the drug reveal its effects are dependent on CFTR-mediated pathways.
Figure 1
Figure 1
A - Representative Ussing chamber tracings show pharmacologic manipulation of ion transport in murine nasal septal epithelial cultures. B - Summary data reveals marked activation of Cl− secretion by chlorogenic acid (*p<0.05). Chlorogenic acid-stimulated ΔISC is also greater than water control when CFTR is maximally activated with forskolin in both sets of cultures (*p<0.05). INH-172 also significantly inhibited ΔISC in chlorogenic acid treated monolayers (*p<0.05). C - CFTR−/− cultures tested with the drug reveal its effects are dependent on CFTR-mediated pathways.
Figure 2
Figure 2
A – Ussing chamber tracings reveal significant ΔISC in human sinonasal epithelium with administration of 1.5 mM chlorogenic acid. B - Summary data demonstrate increased Cl- transport with forskolin in cultures pre-treated with chlorogenic acid as well as strong inhibition with addition of INH-172 (*p<0.05). C - Ussing chamber tracings show human (F508del/F508del) monolayers are unresponsive the drug.
Figure 2
Figure 2
A – Ussing chamber tracings reveal significant ΔISC in human sinonasal epithelium with administration of 1.5 mM chlorogenic acid. B - Summary data demonstrate increased Cl- transport with forskolin in cultures pre-treated with chlorogenic acid as well as strong inhibition with addition of INH-172 (*p<0.05). C - Ussing chamber tracings show human (F508del/F508del) monolayers are unresponsive the drug.
Figure 2
Figure 2
A – Ussing chamber tracings reveal significant ΔISC in human sinonasal epithelium with administration of 1.5 mM chlorogenic acid. B - Summary data demonstrate increased Cl- transport with forskolin in cultures pre-treated with chlorogenic acid as well as strong inhibition with addition of INH-172 (*p<0.05). C - Ussing chamber tracings show human (F508del/F508del) monolayers are unresponsive the drug.
Figure 3
Figure 3
MNSE were exposed to forskolin (20 μM), vehicle (water), or 1.5 mM chlorogenic acid for 15 minutes prior to assay. Chlorogenic acid did not increase cAMP compared to vehicle control, while forskolin markedly elevated cAMP. The drug had no detectable effect on R-domain phosphorylation. A 2–4 kD mobility shift (black arrow) is seen following treatment with forskolin.
Figure 4
Figure 4
Quantitative RT-PCR shows chlorogenic acid has no significant effect on CFTR gene expression.
See this image and copyright information in PMC

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