Abstract
The inhalation of particulate matter (PM) is closely related to respiratory damage, including acute lung injury (ALI), characterized by inflammatory fluid edema and disturbed alveolar-capillary permeability. Ruscogenin (RUS), the main active ingredient in the traditional Chinese medicine Ophiopogonis japonicus, has been found to exhibit anti-inflammatory activity and rescue LPS-induced ALI. In this study, we investigated whether and how RUS exerted therapeutic effects on PM-induced ALI. RUS (0.1, 0.3, 1 mg·kg−1·d−1) was orally administered to mice prior to or after intratracheal instillation of PM suspension (50 mg/kg). We showed that RUS administration either prior to or after PM challenge significantly attenuated PM-induced pathological injury, lung edema, vascular leakage and VE-cadherin expression in lung tissue. RUS administration significantly decreased the levels of cytokines IL-6 and IL-1β, as well as the levels of NO and MPO in both bronchoalveolar lavage fluid (BALF) and serum. RUS administration dose-dependently suppressed the phosphorylation of NF-κB p65 and the expression of TLR4 and MyD88 in lung tissue. Furthermore, TLR4 knockout partly diminished PM-induced lung injury, and abolished the protective effects of RUS in PM-instilled mice. In conclusion, RUS effectively alleviates PM-induced ALI probably by inhibition of vascular leakage and TLR4/MyD88 signaling. TLR4 might be crucial for PM to initiate pulmonary lesion and for RUS to exert efficacy against PM-induced lung injury.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Landrigan PJ, Fuller R, Acosta NJR, Adeyi O, Arnold R, Basu NN, et al. The lancet commission on pollution and health. Lancet. 2018;391:462–512.
Cohen AJ, Brauer M, Burnett R, Anderson HR, Frostad J, Estep K, et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the global burden of diseases study 2015. Lancet. 2017;389:1907–18.
Liu L, Xia Z, Li J, Hu Y, Wang Q, Chen J, et al. Fibroblast growth factor 10 protects against particulate matter-induced airway inflammatory response through regulating inflammatory signaling and apoptosis. Am J Transl Res. 2019;11:6977–88.
Li D, Li Y, Li G, Zhang Y, Li J, Chen H. Fluorescent reconstitution on deposition of PM2.5 in lung and extrapulmonary organs. Proc Natl Acad Sci U S A. 2019;116:2488–93.
Deng Q, Deng L, Miao Y, Guo X, Li Y. Particle deposition in the human lung: health implications of particulate matter from different sources. Environ Res. 2019;169:237–45.
Feng S, Gao D, Liao F, Zhou F, Wang X. The health effects of ambient PM2.5 and potential mechanisms. Ecotoxicol Environ Saf. 2016;128:67–74.
Pope CA 3rd, Bhatnagar A, McCracken JP, Abplanalp W, Conklin DJ, O’Toole T. Exposure to fine particulate air pollution is associated with endothelial injury and systemic inflammation. Circ Res. 2016;119:1204–14.
Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nat Rev Dis Prim. 2019;5:18. https://doi.org/10.1038/s41572-019-0069-0.
Reilly JP, Zhao Z, Shashaty M, Koyama T, Christie JD, Lanken PN, et al. Low to moderate air pollutant exposure and acute respiratory distress syndrome after severe trauma. Am J Respir Crit Care Med. 2019;199:62–70.
Li Y, Dong T, Jiang X, Wang C, Zhang Y, Li Y, et al. Chronic and low-level particulate matter exposure can sustainably mediate lung damage and alter CD4 T cells during acute lung injury. Mol Immunol. 2019;112:51–8.
Karki P, Meliton A, Sitikov A, Tian Y, Ohmura T, Birukova AA. Microtubule destabilization caused by particulate matter contributes to lung endothelial barrier dysfunction and inflammation. Cell Signal. 2019;53:246–55.
Lin CI, Tsai CH, Sun YL, Hsieh WY, Lin YC, Chen CY, et al. Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice. Int J Biol Sci. 2018;14:253–65.
Xu C, Shi Q, Zhang L, Zhao H. High molecular weight hyaluronan attenuates fine particulate matter-induced acute lung injury through inhibition of ROS-ASK1-p38/JNK-mediated epithelial apoptosis. Environ Toxicol Pharmacol. 2018;59:190–8.
Xia Y, S D, Jiang S, Fan R, Wang Y, Wang Y, et al. YiQiFuMai lyophilized injection attenuates particulate matter-induced acute lung injury in mice via TLR4-mTOR-autophagy pathway. Biomed Pharmacother. 2018;108:906–13.
Gu LZ, Sun H, Chen JH. Histone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathways. Biomed Pharmacother. 2017;85:756–62.
Panday A, Inda ME, Bagam P, Sahoo MK, Osorio D, Batra S. Transcription factor NF-κB: an update on intervention strategies. Arch Immunol Ther Exp (Warsz). 2016;64:463–83.
Traboulsi H, Guerrina N, Iu M, Maysinger D, Ariya P, Baglole CJ. Inhaled pollutants: the molecular scene behind respiratory and systemic diseases associated with ultrafine particulate matter. Int J Mol Sci. 2017;18:243.
Jiang D, Liang J, Li Y, Noble PW. The role of toll-like receptors in non-infectious lung injury. Cell Res. 2006;16:693–701.
Peri F, Piazza M. Therapeutic targeting of innate immunity with toll-like receptor 4 (TLR4) antagonists. Biotechnol Adv. 2012;30:251–60.
Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva-Lyubimova TN, Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines (Basel). 2017;5:34. https://doi.org/10.3390/vaccines5040034.
Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al. Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–49.
Hsieh YH, Deng JS, Chang YS, Huang GJ. Ginsenoside Rh2 ameliorates lipopolysaccharide-induced acute lung injury by regulating the TLR4/PI3K/Akt/mTOR, Raf-1/MEK/ERK, and Keap1/Nrf2/HO-1 signaling pathways in mice. Nutrients. 2018;10:1208. https://doi.org/10.3390/nu10091208.
Yan J, Li J, Zhang L, Sun Y, Jiang J, Huang Y, et al. Nrf2 protects against acute lung injury and inflammation by modulating TLR4 and Akt signaling. Free Radic Biol Med. 2018;121:78–85.
Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, et al. Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways. Biomed Pharmacother. 2017;89:660–72.
Tang Q, Huang K, Liu J, Wu S, Shen D, Dai P, et al. Fine particulate matter from pig house induced immune response by activating TLR4/MAPK/NF-κB pathway and NLRP3 inflammasome in alveolar macrophages. Chemosphere. 2019;236:124373.
Dai P, Shen D, Shen J, Tang Q, Xi M, Li Y, et al. The roles of Nrf2 and autophagy in modulating inflammation mediated by TLR4-NFκB in A549 cell exposed to layer house particulate matter 2.5 (PM 2.5). Chemosphere. 2019;235:1134–45.
Chen MH, Chen XJ, Wang M, Lin LG, Wang YT. Ophiopogon japonicus-a phytochemical, ethnomedicinal and pharmacological review. J Ethnopharmacol. 2016;181:193–213.
Sun Q, Chen L, Gao M, Jiang W, Shao F, Li J, et al. Ruscogenin inhibits lipopolysaccharide-induced acute lung injury in mice: involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-κB. Int Immunopharmacol. 2012;12:88–93.
Bi LQ, Zhu R, Kong H, Wu SL, Li N, Zuo XR, et al. Ruscogenin attenuates monocrotaline-induced pulmonary hypertension in rats. Int Immunopharmacol. 2013;16:7–16.
Song J, Kou J, Huang Y, Yu B. Ruscogenin mainly inhibits nuclear factor-kappaB but not Akt and mitogen-activated protein kinase signaling pathways in human umbilical vein endothelial cells. J Pharmacol Sci. 2010;113:409–13.
Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M, et al. Ruscogenin attenuates cerebral ischemia-induced blood-brain barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int J Mol Sci. 2016;17:1418.
Wu Y, Wang Y, Gong S, Tang J, Zhang J, Li F, et al. Ruscogenin alleviates LPS-induced pulmonary endothelial cell apoptosis by suppressing TLR4 signaling. Biomed Pharmacother. 2020;125:109868.
Liu C, Chen R, Sera F, Vicedo-Cabrera AM, Guo Y, Tong S, et al. Ambient particulate air pollution and daily mortality in 652 cities. N Engl J Med. 2019;381:705–15.
Li J, Li H, Li H, Guo W, An Z, Zeng X, et al. Amelioration of PM2.5-induced lung toxicity in rats by nutritional supplementation with fish oil and vitamin E. Respir Res. 2019;20:76. https://doi.org/10.1186/s12931-019-1045-7.
Schraufnagel DE, Balmes JR, Cowl CT, De Matteis S, Jung SH, Mortimer K, et al. Air pollution and noncommunicable diseases: a review by the forum of international respiratory societies’ environmental committee, part 2: air pollution and organ systems. Chest. 2019;155:417–26.
González LT, Longoria-Rodríguez FE, Sánchez-Domínguez M, Leyva-Porras C, Acuña-Askar K, Kharissov BI, et al. Seasonal variation and chemical composition of particulate matter: a study by XPS, ICP-AES and sequential microanalysis using raman with SEM/EDS. J Environ Sci (China). 2018;74:32–49.
Xu XC, Wu YF, Zhou JS, Leyva-Porras C, Acuña-Askar K, Kharissov BI, et al. Autophagy inhibitors suppress environmental particulate matter-induced airway inflammation. Toxicol Lett. 2017;280:206–12.
Wang Y, Tang M. Integrative analysis of mRNAs, miRNAs and lncRNAs in urban particulate matter SRM 1648a-treated EA.hy926 human endothelial cells. Chemosphere. 2019;233:711–23.
Schantz MM, McGaw E, Wise SA. Pressurized liquid extraction of diesel and air particulate standard reference materials: effect of extraction temperature and pressure. Anal Chem. 2012;84:8222–31.
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40.
Chan YL, Wang B, Chen H, Ho KF, Cao J, Hai G, et al. Pulmonary inflammation induced by low-dose particulate matter exposure in mice. Am J Physiol Lung Cell Mol Physiol. 2019;317:L424–30.
Wu YX, He HQ, Nie YJ, Ding YH, Sun L, Qian F. Protostemonine effectively attenuates lipopolysaccharide-induced acute lung injury in mice. Acta Pharmacol Sin. 2018;39:85–96.
Rao X, Zhong J, Brook RD, Rajagopalan S. Effect of particulate matter air pollution on cardiovascular oxidative stress pathways. Antioxid Redox Signal. 2018;28:797–818.
Rückerl R, Schneider A, Hampel R, Breitner S, Cyrys J, Kraus U, et al. Association of novel metrics of particulate matter with vascular markers of inflammation and coagulation in susceptible populations -results from a panel study. Environ Res. 2016;150:337–47.
Farina F, Lonati E, Milani C, Massimino L, Ballarini E, Donzelli E, et al. In vivo comparative study on acute and sub-acute biological effects induced by ultrafine particles of different anthropogenic sources in BALB/c mice. Int J Mol Sci. 2019;20:2805.
Haberzettl P, Conklin DJ, Abplanalp WT, Bhatnagar A, O’Toole TE. Inhalation of fine particulate matter impairs endothelial progenitor cell function via pulmonary oxidative stress. Arterioscler Thromb Vasc Biol. 2018;38:131–42.
Li Y, Fu S, Li E, Sun X, Xu H, Meng Y, et al. Modulation of autophagy in the protective effect of resveratrol on PM2.5-induced pulmonary oxidative injury in mice. Phytother Res. 2018;32:2480–6.
Wang J, Huang J, Wang L, Chen C, Yang D, Jin M, et al. Urban particulate matter triggers lung inflammation via the ROS-MAPK-NF-κB signaling pathway. J Thorac Dis. 2017;9:4398–412.
Ding YH, Song YD, Wu YX, He HQ, Yu TH, Hu YD, et al. Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. Acta Pharmacol Sin. 2019;40:64–74.
Englert JA, Bobba C, Baron RM. Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome. JCI Insight. 2019;4:e124061. https://doi.org/10.1172/jci.insight.124061.
Cui A, Xiang M, Xu M, Lu P, Wang S, Zou Y, et al. VCAM-1-mediated neutrophil infiltration exacerbates ambient fine particle-induced lung injury. Toxicol Lett. 2019;302:60–74.
Gong H, Rehman J, Tang H, Wary K, Mittal M, Chaturvedi P, et al. HIF2α signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest. 2015;125:652–64.
Dong W, He B, Qian H, Liu Q, Wang D, Li J, et al. RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury. Autophagy. 2018;14:1677–92.
Long YM, Yang XZ, Yang QQ, Clermont AC, Yin YG, Liu GL, et al. PM2.5 induces vascular permeability increase through activating MAPK/ERK signaling pathway and ROS generation. J Hazard Mater. 2020;386:121659. https://doi.org/10.1016/j.jhazmat.2019.121659.
Xu M, Li F, Wang M, Zhang H, Xu L, Adcock IM, et al. Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness. Eur J Pharmacol. 2019;842:373–83.
Kampfrath T, Maiseyeu A, Ying Z, Shah Z, Deiuliis JA, Xu X, et al. Chronic fine particulate matter exposure induces systemic vascular dysfunction via NADPH oxidase and TLR4 pathways. Circ Res. 2011;108:716–26.
Bekki K, Ito T, Yoshida Y, Shah Z, Deiuliis JA, Xu X, et al. PM2.5 collected in china causes inflammatory and oxidative stress responses in macrophages through the multiple pathways. Environ Toxicol Pharmacol. 2016;45:362–9.
Shoenfelt J, Mitkus RJ, Zeisler R, Spatz RO, Powell J, Fenton MJ, et al. Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. J Leukoc Biol. 2009;86:303–12.
Miyake T, Wang D, Matsuoka H, Morita K, Yasuda H, Yatera K, et al. Endocytosis of particulate matter induces cytokine production by neutrophil via toll-like receptor 4. Int Immunopharmacol. 2018;57:190–9.
Huang YL, Kou JP, Ma L, Song JX, Yu BY. Possible mechanism of the anti-inflammatory activity of ruscogenin: role of intercellular adhesion molecule-1 and nuclear factor-kappaB. J Pharmacol. 2008;108:198–205.
Guan T, Liu Q, Qian Y, Yang H, Kong J, Kou J, et al. Ruscogenin reduces cerebral ischemic injury via NF-κB-mediated inflammatory pathway in the mouse model of experimental stroke. Eur J Pharmacol. 2013;714:303–11.
Lu HJ, Tzeng TF, Liou SS, Da Lin S, Wu MC, Liu IM. Ruscogenin ameliorates diabetic nephropathy by its anti-inflammatory and anti-fibrotic effects in streptozotocin-induced diabetic rat. BMC Complement Alter Med. 2014;14:110. https://doi.org/10.1186/1472-6882-14-110.
Lu HJ, Tzeng TF, Liou SS, Chang CJ, Yang C, Wu MC, et al. Ruscogenin ameliorates experimental nonalcoholic steatohepatitis via suppressing lipogenesis and inflammatory pathway. Biomed Res Int. 2014;2014:652680.
Lin YN, Jia R, Liu YH, Gao Y, Wang LL, Kou JP, et al. Ruscogenin suppresses mouse neutrophil activation: involvement of protein kinase A pathway. J Steroid Biochem Mol Biol. 2015;154:85–93.
Li F, Lv YN, Tan YS, Shen K, Zhai KF, Chen HL, et al. An integrated pathway interaction network for the combination of four effective compounds from ShengMai preparations in the treatment of cardio-cerebral ischemic diseases. Acta Pharmacol Sin. 2015;36:1337–48.
Li F, Zhang Y, Zeng D, Xia Y, Fan X, Tan Y, et al. The combination of three components derived from Sheng MaiSan protects myocardial ischemic diseases and inhibits oxidative stress via modulating MAPKs and JAK2-STAT3 signaling pathways based on bioinformatics approach. Front Pharmacol. 2017;8:21. https://doi.org/10.3389/fphar.2017.00021.
Jeong SY, Kim J, Park EK, Baek MC, Bae JS. Inhibitory functions of maslinic acid on particulate matter-induced lung injury through TLR4-mTOR-autophagy pathways. Environ Res. 2020;183:109230.
Liu L, Song C, Li J, Wang Q, Zhu M, Hu Y, et al. Fibroblast growth factor 10 alleviates particulate matter-induced lung injury by inhibiting the HMGB1-TLR4 pathway. Aging (Albany NY). 2020;12:1186–200.
Asensio-Juárez G, Llorente-González C, Vicente-Manzanares M. Linking the landscape of MYH9-related diseases to the molecular mechanisms that control non-muscle myosin II-A function in cells. Cells. 2020;9:E1458.
Lv Y, Liu W, Ruan Z, Xu Z, Fu L. Myosin IIA regulated tight junction in oxygen glucose-deprived brain endothelial cells via activation of TLR4/PI3K/Akt/JNK1/2/14-3-3ε/NF-κB/MMP9 signal transduction pathway. Cell Mol Neurobiol. 2019;39:301–19.
Yu BY, Kou JP, Huang YL, Jiang WW, Liu JH, inventors; Nanjing Suke Patent Agency Co. LTD, assignee. A potential drug target and its inhibitors for the prevention and treatment of cardio-cerebrovascular diseases related to inflammation. CN patent 101125146. 2008.
Zhai KF, Zheng JR, Tang YM, Li F, Lv YN, Zhang YY, et al. The saponin D39 blocks dissociation of non-muscular myosin heavy chain IIA from TNF receptor 2, suppressing tissue factor expression and venous thrombosis. Br J Pharmacol. 2017;174:2818–31.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81773971) and the Double First-Class University Project of China Pharmaceutical University (CPU2018GF07).
Author information
Authors and Affiliations
Contributions
YWW, JPK, and YYZ designed the project; YWW, YHW, JZZ, JHT, and RPF performed the experiments; YWW and YHW contributed to analyzing the data; YWW and RPF conducted the literature research; YWW organized the results and drafted the original manuscript; YWW, YHW, JPK, and YYZ reviewed and modified the manuscript; FL, BYY, JPK, and YYZ contributed to the funding acquisition.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Wang, Yw., Wu, Yh., Zhang, Jz. et al. Ruscogenin attenuates particulate matter-induced acute lung injury in mice via protecting pulmonary endothelial barrier and inhibiting TLR4 signaling pathway. Acta Pharmacol Sin 42, 726–734 (2021). https://doi.org/10.1038/s41401-020-00502-6
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-00502-6
Keywords
This article is cited by
-
Amelioration of acute lung injury by Salvia miltiorrhiza-derived extracellular vesicles: through repair of the vascular barrier and modulation of lung microbiota
Chinese Medicine (2026)
-
Acute lung injury: pathogenesis and treatment
Journal of Translational Medicine (2025)
-
Inhibition of TLR4 mitigates sensorineural hearing loss resulting from cochlear inflammation
Molecular Medicine (2025)
-
Natural products ameliorating the adverse health effects by air particulate matter
Biotechnology and Bioprocess Engineering (2024)
-
Simultaneous Determination of Ruscogenin, Neoruscogenin, Trimebutin, and Parabens in Cream Formulation by Reverse Phase High Performance Liquid Chromatography
Chromatographia (2023)
