三叶因子对小鼠急性过敏性气道炎症及黏液分泌的影响
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摘要
目的检测不同干预措施后急性过敏性气道炎症小鼠的气道中三叶因子1(TFF1)、三叶因子3(TFF3)的表达水平,并初步探讨重组TFF3对气道炎症反应及黏液分泌水平的影响。方法 40只BALB/c小鼠随机分为生理盐水对照组(A组)、急性过敏性气道炎症组(B组)、布地奈德干预组(C组)、TFF3重组体干预组(D组)、TFF3+布地奈德干预组(E组),每组8只。卵清蛋白致敏及激发构建小鼠急性过敏性气道炎症期模型,苏木精–伊红染色光镜下观察肺组织炎症情况,阿辛蓝染色分析气道黏液分泌情况,免疫组织化学分析气道TFF1、TFF3表达情况。结果气道炎症评分及黏液分泌情况:B组显著大于A组(P<0.01),C组小于B组(P<0.05),D组与B组相比无明显差异(P>0.05),C组与E组相比无明显差异(P>0.05)。TFFs的表达:TFF1、TFF3在A、B、C组支气管及细支气管上皮细胞、杯状细胞及黏膜下腺细胞中均有表达;其中B组的TFF1及TFF3表达均显著高于A组(P<0.01),C组的TFF1及TFF3表达低于B组(P<0.05)。气道上皮TFF1水平与气道炎性评分、黏蛋白表达水平均呈显著正相关(r=0.876、0.807,均P=0.000),TFF3水平与炎性评分、黏蛋白表达水平均呈显著正相关(r=0.654,P=0.006;r=0.666,P=0.005)。结论小鼠急性过敏性气道炎症期气道TFF1、TFF3表达增高。经鼻滴入外源性TFF3对气道炎症及黏液分泌均无明显影响,吸入糖皮质激素可一定程度抑制TFF1和TFF3的表达,同时抑制气道炎症及黏液分泌。
Objectives To detect expressions of trefoil factor 1(TFF1) and TFF3 in the mice with acute allergic airway disease(AAD) after different interventions, and explore primitively the effect of recombinant TFF3 on airway inflammation and mucous secretion. Methods Forty BALB/c mice were randomly divided into 5 groups, each group with 8 mice, ie. a normal saline control group(group A), an AAD group(group B), a budesonide intervention group(group C), a recombinant TFF3 intervention group(group D), and a budesonide+recombinant TFF3 intervention group(group D). The BALB/c mice were sensitized and challenged with ovalbumin to induce AAD. Lung tissue sections were stained with hematoxylin-eosin staining for assessment of airway inflammation, and immunohistochemistry was used for detecting TFF1/TFF3 expression in the airway. Alcian blue stain was applied to determine mucous secretion. Results Airway inflammation score and airway mucous secretion: Group B was significantly more than group A(P<0.01); Group C was less than group B(P<0.05), and there was no significant difference between group D and group B(P>0.05); There was no significant difference between group C and group E(P>0.05). Expression of TFFs: TFF1 and TFF3 were expressed in epithelial cells, goblet cells and submucosal gland cells of bronchi and bronchioles in all groups; The expressions of TFF1 and TFF3 in group B were significantly higher than those in group A(P<0.01), while the expressions of TFF1 and TFF3 in group C were lower than those in group B(P<0.05). TFF1 expression in airway epithelium was positively correlated with inflammatory score(r=0.876, P=0.000) and mucin expression(r=0.807, P=0.000). TFF3 level was positively correlated with inflammatory score(r=0.654, P=0.006) and mucin expression(r=0.666, P=0.005). Conclusions Ovalbumininduced acute allergic airway inflammation significantly increases TFF1/TFF3 expression. Intranasal TFF3 treatment may not influence airway inflammation and mucus secretion. Inhaled corticosteroids to some extent inhibit expressions of TFF1 and TFF3, simultaneously suppress airway inflammation and mucus secretion in the mouse model of acute AAD.
Objectives To detect expressions of trefoil factor 1(TFF1) and TFF3 in the mice with acute allergic airway disease(AAD) after different interventions, and explore primitively the effect of recombinant TFF3 on airway inflammation and mucous secretion. Methods Forty BALB/c mice were randomly divided into 5 groups, each group with 8 mice, ie. a normal saline control group(group A), an AAD group(group B), a budesonide intervention group(group C), a recombinant TFF3 intervention group(group D), and a budesonide+recombinant TFF3 intervention group(group D). The BALB/c mice were sensitized and challenged with ovalbumin to induce AAD. Lung tissue sections were stained with hematoxylin-eosin staining for assessment of airway inflammation, and immunohistochemistry was used for detecting TFF1/TFF3 expression in the airway. Alcian blue stain was applied to determine mucous secretion. Results Airway inflammation score and airway mucous secretion: Group B was significantly more than group A(P<0.01); Group C was less than group B(P<0.05), and there was no significant difference between group D and group B(P>0.05); There was no significant difference between group C and group E(P>0.05). Expression of TFFs: TFF1 and TFF3 were expressed in epithelial cells, goblet cells and submucosal gland cells of bronchi and bronchioles in all groups; The expressions of TFF1 and TFF3 in group B were significantly higher than those in group A(P<0.01), while the expressions of TFF1 and TFF3 in group C were lower than those in group B(P<0.05). TFF1 expression in airway epithelium was positively correlated with inflammatory score(r=0.876, P=0.000) and mucin expression(r=0.807, P=0.000). TFF3 level was positively correlated with inflammatory score(r=0.654, P=0.006) and mucin expression(r=0.666, P=0.005). Conclusions Ovalbumininduced acute allergic airway inflammation significantly increases TFF1/TFF3 expression. Intranasal TFF3 treatment may not influence airway inflammation and mucus secretion. Inhaled corticosteroids to some extent inhibit expressions of TFF1 and TFF3, simultaneously suppress airway inflammation and mucus secretion in the mouse model of acute AAD.
引文
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2 Hoffmann W.TFF(trefoil factor family)peptides and their potential roles for differentiation processes during airway remodeling.Curr Med Chem,2007,14(25):2716-2719.
3 LeSimple P,van Seuningen I,Buisine MP,et al.Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation.Am J Respir Cell Mol Biol,2007,36(3):296-303.
4 Aihara E,Engevik KA,Montrose MH.Trefoil factor peptides and gastrointestinal function.Annu Rev Physiol,2017,79:357-380.
5 Royce SG,Li X,Goodings L,et al.Mechanistic insights into the contribution of epithelial damage to airway remodeling.Novel therapeutic targets for asthma.Am J Respir Cell Mol Biol,2014,50(1):180-192.
6 Nourani MR,Farajpour Z,Najafi A,et al.Trefoil factor family 1 is involved in airway remodeling of mustard lung.Iran J Allergy Asthma Immunol,2016,15(4):275-282.
7 Fuchs B,Knothe S,Rochlitzer S,et al.A Toll-like receptor 2/6agonist reduces allergic airway inflammation in chronic respiratory sensitisation to Timothy grass pollen antigens.Int Arch Allergy Immunol,2010,152(2):131-139.
8 Zhu Z,Zheng T,Homer RJ,et al.Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation.Science,2004,304(5677):1678-1682.
9 Siddiqui S,Martin JG.Structural aspects of airway remodeling in asthma.Curr Allergy Asthma Rep,2008,8(6):540-547.
10 Bosse Y,Pare PD,Seow CY.Airway wall remodeling in asthma:from the epithelial layer to the adventitia.Curr Allergy Asthma Rep,2008,8(4):357-366.
11 Locke NR,Royce SG,Wainewright JS,et al.Comparison of airway remodeling in acute,subacute,and chronic models of allergic airways disease.Am J Respir Cell Mol Biol,2007,36(5):625-632.
12 Ray A,Cohn L.Th2 cells and GATA-3 in asthma:new insights into the regulation of airway inflammation.J Clin Inves,1999,104(8):985-993.
13 Madsen J,Nielsen O,Tornoe I,et al.Tissue localization of human trefoil factors 1,2,and 3.J Histochem Cytochem,2007,55(5):505-513.
14 dos Santos Silva E,Ulrich M,During G,et al.Trefoil factor family domain peptides in the human respiratory tract.J Pathol,2000,190(2):133-142.
15 Viby NE,Nexo E,Kissow H,et al.Trefoil factors(TFFs)areincreased in bronchioalveolar lavage fluid from patients with chronic obstructive lung disease(COPD).Peptides,2015,63:90-95.
16 Viby NE,Pedersen L,Lund TK,et al.Trefoil factor peptides in serum and sputum from subjects with asthma and COPD.Clin Respir J,2015,9(3):322-329.
17 Royce SG,Lim C,Muljadi RC,et al.Trefoil factor 2 reverses airway remodeling changes in allergic airways disease.Am J Respir Cell Mol Biol,2013,48(1):135-144.
18 Oertel M,Graness A,Thim L,et al.Trefoil factor family-peptides promote migration of human bronchial epithelial cells.Am J Respir Cell Mol Biol,2001,25(4):418-424.
19 Nikolaidis NM,Wang TC,Hogan SP,et al.Allergen induced TFF2is expressed by mucus-producing airway epithelial cells but is not a major regulator of inflammatory responses in the murine lung.Exp Lung Res,2006,32(10):483-497.
20 Nikolaidis NM,Zimmermann N,King NE,et al. Trefoil factor-2 is an allergen-induced gene regulated by Th2 cytokines and STAT6 in the lung.Am J Respir Cell Mol Biol,2003,29(4):458-464.
21 Arnold P,Rickert U,Helmers AK,et al.Trefoil factor 3 shows antiinflammatory effects on activated microglia.Cell Tissue Res,2016,365(1):3-11.
2 Hoffmann W.TFF(trefoil factor family)peptides and their potential roles for differentiation processes during airway remodeling.Curr Med Chem,2007,14(25):2716-2719.
3 LeSimple P,van Seuningen I,Buisine MP,et al.Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation.Am J Respir Cell Mol Biol,2007,36(3):296-303.
4 Aihara E,Engevik KA,Montrose MH.Trefoil factor peptides and gastrointestinal function.Annu Rev Physiol,2017,79:357-380.
5 Royce SG,Li X,Goodings L,et al.Mechanistic insights into the contribution of epithelial damage to airway remodeling.Novel therapeutic targets for asthma.Am J Respir Cell Mol Biol,2014,50(1):180-192.
6 Nourani MR,Farajpour Z,Najafi A,et al.Trefoil factor family 1 is involved in airway remodeling of mustard lung.Iran J Allergy Asthma Immunol,2016,15(4):275-282.
7 Fuchs B,Knothe S,Rochlitzer S,et al.A Toll-like receptor 2/6agonist reduces allergic airway inflammation in chronic respiratory sensitisation to Timothy grass pollen antigens.Int Arch Allergy Immunol,2010,152(2):131-139.
8 Zhu Z,Zheng T,Homer RJ,et al.Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation.Science,2004,304(5677):1678-1682.
9 Siddiqui S,Martin JG.Structural aspects of airway remodeling in asthma.Curr Allergy Asthma Rep,2008,8(6):540-547.
10 Bosse Y,Pare PD,Seow CY.Airway wall remodeling in asthma:from the epithelial layer to the adventitia.Curr Allergy Asthma Rep,2008,8(4):357-366.
11 Locke NR,Royce SG,Wainewright JS,et al.Comparison of airway remodeling in acute,subacute,and chronic models of allergic airways disease.Am J Respir Cell Mol Biol,2007,36(5):625-632.
12 Ray A,Cohn L.Th2 cells and GATA-3 in asthma:new insights into the regulation of airway inflammation.J Clin Inves,1999,104(8):985-993.
13 Madsen J,Nielsen O,Tornoe I,et al.Tissue localization of human trefoil factors 1,2,and 3.J Histochem Cytochem,2007,55(5):505-513.
14 dos Santos Silva E,Ulrich M,During G,et al.Trefoil factor family domain peptides in the human respiratory tract.J Pathol,2000,190(2):133-142.
15 Viby NE,Nexo E,Kissow H,et al.Trefoil factors(TFFs)areincreased in bronchioalveolar lavage fluid from patients with chronic obstructive lung disease(COPD).Peptides,2015,63:90-95.
16 Viby NE,Pedersen L,Lund TK,et al.Trefoil factor peptides in serum and sputum from subjects with asthma and COPD.Clin Respir J,2015,9(3):322-329.
17 Royce SG,Lim C,Muljadi RC,et al.Trefoil factor 2 reverses airway remodeling changes in allergic airways disease.Am J Respir Cell Mol Biol,2013,48(1):135-144.
18 Oertel M,Graness A,Thim L,et al.Trefoil factor family-peptides promote migration of human bronchial epithelial cells.Am J Respir Cell Mol Biol,2001,25(4):418-424.
19 Nikolaidis NM,Wang TC,Hogan SP,et al.Allergen induced TFF2is expressed by mucus-producing airway epithelial cells but is not a major regulator of inflammatory responses in the murine lung.Exp Lung Res,2006,32(10):483-497.
20 Nikolaidis NM,Zimmermann N,King NE,et al. Trefoil factor-2 is an allergen-induced gene regulated by Th2 cytokines and STAT6 in the lung.Am J Respir Cell Mol Biol,2003,29(4):458-464.
21 Arnold P,Rickert U,Helmers AK,et al.Trefoil factor 3 shows antiinflammatory effects on activated microglia.Cell Tissue Res,2016,365(1):3-11.
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