N-acetylcysteine decreases airway inflammation and responsiveness in asthma by modulating claudin 18 expression
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Background/Aims: N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how the signal mechanism for tight junctional protein claudin (CLDN) 18 is regulated in asthma patients. Methods: To investigate the effects of NAC on CLDN18 expression in a mouse model of asthma, and to assess plasma levels of CLDN18 in asthma patients. A murine model of asthma induced by ovalbumin (OVA) was established using wild-type BALB/c female mice, and the levels of CLDNs, phosphorylated-pyruvate dehydrogenase kinase 1 (p-PDK1), and protein kinase B (Akt) pathway proteins following NAC treatment were examined by Western blotting and immunohistochemistry. In addition, the plasma levels of CLDN18 were evaluated in asthmatic patients and control subjects. Results: NAC diminished OVA-induced airway hyper-responsiveness and inflammation. Levels of CLDN18 protein were higher in lung tissue from OVA mice than tissue from control mice, and were increased by treatment with NAC or dexamethasone. Treatment with NAC or dexamethasone decreased the OVA-induced increase in interleukin-1α protein levels. Although treatment with NAC increased OVA-induced p-PDK1 protein levels, it decreased phosphorylated Akt (pAkt)/Akt levels. Soluble CLDN18 levels were lower in patients with asthma than in controls and were correlated with the percentage of neutrophils, forced expiratory volume in 1 second (FEV1)/forced vital capacity % (FVC%) and FEV1%. Conclusions: CLDN18 plays a role in the pathogenesis of asthma and NAC diminishes airway inflammation and responsiveness by modulating CLDN18 expression.
Abstract
Background/Aims: N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how the signal mechanism for tight junctional protein claudin (CLDN) 18 is regulated in asthma patients. Methods: To investigate the effects of NAC on CLDN18 expression in a mouse model of asthma, and to assess plasma levels of CLDN18 in asthma patients. A murine model of asthma induced by ovalbumin (OVA) was established using wild-type BALB/c female mice, and the levels of CLDNs, phosphorylated-pyruvate dehydrogenase kinase 1 (p-PDK1), and protein kinase B (Akt) pathway proteins following NAC treatment were examined by Western blotting and immunohistochemistry. In addition, the plasma levels of CLDN18 were evaluated in asthmatic patients and control subjects. Results: NAC diminished OVA-induced airway hyper-responsiveness and inflammation. Levels of CLDN18 protein were higher in lung tissue from OVA mice than tissue from control mice, and were increased by treatment with NAC or dexamethasone. Treatment with NAC or dexamethasone decreased the OVA-induced increase in interleukin-1α protein levels. Although treatment with NAC increased OVA-induced p-PDK1 protein levels, it decreased phosphorylated Akt (pAkt)/Akt levels. Soluble CLDN18 levels were lower in patients with asthma than in controls and were correlated with the percentage of neutrophils, forced expiratory volume in 1 second (FEV1)/forced vital capacity % (FVC%) and FEV1%. Conclusions: CLDN18 plays a role in the pathogenesis of asthma and NAC diminishes airway inflammation and responsiveness by modulating CLDN18 expression.
참고문헌 (26)
- Harkness LM, "Tumstatin regulates the angiogenic and inflammatory potential of airway smooth muscle extracellular matrix", J Cell Mol Med, 21, pp.3288~3297 (2017)
- Ebina M, "Hyperreactive site in the airway tree of asthmatic patients revealed by thickening of bronchial muscles : a morphometric study", Am Rev Respir Dis, 141, pp.1327~1332 (1990)
- Wilson J, "The bronchial microcirculation in asthma", Clin Exp Allergy, 30(Suppl 1), pp.51~53 (2000)
- Davies DE, "Epithelial barrier function and immunity in asthma", Ann Am Thorac Soc, 11(Suppl 5), pp.S244~S251 (2014)
- Park CS, "Collection between RAST and skin test for inhalant offending allergens", Allergy, 3, pp.1~9 (1983)
- Hammad H, "House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells", Nat Med, 15, pp.410~416 (2009)
- Georas SN, "Epithelial barrier function : at the front line of asthma immunology and allergic airway inflammation", J Allergy Clin Immunol, 134, pp.509~520 (2014)
- 진현정, "Claudin may be a Potential Biomarker for Epithelial Barrier Dysfunction in Asthma", Allergy, Asthma & Immunology Research, 10(1), pp.4~5 (2018), 대한천식알레르기학회
- Schleimer RP, "Epithelium : at the interface of innate and adaptive immune responses", J Allergy Clin Immunol, 120, pp.1279~1284 (2007)
- Tsukita S, "Multifunctional strands in tight junctions", Nat Rev Mol Cell Biol, 2, pp.285~293 (2001)
- Farquhar MG, "Junctional complexes in various epithelia", J Cell Biol, 17, pp.375~412 (1963)
- van Meer G, "The tight junction does not allow lipid molecules to diffuse from one epithelial cell to the next", Nature, 322, pp.639~641 (1986)
- "Global strategy for asthma management and prevention 2014" (2014)[URL]
- Furuse M, "Claudin-1 and-2 : novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin", J Cell Biol, 141, pp.1539~1550 (1998)
- Morita K, "Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands", Proc Natl Acad Sci U S A, 96, pp.511~516 (1999)
- Cereijido M, "Tight junction and polarity interaction in the transporting epithelial phenotype", Biochim Biophys Acta, 1778, pp.770~793 (2008)
- Furuse M, "A single gene product, claudin-1 or-2, reconstitutes tight junction strands and recruits occludin in fibroblasts", J Cell Biol, 143, pp.391~401 (1998)
- Cording J, "In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization", J Cell Sci, 126, pp.554~564 (2013)
- Van Itallie CM, "Claudin interactions in and out of the tight junction", Tissue Barriers, 1, pp.e25247~ (2013)
- Koval M, "Claudin heterogeneity and control of lung tight junctions", Annu Rev Physiol, 75, pp.551~567 (2013)
- Schlingmann B, "Claudins : gatekeepers of lung epithelial function", Semin Cell Dev Biol, 42, pp.47~57 (2015)
- Ohta H, "Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis", Am J Physiol Lung Cell Mol Physiol, 302, pp.L193~L205 (2012)
- Ouban A, "Claudins in human cancer : a review", Histol Histopathol, 25, pp.83~90 (2010)
- Soini Y, "Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumours", Histopathology, 46, pp.551~560 (2005)
- Sweerus K, "Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma", J Allergy Clin Immunol, 139, pp.72~81 (2017)
- Shimobaba S, "Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells", Biochim Biophys Acta, 1863, pp.1170~1178 (2016)