Objective To investigate the effect and regulatory mechanism of spermidine on extracellular matrix (ECM) remodeling in the lung tissue of acute lung injury (ALI) mice. Method An ALI mouse model was constructed. Masson staining was used to observe collagen deposition in lung tissue. Real-time PCR and Western blot were employed to detect the expression of nuclear factor erythroid 2-related factor 2(Nrf2), Keap1, HO-1, PI3K, p-PI3K, MEK1, p-ERK1/2, MMP2, MMP9, TGF-β, TIMP-1, Smad2/3, and collagen I mRNA and protein in lung tissue and macrophages, respectively. Results (1) Masson staining results showed that compared with the spermidine+ALI group, the collagen deposition in the lung tissue of ALI mice pretreated with an Nrf2 agonist was significantly reduced. PCR results demonstrated that spermidine could reduce the expression of Mmp2, Mmp9, and Tgf-β mRNA in ALI lung tissue while increasing Timp-1 mRNA expression. After pretreatment with Nrf2 inhibitors, the expression of Mmp2, Mmp9, and Tgf-β mRNA in the lung tissue of ALI mice increased, whereas Timp-1 mRNA expression decreased. The use of Nrf2 agonists reduced Mmp9 mRNA expression in lung tissue and increased TIMP-1 mRNA expression. (2) Spermidine was found to increase PI3K and MEK protein levels in lung tissue during ALI. In LPS-induced macrophages, spermidine increased the protein expression of PI3K, p-PI3K, MEK1, and p-ERK1/2. Compared with the spermidine+LPS group, the use of PI3K inhibitors resulted in decreased Nrf2 expression, increased Keap1 expression, and decreased HO-1 expression in LPS-induced macrophages pretreated with spermidine. Furthermore, the use of MAPK inhibitors attenuated the LPS-induced upregulation of Nrf2 and HO-1 expression in macrophages, accompanied by decreased Keap1 expression. Conclusion Spermidine, through PI3K and MAPK signaling pathways, activates the Nrf2-Keap1 functional axis, thereby inhibiting macrophage activation, leading to decreased matrix production, ultimately inhibiting pathological ECM remodeling in the lung tissue of ALI mice.
Key words
acute lung injury /
extracellular matrix /
nuclear factor-erythroid 2 related factor 2 /
spermidine
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References
[1] MEYER NJ, GATTINONI L, CALFEE CS.Acute respiratory distress syndrome[J]. Lancet, 2021, 398(10300): 622-37.
[2] BOS LDJ, WARE LB.Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes[J]. Lancet, 2022, 400(10358): 1145-1156.
[3] RUMENDE CM, SUSANTO EC, SITORUS TP.The Management of Pulmonary Fibrosis in COVID-19[J]. Acta Med Indones, 2021, 53(2): 233-241.
[4] LIU X, ZHANG JQ, XIE W.The role of ferroptosis in acute lung injury[J]. Mol Cell Biochem, 2022, 477(5): 1453-1461.
[5] KOPACZ A, KLOSKA D, FORMAN HJ, et al.Beyond repression of Nrf2: an update on Keap1[J]. Free Radic Biol Med, 2020, 157: 63-74.
[6] SUZUKI T, TAKAHASHI J, YAMAMOTO M.Molecular basis of the KEAP1-Nrf2 signaling pathway[J]. Mol Cells, 2023, 46(3): 133-141.
[7] AUDI SH, JACOBS ER, TAHERI P, et al.Assessment of protection offered by the Nrf2 pathway against hyperoxia-induced acute lung injury in Nrf2 knockout rats[J]. Shock, 2022, 57(2): 274-280.
[8] WANG Y, MA J, JIANG Y.Transcription factor Nrf2 as a potential therapeutic target for COVID-19[J]. Cell Stress Chaperones, 2023, 28(1): 11-20.
[9] RODRIGUES D, MACHADO M R, ALVES J V, et al.Cytokine storm in individuals with severe COVID-19 decreases endothelial cell antioxidant defense via downregulation of the Nrf2 transcriptional factor[J]. Am J Physiol Heart Circ Physiol, 2023, 325(2): H252-H263.
[10] DE ALMEIDA LGN, THODE H, ESLAMBOLCHI Y, et al.Matrix Metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology[J]. Pharmacol Rev, 2022, 74(3): 712-768.
[11] LIANG W, YAMAHARA K, HERNANDO-ERHARD C, et al.A reciprocal regulation of spermidine and autophagy in podocytes maintains the filtration barrier[J]. Kidney Int, 2020, 98(6): 1434-1448.
[12] SHI B, WANG W, YE M, et al.Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S[J]. Liver Int, 2023, 43(6): 1307-1319.
[13] 粟青. 亚精胺对脂多糖诱导的小鼠急性肺损伤的影响[D]. 湖南师范大学, 2020.
[14] 孙国瑛. ALI时肺内TREMs家族表达谱的变化、TREM-2的保护作用及血管活性肠肽的调控[D]. 中南大学, 2012.
[15] ORONSKY B, LARSON C, HAMMOND TC, et al.A Review of Persistent Post-COVID Syndrome (PPCS)[J]. Clin Rev Allergy Immunol, 2023, 64(1): 66-74.
[16] SHA JF, XIE QM, CHEN N, et al.TLR2-hif1alpha-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation[J]. Free Radic Biol Med, 2023, 200: 102-116.
[17] HONG H, LOU S, ZHENG F, et al.Hydnocarpin D attenuates lipopolysaccharide-induced acute lung injury via MAPK/NF-kappaB and Keap1/Nrf2/HO-1 pathway[J]. Phytomedicine, 2022, 101: 154143.
[18] WU YX, ZHANG YR, JIANG FJ, et al.4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition[J]. Inflamm Res, 2023, 72(6): 1133-1145.
[19] ALMUNTASHIRI S, ALHUMAID A, ZHU Y, et al.TIMP-1 and its potential diagnostic and prognostic value in pulmonary diseases[J]. Chin Med J Pulm Crit Care Med, 2023, 1(2): 67-76.
[20] SUN K, LI X, SCHERER P E. Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives[M]. Comprehensive Physiology, 2023: 4387-4407.
[21] GAO Y, DAI W, OUYANG Z, et al.Dendrimer-mediated intracellular delivery of fibronectin guides macrophage polarization to alleviate acute lung injury[J]. Biomacromolecules, 2023, 24(2): 886-895.
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