Effects of fine particulate matter on airway remodeling and Notch signaling pathway in asthmatic mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WU Jirong , HE Zhen , ZENG Xiaoli , BAO Hairong ,  LIU Xiaoju

Department of Geriatric Respiratory Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding?author：

LIU Xiaoju, Email: liuxiaoju835@126.com

Keywords：

Asthma; particulate matter 2.5; Notch signaling pathway; airway remodeling

DOI：

10.7507/1671-6205.202202004

Video：

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Objective To observe the effects of fine particulate matter (PM2.5) on airway remodeling and Notch signaling pathway in mice with bronchial asthma, and explore the possible mechanism of its influence on airway remodeling in asthmatic mice. Methods Forty eight-week-old SPF female BALB/c mice were divided into a healthy control group, a healthy PM2.5 group, an asthma group and an asthma PM2.5 group by random number table, with 10 mice in each group. The asthma group and the asthma PM2.5 group were sensitized with ovalbumin to establish asthma mouse model, and the healthy PM2.5 group and the asthma PM2.5 group received aerosol inhalation of PM2.5 (510 μg/m³) after each provocation. After modeling, lung function was measured in each group. Hematoxylin and eosin staining and Masson staining were performed on the lung tissue sections of mice. Image analysis software was used to determine the circumference of the bronchial basement membrane, the total area of the bronchial wall, the area of bronchial smooth muscle and the area of collagen deposition. The expressions of Notch1, Hes1, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and type Ⅰ collagen (Col-Ⅰ) were detected by immunohistochemistry and western blotting. The content of hydroxyproline (HYP) in lung tissue was determined by alkaline water method. Results The total airway wall area, airway smooth muscle area and collagen deposition area in the asthma group [(365.81±46.10), (132.80±20.14), (221.82±25.20) μm²/μm] were significantly higher than those in the healthy control group [(187.70±14.80), (89.73±8.49), (123.91±16.88) μm²/μm] (P<0.01). The healthy PM2.5 group [(244.62±42.86), (116.40±20.40), (174.91±57.41) μm²/μm] and the asthma PM2.5 group [(447.70±76.14), (236.14±36.35), (294.89±75.96) μm²/μm] were higher than those in the control group (all P<0.01). The expressions of Notch1, Hes1, α-SMA, TGF-β1 and Col-Ⅰ were strongly positive in the lung tissues of the asthmatic mice, but weak in the healthy control group. After PM2.5 intervention, compared with the control group, the expression intensity of the above molecules increased. Notch1 receptor and downstream Hes1 protein in the asthma group (0.86±0.10, 1.02±0.06) were significantly higher than those in the healthy control group (0.26±0.07, 0.56±0.09) (all P<0.01). The healthy PM2.5 group (0.44±0.06, 0.77±0.07) and asthma PM2.5 group (1.33±0.23, 1.25±0.18) were higher than the control group (all P<0.01). Airway remodeling related molecules α-SMA, TGF-β1 and Col-Ⅰ protein in the asthma group (0.60±0.04, 0.52±0.09, 0.36±0.04) were significantly higher than those in the healthy control group (0.31±0.03, 0.22±0.04, 0.23±0.04) (all P<0.01). The health PM2.5 group (0.49±0.02, 0.30±0.03, 0.28±0.03) and the asthma PM2.5 group (0.88±0.09, 0.62±0.03, 0.49±0.07) were higher than the control group (P<0.05 or P<0.01), respectively. The content of HYP in lung tissue of the asthma group (57.71±7.60) μg/100mg was significantly higher than that of healthy control group (40.53±5.73) μg/100mg. The healthy PM2.5 group (53.92±6.82) μg/100mg and asthma PM2.5 group (70.96±4.44) μg/100mg were higher than the control group (P<0.01), respectively. In asthma group and asthma PM2.5 group, the expression of Notch1 and Hes1 protein was positively correlated with the total airway wall area, airway smooth muscle area, collagen deposition area, α-SMA, TGF-β1, Col-Ⅰ and HYP (all P<0.01). Conclusion PM2.5 can promote early airway remodeling in asthma, and the activation of Notch signaling pathway may be involved in the promoting effect of PM2.5 on early airway remodeling.

Citation： WU Jirong, HE Zhen, ZENG Xiaoli, BAO Hairong, LIU Xiaoju. Effects of fine particulate matter on airway remodeling and Notch signaling pathway in asthmatic mice. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(4): 274-281. doi: 10.7507/1671-6205.202202004 Copy

1.	Liu JN, Suh DH, Trinh HK, et al. The role of autophagy in allergic inflammation: a new target for severe asthma. Exp Mol Med, 2016, 48(7): e243.
2.	Zuo B, Liu C, Chen R, et al. Associations between short-term exposure to fine particulate matter and acute exacerbation of asthma in Yancheng, China. Chemosphere, 2019, 237: 124497.
3.	Ma Y, Yu Z, Jiao H, et al. Short-term effect of PM2.5 on pediatric asthma incidence in Shanghai, China. Environ Sci Pollut Res Int, 2019, 26(27): 27832-27841.
4.	Xu X, Wang H, Liu S, et al. TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2. 5). Autophagy, 2016, 12(10): 1832-1848.
5.	Ye X, Hong W, Hao B, et al. PM2. 5 promotes human bronchial smooth muscle cell migration via the sonic hedgehog signaling pathway. Respir Res, 2018, 19(1): 37.
6.	Hussain M, Xu C, Ahmad M, et al. Notch signaling: linking embryonic lung development and asthmatic airway remodeling. Mol Pharmacol, 2017, 92(6): 676-693.
7.	Liu Y, Zhou L, Wu H, et al. Role of notch signaling pathway in Muc5ac secretion induced by atmospheric PM2.5 in rats. Ecotoxicol Environ Saf, 2022, 229: 113052.
8.	Janulaityte I, Januskevicius A, Kalinauskaite-Zukauske V, et al. In vivo allergen-activated eosinophils promote collagen I and fibronectin gene expression in airway smooth muscle cells via TGF-β1 signaling pathway in asthma. Int J Mol Sci, 2020, 21(5): 1837.
9.	Jiang JX, Guan Y, Shen HJ, et al. Inhibition of soluble epoxide hydrolase attenuates airway remodeling in a chronic asthma model. Eur J Pharmacol, 2020, 868: 172874.
10.	Chu X, Liu XJ, Qiu JM, et al. Effects of Astragalus and Codonopsis pilosula polysaccharides on alveolar macrophage phagocytosis and inflammation in chronic obstructive pulmonary disease mice exposed to PM2.5. Environ Toxicol Pharmacol, 2016, 48: 76-84.
11.	雷澤林, 劉曉菊, 馬建秀, 等. 苦參堿對支氣管哮喘小鼠氣道炎癥和早期氣道重塑的影響. 中華結核和呼吸雜志, 2009, 32(3): 165-170.
12.	Temelkovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax, 1998, 53(10): 849-856.
13.	Gu XY, Chu X, Zeng XL, et al. Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease. Environ Pollut, 2017, 226: 163-173.
14.	藍凰齊, 張世田, 唐漢慶, 等. 木姜子和忍冬藤配伍乙醇提取物減輕哮喘小鼠氣道炎癥的效果. 中國老年學雜志, 2020, 40(14): 3057-3061.
15.	Henderson WR Jr, Tang LO, Chu SJ, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med, 2002, 165(1): 108-116.
16.	Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond), 2017, 131(13): 1541-1558.
17.	Zhou-Suckow Z, Duerr J, Hagner M, et al. Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases. Cell Tissue Res, 2017, 367(3): 537-550.
18.	Elliot JG, Noble PB, Mauad T, et al. Inflammation-dependent and independent airway remodelling in asthma. Respirology, 2018, 23(12): 1138-1145.
19.	顧曉菲, 陳慧君, 陳鑫淼, 等. RAGE 在哮喘大鼠中的表達及羅紅霉素的干預作用. 中華醫學雜志, 2019, 99(32): 2542-2546.
20.	王瑞茵, 李紅雯, 張清, 等. 青蒿琥酯對哮喘小鼠氣道反應性和氣道炎癥的影響. 中華醫學雜志, 2019, 99(32): 2536-2541.
21.	Zhu X, Li Q, Hu G, et al. BMS-345541 inhibits airway inflammation and epithelial-mesenchymal transition in airway remodeling of asthmatic mice. Int J Mol Med, 2018, 42(4): 1998-2008.
22.	Ojiaku CA, Cao G, Zhu W, et al. TGF-β1 evokes human airway smooth muscle cell shortening and hyperresponsiveness via Smad3. Am J Respir Cell Mol Biol, 2018, 58(5): 575-584.
23.	Shen QY, Wu L, Wei CS, et al. Sevoflurane prevents airway remodeling via downregulation of VEGF and TGF-β1 in mice with ova-induced chronic airway inflammation. Inflammation, 2019, 42(3): 1015-1022.
24.	Dong L, Wang Y, Zheng T, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Res Ther, 2021, 12(1): 4.
25.	常琴, 田新利, 霍如婕, 等. 人臍帶間充質干細胞對支氣管哮喘大鼠氣道重塑的治療作用及可能機制. 中華醫學雜志, 2018, 98(28): 2258-2263.
26.	Huang C, Zhang Z, Wang L, et al. ML-7 attenuates airway inflammation and remodeling via inhibiting the secretion of Th2 cytokines in mice model of asthma. Mol Med Rep, 2018, 17(5): 6293-6300.
27.	門翔, 李蘊麟, 曾曉麗, 等. 青藤堿對博萊霉素致小鼠肺纖維化的影響及其機制. 中華結核和呼吸雜志, 2012, 35(10): 783-785.
28.	霍少娟, 胡悅, 曾曉麗, 等. 吸入細顆粒物通過 Arp2/3 復合體影響慢性阻塞性肺疾病肺泡巨噬細胞吞噬功能的可能機制研究. 中華結核和呼吸雜志, 2019, 42(12): 907-915.
29.	Li Y, Chen L, Guo F, et al. Effects of epigallocatechin-3-gallate on the HMGB1/RAGE pathway in PM2.5-exposed asthmatic rats. Biochem Biophys Res Commun, 2019, 513(4): 898-903.
30.	Chen WH, Lee KH, Mutuku JK, et al. Flow dynamics and PM2.5 deposition in healthy and asthmatic airways at different inhalation statuses. Aerosol Air Qual Res, 2018, 18(4): 866-883.
31.	Liu Y, Feng GZ, Du Q, et al. Fine particulate matter aggravates allergic airway inflammation through thymic stromal lymphopoietin activation in mice. Mol Med Rep, 2017, 16(4): 4201-4207.
32.	Hu C, Li Z, Feng J, et al. Glucocorticoids modulate Th1 and Th2 responses in asthmatic mouse models by inhibition of Notch1 signaling. Int Arch Allergy Immunol, 2018, 175(1-2): 44-52.
33.	Hu M, Ou-Yang HF, Han XP, et al. KyoT2 downregulates airway remodeling in asthma. Int J Clin Exp Pathol, 2015, 8(11): 14171-14179.
34.	Liu Y, Zhou T, Sun L, et al. The effect of Notch signal pathway on PM2.5-induced Muc5ac in Beas-2B cells. Ecotoxicol Environ Saf, 2020, 203: 110956.
35.	Xia M, Harb H, Saffari A, et al. A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles. J Allergy Clin Immunol, 2018, 142(4): 1243-1256.e17.

1. Liu JN, Suh DH, Trinh HK, et al. The role of autophagy in allergic inflammation: a new target for severe asthma. Exp Mol Med, 2016, 48(7): e243.
2. Zuo B, Liu C, Chen R, et al. Associations between short-term exposure to fine particulate matter and acute exacerbation of asthma in Yancheng, China. Chemosphere, 2019, 237: 124497.
3. Ma Y, Yu Z, Jiao H, et al. Short-term effect of PM2.5 on pediatric asthma incidence in Shanghai, China. Environ Sci Pollut Res Int, 2019, 26(27): 27832-27841.
4. Xu X, Wang H, Liu S, et al. TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2. 5). Autophagy, 2016, 12(10): 1832-1848.
5. Ye X, Hong W, Hao B, et al. PM2. 5 promotes human bronchial smooth muscle cell migration via the sonic hedgehog signaling pathway. Respir Res, 2018, 19(1): 37.
6. Hussain M, Xu C, Ahmad M, et al. Notch signaling: linking embryonic lung development and asthmatic airway remodeling. Mol Pharmacol, 2017, 92(6): 676-693.
7. Liu Y, Zhou L, Wu H, et al. Role of notch signaling pathway in Muc5ac secretion induced by atmospheric PM2.5 in rats. Ecotoxicol Environ Saf, 2022, 229: 113052.
8. Janulaityte I, Januskevicius A, Kalinauskaite-Zukauske V, et al. In vivo allergen-activated eosinophils promote collagen I and fibronectin gene expression in airway smooth muscle cells via TGF-β1 signaling pathway in asthma. Int J Mol Sci, 2020, 21(5): 1837.
9. Jiang JX, Guan Y, Shen HJ, et al. Inhibition of soluble epoxide hydrolase attenuates airway remodeling in a chronic asthma model. Eur J Pharmacol, 2020, 868: 172874.
10. Chu X, Liu XJ, Qiu JM, et al. Effects of Astragalus and Codonopsis pilosula polysaccharides on alveolar macrophage phagocytosis and inflammation in chronic obstructive pulmonary disease mice exposed to PM2.5. Environ Toxicol Pharmacol, 2016, 48: 76-84.
11. 雷澤林, 劉曉菊, 馬建秀, 等. 苦參堿對支氣管哮喘小鼠氣道炎癥和早期氣道重塑的影響. 中華結核和呼吸雜志, 2009, 32(3): 165-170.
12. Temelkovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax, 1998, 53(10): 849-856.
13. Gu XY, Chu X, Zeng XL, et al. Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease. Environ Pollut, 2017, 226: 163-173.
14. 藍凰齊, 張世田, 唐漢慶, 等. 木姜子和忍冬藤配伍乙醇提取物減輕哮喘小鼠氣道炎癥的效果. 中國老年學雜志, 2020, 40(14): 3057-3061.
15. Henderson WR Jr, Tang LO, Chu SJ, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med, 2002, 165(1): 108-116.
16. Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci (Lond), 2017, 131(13): 1541-1558.
17. Zhou-Suckow Z, Duerr J, Hagner M, et al. Airway mucus, inflammation and remodeling: emerging links in the pathogenesis of chronic lung diseases. Cell Tissue Res, 2017, 367(3): 537-550.
18. Elliot JG, Noble PB, Mauad T, et al. Inflammation-dependent and independent airway remodelling in asthma. Respirology, 2018, 23(12): 1138-1145.
19. 顧曉菲, 陳慧君, 陳鑫淼, 等. RAGE 在哮喘大鼠中的表達及羅紅霉素的干預作用. 中華醫學雜志, 2019, 99(32): 2542-2546.
20. 王瑞茵, 李紅雯, 張清, 等. 青蒿琥酯對哮喘小鼠氣道反應性和氣道炎癥的影響. 中華醫學雜志, 2019, 99(32): 2536-2541.
21. Zhu X, Li Q, Hu G, et al. BMS-345541 inhibits airway inflammation and epithelial-mesenchymal transition in airway remodeling of asthmatic mice. Int J Mol Med, 2018, 42(4): 1998-2008.
22. Ojiaku CA, Cao G, Zhu W, et al. TGF-β1 evokes human airway smooth muscle cell shortening and hyperresponsiveness via Smad3. Am J Respir Cell Mol Biol, 2018, 58(5): 575-584.
23. Shen QY, Wu L, Wei CS, et al. Sevoflurane prevents airway remodeling via downregulation of VEGF and TGF-β1 in mice with ova-induced chronic airway inflammation. Inflammation, 2019, 42(3): 1015-1022.
24. Dong L, Wang Y, Zheng T, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Res Ther, 2021, 12(1): 4.
25. 常琴, 田新利, 霍如婕, 等. 人臍帶間充質干細胞對支氣管哮喘大鼠氣道重塑的治療作用及可能機制. 中華醫學雜志, 2018, 98(28): 2258-2263.
26. Huang C, Zhang Z, Wang L, et al. ML-7 attenuates airway inflammation and remodeling via inhibiting the secretion of Th2 cytokines in mice model of asthma. Mol Med Rep, 2018, 17(5): 6293-6300.
27. 門翔, 李蘊麟, 曾曉麗, 等. 青藤堿對博萊霉素致小鼠肺纖維化的影響及其機制. 中華結核和呼吸雜志, 2012, 35(10): 783-785.
28. 霍少娟, 胡悅, 曾曉麗, 等. 吸入細顆粒物通過 Arp2/3 復合體影響慢性阻塞性肺疾病肺泡巨噬細胞吞噬功能的可能機制研究. 中華結核和呼吸雜志, 2019, 42(12): 907-915.
29. Li Y, Chen L, Guo F, et al. Effects of epigallocatechin-3-gallate on the HMGB1/RAGE pathway in PM2.5-exposed asthmatic rats. Biochem Biophys Res Commun, 2019, 513(4): 898-903.
30. Chen WH, Lee KH, Mutuku JK, et al. Flow dynamics and PM2.5 deposition in healthy and asthmatic airways at different inhalation statuses. Aerosol Air Qual Res, 2018, 18(4): 866-883.
31. Liu Y, Feng GZ, Du Q, et al. Fine particulate matter aggravates allergic airway inflammation through thymic stromal lymphopoietin activation in mice. Mol Med Rep, 2017, 16(4): 4201-4207.
32. Hu C, Li Z, Feng J, et al. Glucocorticoids modulate Th1 and Th2 responses in asthmatic mouse models by inhibition of Notch1 signaling. Int Arch Allergy Immunol, 2018, 175(1-2): 44-52.
33. Hu M, Ou-Yang HF, Han XP, et al. KyoT2 downregulates airway remodeling in asthma. Int J Clin Exp Pathol, 2015, 8(11): 14171-14179.
34. Liu Y, Zhou T, Sun L, et al. The effect of Notch signal pathway on PM2.5-induced Muc5ac in Beas-2B cells. Ecotoxicol Environ Saf, 2020, 203: 110956.
35. Xia M, Harb H, Saffari A, et al. A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles. J Allergy Clin Immunol, 2018, 142(4): 1243-1256.e17.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of fine particulate matter on airway remodeling and Notch signaling pathway in asthmatic mice

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