Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing

Abstract

Objective:

Cell migration is an essential process in skin wound healing. Photodynamic therapy (PDT) enhances wound healing by photoactivating a photosensitizer with a specific wavelength of light. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel expressed in multiple layers of keratinocytes. Recent studies showed that the activation of CFTR-related downstream signaling affects skin wound healing. We examined whether indocyanine green (ICG)-mediated PDT-enhanced cell migration is related to CFTR activation.

Approach:

The spatial and temporal expression levels of CFTR and proteins involved in focal adhesion, including focal adhesion kinase (FAK) and paxillin, were evaluated during cell migration in vitro and in vivo for wound healing.

Results:

ICG-PDT-conditioned medium collected from cells exposed to 5 J/cm² near-infrared light in the presence of 100 μg/mL ICG activated CFTR and enhanced HaCaT cell migration. The expression of phosphorylated FAK Tyr861 and phosphorylated paxillin in focal adhesions was spatially and temporally regulated in parallel by ICG-PDT-conditioned medium. Curcumin, a nonspecific activator of CFTR, further increased PDT-enhanced cell migration, whereas inhibition of CFTR and FAK delayed cell migration. The involvement of CFTR in ICG-PDT-enhanced skin wound healing was confirmed in a mouse back skin wound model.

Innovation:

CFTR is a potential new therapeutic target in ICG-PDT to enhance wound healing.

Conclusion:

ICG-PDT-enhanced cell migration may be related to activation of the CFTR and FAK pathway. Conditioned medium collected from ICG-PDT may be useful for treating patients with chronic skin ulcer by regulating CFTR expression in keratinocytes.

Get full access to this article

View all access options for this article.

References

Sen

, Gordillo

, Roy

, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen, 2009; 17:763–771.

Jarbrink

, Ni

, Sonnergren

, et al. Prevalence and incidence of chronic wounds and related complications: a protocol for a systematic review. Syst Rev, 2016; 5:152.

Singer

, Clark

. Cutaneous wound healing. N Engl J Med, 1999; 341:738–746.

Avishai

, Yeghiazaryan

, Golubnitschaja

. Impaired wound healing: facts and hypotheses for multi-professional considerations in predictive, preventive and personalised medicine. EPMA J, 2017; 8:23–33.

Nesi-Reis

, Lera-Nonose

, Oyama

, et al. Contribution of photodynamic therapy in wound healing: a systematic review. Photodiagnosis Photodyn Ther, 2018; 21:294–305.

Dougherty

TJ.

An update on photodynamic therapy applications. J Clin Laser Med Surg, 2002; 20:3–7.

Dabrowski

, Arnaut

, Pereira

, et al. Combined effects of singlet oxygen and hydroxyl radical in photodynamic therapy with photostable bacteriochlorins: evidence from intracellular fluorescence and increased photodynamic efficacy in vitro. Free Radic Biol Med, 2012; 52:1188–1200.

Wong

, Tracy

, Oseroff

, Baumann

. Photodynamic therapy mediates immediate loss of cellular responsiveness to cytokines and growth factors. Cancer Res, 2003; 63:3812–3818.

Wong

, Cheng

, Hsieh

, Liang

. Effects of blue or violet light on the inactivation of Staphylococcus aureus by riboflavin-5'-phosphate photolysis. J Photochem Photobiol B, 2017; 173:672–680.

10.

Grieve

, Guerriero

, Walker

, et al. Verteporfin photodynamic therapy cohort study: report 3: cost effectiveness and lessons for future evaluations. Ophthalmology, 2009; 116:2471–2477 e2471–2472.

11.

Wong

, Wu

, Ko

, Lee

. Photodynamic inactivation of methicillin-resistant Staphylococcus aureus by indocyanine green and near infrared light. Dermatol Sinica, 2018; 36:8–15.

12.

Fox

, Wood

. Indocyanine green: physical and physiologic properties. Proc Staff Meet Mayo Clin, 1960; 35:732–744.

13.

Urbanska

, Romanowska-Dixon

, Matuszak

, Oszajca

, Nowak-Sliwinska

, Stochel

. Indocyanine green as a prospective sensitizer for photodynamic therapy of melanomas. Acta Biochim Pol, 2002; 49:387–391.

14.

Omar

, Wilson

, Nair

. Lethal photosensitization of wound-associated microbes using indocyanine green and near-infrared light. BMC Microbiol, 2008; 8:111.

15.

Elborn

JS.

Cystic fibrosis. Lancet, 2016; 388:2519–2531.

16.

Zhao

, Guan

. Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev, 2011; 63:610–615.

17.

De Pascalis

, Etienne-Manneville

. Single and collective cell migration: the mechanics of adhesions. Mol Biol Cell, 2017; 28:1833–1846.

18.

Marshall

, Watters

, Hovdestad

, Cozzi

, Katoh

. CFTR Cl- channel functional regulation by phosphorylation of focal adhesion kinase at tyrosine 407 in osmosensitive ion transporting mitochondria rich cells of euryhaline killifish. J Exp Biol, 2009; 212:2365–2377.

19.

Farrell

, Rosenstein

, White

, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: cystic Fibrosis Foundation consensus report. J Pediatr, 2008; 153:S4–S14.

20.

Dong

, Jiang

, Zhang

, et al. Dynamically regulated CFTR expression and its functional role in cutaneous wound healing. J Cell Physiol, 2015; 230:2049–2058.

21.

Shirata

, Kaneko

, Inagaki

, et al. Near-infrared photothermal/photodynamic therapy with indocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress. Sci Rep, 2017; 7:13958.

22.

Ansell

, Campbell

, Thomason

, Brass

, Hardman

. A statistical analysis of murine incisional and excisional acute wound models. Wound Repair Regen, 2014; 22:281–287.

23.

, Su

, Wang

, et al. CO2 delivery to accelerate incisional wound healing following single irradiation of near-infrared lamp on the coordinated colloids. ACS Nano, 2017; 11:5826–5835.

24.

Zhang

, Chen

, Wang

, Peng

, Cai

. Effects of curcumin on ion channels and transporters. Front Physiol, 2014; 5:94.

25.

Kelly

, Trudel

, Brouillard

, et al. Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition. J Pharmacol Exp Ther, 2010; 333:60–69.

26.

Golubovskaya

, Curtin

, Groman

, Sexton

, Cance

. In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride). Arch Toxicol, 2015; 89:1095–1101.

27.

Tedesco

, Jesus

Low level energy photodynamic therapy for skin processes and regeneration. In: Tanaka

, ed. Photomedicine—Advances in Clinical Practice. Rijeka: InTech; 2017:Ch. 05.

28.

de Jesus

, Saeki

, Tedesco

. An ex vivo study of photobiostimulation in the treatment of skin pathologies. J Biophotonics, 2016; 9:1189–1198.

29.

Tian

, Chen

, Cao

, Yang

. Application of ICG-enhanced thermocoagulation method and photodynamic therapy in circumscribed choroidal hemangioma. Oncol Lett, 2018; 15:5760–5766.

30.

Martin

, Barrett

. Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity. Hum Exp Toxicol, 2002; 21:71–75.

31.

Huang

, Jin

, Zhang

, et al. Upregulation of CFTR in patients with endometriosis and its involvement in NFkappaB-uPAR dependent cell migration. Oncotarget, 2017; 8:66951–66959.

32.

Chen

, Chen

, et al. Epidermal CFTR suppresses MAPK/NF-kappaB to promote cutaneous wound healing. Cell Physiol Biochem, 2016; 39:2262–2274.

33.

Bernard

, Wang

, Narlawar

, Schmidt

, Kirk

. Curcumin cross-links cystic fibrosis transmembrane conductance regulator (CFTR) polypeptides and potentiates CFTR channel activity by distinct mechanisms. J Biol Chem, 2009; 284:30754–30765.

34.

Egan

, Pearson

, Weiner

, et al. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science, 2004; 304:600–602.

35.

Leu

, Su

, Chuang

, Maa

. Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity. Biochem Pharmacol, 2003; 66:2323–2331.

36.

Lim

, Park

, Jeon

, et al. Focal adhesion kinase is negatively regulated by phosphorylation at tyrosine 407. J Biol Chem, 2007; 282:10398–10404.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.07 MB

0.16 MB

0.07 MB

0.00 MB