Iranian Journal of Allergy, Asthma and Immunology 2018. 17(1):29-38.

Effects of Connexin 43 Inhibition in an Ovalbumin-induced Mouse Model of Asthma
Jian-Qiang Huang, Xiao-Yang Chen, Fang Huang, Ji-Min Fan, Xiao-Wei Shi, Yan-Kai Ju


Connexion 43 (Cx43), a gap junction protein, is expressed abundantly in the airway and has been implicated in the pathogenesis of asthma. However, the effects of blocking Cx43 in asthma remain unclear. We investigated the therapeutic effects of two specific Cx43 inhibitors (Gap26 and Gap27) on the development of allergic airway disease in mice. Allergic asthma was induced in BALB/c mice by sensitization and challenge with ovalbumin (OVA). Different doses of Cx43 inhibitors were administered by aerosol inhalation 1 h after OVA challenge on days 21 and 23. Airway hyperresponsiveness (AHR), lung pathology, mucus production, and inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were examined. We found that Gap26 significantly inhibited OVA-induced AHR, inflammatory cell infiltration surrounding the bronchia, mucus production, inflammatory cells and cytokines in BALF, and OVA-specific IgE in the serum in a dose-dependent manner. Gap27 showed effects similar to those of Gap26 in inhibiting inflammatory cytokine production in BALF. We conclude Cx43 inhibitor inhalation alleviates asthma featuresin mice and may be a promising therapy for clinical asthma.



Asthma; Connexin 43; Inflammation; Ovalbumin

Full Text:



  1. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31(1):143-78.
  2. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355(21):2226-35.
  3. Szefler SJ. Advancing asthma care: the glass is only half full! J Allergy Clin Immunol 2011; 128(3):485-94.
  4. Baker KE, Bonvini SJ, Donovan C, Foong RE, Han B, Jha A, et al. Novel drug targets for asthma and COPD: lessons learned from in vitro and in vivo models. Pulm Pharmacol Ther 2014; 29(2):181-98.
  5. Locksley RM. Asthma and allergic inflammation. Cell 2010; 140(6):777-83.
  6. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol 2015; 15(1):57-65.
  7. Hervé JC, Derangeon M. Gap-junction-mediated cell-to-cell communication. Cell Tissue Res 2013; 352(1):21-31.
  8. Goodenough DA, Paul DL. Gap junctions. Cold Spring Harb Perspect Biol 2009; 1(1):a002576.
  9. Kar R, Batra N, Riquelme MA, Jiang JX. Biological role of connexin intercellular channels and hemichannels. Arch Biochem Biophys 2012; 524(1):2-15.
  10. Burra S, Jiang JX. Regulation of cellular function by connexin hemichannels. Int J Biochem Mol Biol 2011; 2(2):119-28.
  11. Meşe G, Richard G, White TW. Gap junctions: basic structure and function. J Invest Dermatol 2007; 127(11):2516-24.
  12. Kim R, Chang G, Hu R, Phillips A, Douglas R. Connexin gap junction channels and chronic rhinosinusitis. Int Forum Allergy Rhinol 2016; 6(6):611-7.
  13. Sarieddine MZ, Scheckenbach KE, Foglia B, Maass K, Garcia I, Kwak BR, et al. Connexin43 modulates neutrophil recruitment to the lung. J Cell Mol Med 2009; 13(11-12):4560-70.
  14. Losa D, Chanson M, Crespin S. Connexins as therapeutic targets in lung disease. Expert Opin Ther Targets 2011; 15(8):989-1002.
  15. Freund-Michel V, Muller B, Marthan R, Savineau JP, Guibert C. Expression and role of connexin-based gap junctions in pulmonary inflammatory diseases. Pharmacol Ther 2016; 164:105-19.
  16. Yao Y, Zeng QX, Deng XQ, Tang GN, Guo JB, Sun YQ, et al. Connexin 43 Upregulation in Mouse Lungs during Ovalbumin-Induced Asthma. PLoS One 2015; 10(12):e0144106.
  17. Sun YQ, Deng MX, He J, Zeng QX, Wen W, Wong DS, et al. Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice. Stem Cells 2012; 30(12):2692-9.
  18. Hawat G, Hélie P, Baroudi G. Single intravenous low-dose injections of connexin 43 mimetic peptides protect ischemic heart in vivo against myocardial infarction. J Mol Cell Cardiol 2012; 53(4):559-66.
  19. Kim SG, Lee E, Park NY, Park HH, Jeong KT, Kim KJ, et al. Britanin attenuates ovalbumin-induced airway inflammation in a murine asthma model. Arch Pharm Res 2016; 39(7):1006-12.
  20. Söhl G, Willecke K. Gap junctions and the connexin protein family. Cardiovasc Res 2004; 62(2):228-32.
  21. Bou Saab J, Losa D, Chanson M, Ruez R. Connexins in respiratory and gastrointestinal mucosal immunity. FEBS Lett 2014; 588(8):1288-96.
  22. O'Carroll SJ, Alkadhi M, Nicholson LF, Green CR. Connexin43 mimetic peptides reduce swelling, astrogliosis, and neuronal cell death after spinal cord injury. Cell Commun Adhes 2008; 15(1):27-42.
  23. Hawat G, Benderdour M, Rousseau G, Baroudi G. Connexin 43 mimetic peptide Gap26 confers protection to intact heart against myocardial ischemia injury. Pflugers Arch 2010; 460(3):583-92.
  24. Pollok S, Pfeiffer AC, Lobmann R, Wright CS, Moll I, Martin PE, et al. Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells. J Cell Mol Med 2011; 15(4):861-73.
  25. Li X, Zhao H, Tan X, Kostrzewa RM, Du G, Chen Y, et al. Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats. Glia 2015; 63(9):1553-67.
  26. Elbadawy HM, Mirabelli P, Xeroudaki M, Parekh M, Bertolin M, Breda C, et al. Effect of connexin 43 inhibition by the mimetic peptide Gap27 on corneal wound healing, inflammation and neovascularization. Br J Pharmacol 2016; 173(19):2880-93.
  27. Brannan JD, Lougheed MD. Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment. Front Physiol 2012; 3:460.
  28. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282(5397):2258-61.
  29. Kasaian MT, Miller DK. IL-13 as a therapeutic target for respiratory disease. Biochem Pharmacol 2008; 76(2):147-55.
  30. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 2008; 118(11):3546-56.
  31. Kouro T, Takatsu K. IL-5 and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol 2009; 21(12):1303-1309.
  32. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015; 16(1):45-56.
  33. Chung KF. Neutrophilic asthma: a distinct target for treatment? Lancet Respir Med 2016; 4(10):765-7.
  34. Dullaers M, De Bruyne R, Ramadani F, Gould HJ, Gevaert P, Lambrecht BN. The who, where, and when of IgE in allergic airway disease. J Allergy Clin Immunol 2012; 129(3):635-45.
  35. Froidure A, Mouthuy J, Durham SR, Chanez P, Sibille Y, Pilette C. Asthma phenotypes and IgE responses. Eur Respir J 2016; 47(1):304-19.
  36. Djukanovic R, Hanania N, Busse W, Price D. IgE-mediated asthma: New revelations and future insights. Respir Med 2016; 112:128-9.
  37. Paw M, Borek I, Wnuk D, Ryszawy D, Piwowarczyk K, Kmiotek K, et al. Connexin43 Controls the Myofibroblastic Differentiation of Bronchial Fibroblasts from Patients with Asthma. Am J Respir Cell Mol Biol 2017; 57(1):100-10.
  38. Tang GN, Li CL, Yao Y, Xu ZB, Deng MX, Wang SY, et al. MicroRNAs Involved in Asthma After Mesenchymal Stem Cells Treatment. Stem Cells Dev 2016; 25(12):883-96.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.