Effects of trefoil factors on acute allergic airway inflammation and mucous secretion in mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZENG Qingcui ¹ ^# , ZHANG Minhui ² ^# , CHENG Zhengyan ³ ,  LONG Huaicong ¹

1. Geriatric ICU of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, P. R. China;
2. North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
3. Department of Pathology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital (East Hosipital), Chengdu, Sichuan 610100, P. R. China;

Corresponding author：

LONG Huaicong, Email: longhc69@163.com

Keywords：

Trefoil factor; Asthma; Acute allergic inflammation; Mucous secretion

DOI：

10.7507/1671-6205.201812027

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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 Ovalbumin-induced 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 .

Citation： ZENG Qingcui, ZHANG Minhui, CHENG Zhengyan, LONG Huaicong. Effects of trefoil factors on acute allergic airway inflammation and mucous secretion in mice. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(5): 441-446. doi: 10.7507/1671-6205.201812027 Copy

1.	Kjellev S. The trefoil factor family: small peptides with multiple functionalities. Cell Mol Life Sci, 2009, 66(9): 1350-1369.
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 2/6 agonist 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.	Bossé Y, Paré 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, Tornøe 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, UIrich M, Döring G, et al. Trefoil factor family domain peptides in the human respiratory tract. J Pathol, 2000, 190(2): 133-142.
15.	Viby NE, Nexø E, Kissow H, et al. Trefoil factors (TFFs) are increased 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 TFF2 is 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 anti-inflammatory effects on activated microglia. Cell Tissue Res, 2016, 365(1): 3-11.

1. Kjellev S. The trefoil factor family: small peptides with multiple functionalities. Cell Mol Life Sci, 2009, 66(9): 1350-1369.
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 2/6 agonist 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. Bossé Y, Paré 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, Tornøe 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, UIrich M, Döring G, et al. Trefoil factor family domain peptides in the human respiratory tract. J Pathol, 2000, 190(2): 133-142.
15. Viby NE, Nexø E, Kissow H, et al. Trefoil factors (TFFs) are increased 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 TFF2 is 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 anti-inflammatory effects on activated microglia. Cell Tissue Res, 2016, 365(1): 3-11.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of trefoil factors on acute allergic airway inflammation and mucous secretion in mice

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