家畜子宫内膜纤维化的细胞分子机制研究进展

doi:10.11843/j.issn.0366-6964.2024.06.006

摘要/Abstract

摘要：

子宫内膜纤维化是子宫内膜受到持续损伤刺激导致其修复障碍引发的，以细胞外基质过度沉积为特征，可能导致子宫内膜结构破坏和功能障碍甚至衰竭，影响家畜繁殖力和生殖质量。因此，解析子宫内膜纤维化的形成机制对提高家畜繁殖力具有一定意义。本文阐述了纤维化发生的触发因素，形成的细胞分子机制及细胞代谢调节与细胞外基质之间的关系，并探讨了纤维化的治疗策略和未来研究方向，旨在为家畜子宫内膜纤维化的研究提供参考。

关键词: 子宫内膜纤维化, 细胞外基质, 肌成纤维细胞, 上皮间充质转化, 应激, 细胞代谢

Abstract:

Endometrial fibrosis is caused by persistent damage stimulation of the endometrium leading to its impaired repair, characterized by excessive deposition of extracellular matrix, which may lead to endometrial structural damage and dysfunction or even failure of the endometrium, affecting the fertility and reproductive quality of domestic animals. Therefore, analyzing the formation mechanism of endometrial fibrosis is of significance for improving the fertility of domestic animals. This article elaborates on the trigger factors of endometrial fibrosis, the relationship between the cellular and molecular mechanisms of fibrosis formation, cellular metabolic regulation and extracellular matrix, further discusses the therapeutic strategies for fibrosis and future research directions aiming to provide a reference for the study of endometrial fibrosis in domestic animals.

Key words: endometrial fibrosis, extracellular matrix, myofibroblast, epithelial mesenchymal transition, stress, cellular metabolism

中图分类号:

S814

褚婷婷, 张晓宇, 孙磊, 童嘉顺, 张磊, 宋宇轩. 家畜子宫内膜纤维化的细胞分子机制研究进展[J]. 畜牧兽医学报, 2024, 55(6): 2334-2344.

Tingting CHU, Xiaoyu ZHANG, Lei SUN, Jiashun TONG, Lei ZHANG, Yuxuan SONG. Advances in Cellular and Molecular Mechanisms of Endometrial Fibrosis in Domestic Animals[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55(6): 2334-2344.

图/表 3

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参考文献 88

1	ZHANG S H , ZHANG R Y , YIN X Y , et al. MenSCs transplantation improve the viability of injured endometrial cells through activating PI3K/Akt pathway[J]. Reprod Sci, 2023, 30 (11): 3325- 3338. doi: 10.1007/s43032-023-01282-0
2	HENDERSON N C , RIEDER F , WYNN T A . Fibrosis: from mechanisms to medicines[J]. Nature, 2020, 587 (7835): 555- 566. doi: 10.1038/s41586-020-2938-9
3	HINZ B , LAGARES D . Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases[J]. Nat Rev Rheumatol, 2020, 16 (1): 11- 31. doi: 10.1038/s41584-019-0324-5
4	ZULLO A , MANCINI F P , SCHLEIP R , et al. Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity[J]. Wound Repair Regen, 2021, 29 (4): 650- 666. doi: 10.1111/wrr.12943
5	ZHAO M Y , WANG L Q , WANG M Z , et al. Targeting fibrosis: mechanisms and clinical trials[J]. Signal Transduct Target Ther, 2022, 7 (1): 206. doi: 10.1038/s41392-022-01070-3
6	GOMES G M , CRESPILHO A M , LEÃO K M , et al. Can sperm selection, inseminating dose, and artificial insemination technique influence endometrial inflammatory response in mares[J]. J Equine Vet Sci, 2019, 73, 43- 47. doi: 10.1016/j.jevs.2018.09.010
7	LI H Q , YUAN C N , WANG H , et al. The effect of selenium on endometrial repair in goats with endometritis at high cortisol levels[J]. Biol Trace Elem Res, 2023, doi: 10.1007/s12011-023-03866-y
8	RUA M A S , QUIRINO C R , RIBEIRO R B , et al. Diagnostic methods to detect uterus illnesses in mares[J]. Theriogenology, 2018, 114, 285- 292. doi: 10.1016/j.theriogenology.2018.03.042
9	SKARZYNSKI D J , SZÓSTEK-MIODUCHOWSKA A Z , REBORDÃO M R , et al. Neutrophils, monocytes and other immune components in the equine endometrium: friends or foes[J]. Theriogenology, 2020, 150, 150- 157. doi: 10.1016/j.theriogenology.2020.01.018
10	罗芳, 张萌, 李亚超, 等. 影响奶牛早期胚胎丢失的因素[J]. 畜牧兽医学报, 2020, 51 (5): 907- 913. doi: 10.11843/j.issn.0366-6964.2020.05.002
	LUO F , ZHANG M , LI Y C , et al. Factors associated with early embryo loss in dairy cows[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51 (5): 907- 913. doi: 10.11843/j.issn.0366-6964.2020.05.002
11	王瑞玲, 王雪妍, 王菲菲, 等. 奶牛产后急性子宫内膜炎血液氧化脂质组变化特征[J]. 畜牧兽医学报, 2024, 55 (1): 373- 387. doi: 10.11843/j.issn.0366-6964.2024.01.035
	WANG R L , WANG X Y , WANG F F , et al. Study on the changes of blood oxidized lipid group in postpartum dairy cows with acute endometritis[J]. Acta Veterinaria et Zootechnica Sinica, 2024, 55 (1): 373- 387. doi: 10.11843/j.issn.0366-6964.2024.01.035
12	PLIKUS M V , WANG X J , SINHA S , et al. Fibroblasts: origins, definitions, and functions in health and disease[J]. Cell, 2021, 184 (15): 3852- 3872. doi: 10.1016/j.cell.2021.06.024
13	MUHL L , GENOVÉ G , LEPTIDIS S , et al. Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination[J]. Nat Commun, 2020, 11 (1): 3953. doi: 10.1038/s41467-020-17740-1
14	TALBOTT H E , MASCHARAK S , GRIFFIN M , et al. Wound healing, fibroblast heterogeneity, and fibrosis[J]. Cell Stem Cell, 2022, 29 (8): 1161- 1180. doi: 10.1016/j.stem.2022.07.006
15	LEMOS D R , DUFFIELD J S . Tissue-resident mesenchymal stromal cells: implications for tissue-specific antifibrotic therapies[J]. Sci Transl Med, 2018, 10 (426): eaan5174. doi: 10.1126/scitranslmed.aan5174
16	LEBLEU V S , NEILSON E G . Origin and functional heterogeneity of fibroblasts[J]. FASEB J, 2020, 34 (3): 3519- 3536. doi: 10.1096/fj.201903188R
17	LI L , LU M Z , PENG Y L , et al. Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis[J]. Redox Biol, 2023, 67, 102868. doi: 10.1016/j.redox.2023.102868
18	PAKSHIR P , ALIZADEHGIASHI M , WONG B , et al. Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix[J]. Nat Commun, 2019, 10 (1): 1850. doi: 10.1038/s41467-019-09709-6
19	SCHUSTER R , YOUNESI F , EZZO M , et al. The role of myofibroblasts in physiological and pathological tissue repair[J]. Cold Spring Harb Perspect Biol, 2023, 15 (1): a041231. doi: 10.1101/cshperspect.a041231
20	LURJE I , GAISA N T , WEISKIRCHEN R , et al. Mechanisms of organ fibrosis: emerging concepts and implications for novel treatment strategies[J]. Mol Aspects Med, 2023, 92, 101191. doi: 10.1016/j.mam.2023.101191
21	KATO K , LOGSDON N J , SHIN Y J , et al. Impaired myofibroblast dedifferentiation contributes to nonresolving fibrosis in aging[J]. Am J Respir Cell Mol Biol, 2020, 62 (5): 633- 644. doi: 10.1165/rcmb.2019-0092OC
22	WALTER I , HANDLER J , MILLER I , et al. Matrix metalloproteinase 2 (MMP-2) and tissue transglutaminase (TG 2) are expressed in periglandular fibrosis in horse mares with endometrosis[J]. Histol Histopathol, 2005, 20 (4): 1105- 1113.
23	AMACK J D . Cellular dynamics of EMT: lessons from live in vivo imaging of embryonic development[J]. Cell Commun Signal, 2021, 19 (1): 79. doi: 10.1186/s12964-021-00761-8
24	TAKI M , ABIKO K , UKITA M , et al. Tumor immune microenvironment during epithelial-mesenchymal transition[J]. Clin Cancer Res, 2021, 27 (17): 4669- 4679. doi: 10.1158/1078-0432.CCR-20-4459
25	MARCONI G D , FONTICOLI L , RAJAN T S , et al. Epithelial-Mesenchymal Transition (EMT): the type-2 EMT in wound healing, tissue regeneration and organ fibrosis[J]. Cells, 2021, 10 (7): 1587. doi: 10.3390/cells10071587
26	MANFIOLETTI G , FEDELE M . Epithelial-Mesenchymal Transition (EMT) 2021[J]. Int J Mol Sci, 2022, 23 (10): 5848. doi: 10.3390/ijms23105848
27	ZEISBERG M , NEILSON E G . Biomarkers for epithelial-mesenchymal transitions[J]. J Clin Invest, 2009, 119 (6): 1429- 1437. doi: 10.1172/JCI36183
28	XU J , LAMOUILLE S , DERYNCK R . TGF-β-induced epithelial to mesenchymal transition[J]. Cell Res, 2009, 19 (2): 156- 172. doi: 10.1038/cr.2009.5
29	FRANGOGIANNIS N G . Transforming growth factor-β in tissue fibrosis[J]. J Exp Med, 2020, 217 (3): e20190103. doi: 10.1084/jem.20190103
30	LOVISA S . Epithelial-to-mesenchymal transition in fibrosis: concepts and targeting strategies[J]. Front Pharmacol, 2021, 12, 737570. doi: 10.3389/fphar.2021.737570
31	WANG X C , SONG K , TU B , et al. New aspects of the epigenetic regulation of EMT related to pulmonary fibrosis[J]. Eur J Pharmacol, 2023, 956, 175959. doi: 10.1016/j.ejphar.2023.175959
32	YAO L D , CONFORTI F , HILL C , et al. Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis[J]. Cell Death Differ, 2019, 26 (5): 943- 957. doi: 10.1038/s41418-018-0175-7
33	MINKWITZ C , SCHOON H A , ZHANG Q , et al. Plasticity of endometrial epithelial and stromal cells-a new approach towards the pathogenesis of equine endometrosis[J]. Reprod Domest Anim, 2019, 54 (6): 835- 845. doi: 10.1111/rda.13431
34	BORDON Y . CXCL8 blockade reduces fibrosis in endometriosis[J]. Nat Rev Immunol, 2023, 23 (4): 203.
35	XU X X , CAO L B , WANG Z , et al. Creation of a rabbit model for intrauterine adhesions using electrothermal injury[J]. J Zhejiang Univ Sci B, 2018, 19 (5): 383- 389. doi: 10.1631/jzus.B1700086
36	VU R , DRAGAN M , SUN P , et al. Epithelial-mesenchymal plasticity and endothelial-mesenchymal transition in cutaneous wound healing[J]. Cold Spring Harb Perspect Biol, 2023, 15 (8): a041237. doi: 10.1101/cshperspect.a041237
37	MAN S , SANCHEZ DUFFHUES G , TEN DIJKE P , et al. The therapeutic potential of targeting the endothelial-to-mesenchymal transition[J]. Angiogenesis, 2019, 22 (1): 3- 13. doi: 10.1007/s10456-018-9639-0
38	LU D K , JIANG H , ZOU T , et al. Endothelial-to-mesenchymal transition: new insights into vascular calcification[J]. Biochem Pharmacol, 2023, 213, 115579. doi: 10.1016/j.bcp.2023.115579
39	YAN D M , LIU X S , XU H , et al. Platelets induce endothelial-mesenchymal transition and subsequent fibrogenesis in endometriosis[J]. Reprod BioMed Online, 2020, 41 (3): 500- 517. doi: 10.1016/j.rbmo.2020.03.020
40	LEUNG R K K , LIN Y X , LIU Y H . Recent advances in understandings towards pathogenesis and treatment for intrauterine adhesion and disruptive insights from single-cell analysis[J]. Reprod Sci, 2021, 28 (7): 1812- 1826. doi: 10.1007/s43032-020-00343-y
41	HUANG E Y , PENG N , XIAO F , et al. The roles of immune cells in the pathogenesis of fibrosis[J]. Int J Mol Sci, 2020, 21 (15): 5203. doi: 10.3390/ijms21155203
42	SMIGIEL K S , PARKS W C . Macrophages, wound healing, and fibrosis: recent insights[J]. Curr Rheumatol Rep, 2018, 20 (4): 17. doi: 10.1007/s11926-018-0725-5
43	SHEN B , LIU X H , FAN Y , et al. Macrophages regulate renal fibrosis through modulating TGFβ superfamily signaling[J]. Inflammation, 2014, 37 (6): 2076- 2084. doi: 10.1007/s10753-014-9941-y
44	LV H N , SUN H X , WANG L M , et al. Targeting CD301⁺ macrophages inhibits endometrial fibrosis and improves pregnancy outcome[J]. EMBO Mol Med, 2023, 15 (9): e17601. doi: 10.15252/emmm.202317601
45	BORTHWICK L A , WYNN T A , FISHER A J . Cytokine mediated tissue fibrosis[J]. Biochim Biophys Acta Mol Basis Dis, 2013, 1832 (7): 1049- 1060. doi: 10.1016/j.bbadis.2012.09.014
46	YANAGIHARA T , TSUBOUCHI K , GHOLIOF M , et al. Connective-tissue growth factor contributes to TGF-β1-induced lung fibrosis[J]. Am J Respir Cell Mol Biol, 2022, 66 (3): 260- 270. doi: 10.1165/rcmb.2020-0504OC
47	MILLS K H G . IL-17 and IL-17-producing cells in protection versus pathology[J]. Nat Rev Immunol, 2023, 23 (1): 38- 54. doi: 10.1038/s41577-022-00746-9
48	ATAMAS S P . Complex cytokine regulation of tissue fibrosis[J]. Life Sci, 2002, 72 (6): 631- 643. doi: 10.1016/S0024-3205(02)02299-3
49	XIAO F Y , LIU X S , GUO S W . Interleukin-33 derived from endometriotic lesions promotes fibrogenesis through inducing the production of profibrotic cytokines by regulatory T cells[J]. Biomedicines, 2022, 10 (11): 2893. doi: 10.3390/biomedicines10112893
50	MACK M . Inflammation and fibrosis[J]. Matrix Biol, 2018, 68-69, 106- 121. doi: 10.1016/j.matbio.2017.11.010
51	SHI N , WANG Z H , ZHU H C , et al. Research progress on drugs targeting the TGF-β signaling pathway in fibrotic diseases[J]. Immunol Res, 2022, 70 (3): 276- 288. doi: 10.1007/s12026-022-09267-y
52	XU J , TAN Y L , LIU Q Y , et al. Quercetin regulates fibrogenic responses of endometrial stromal cell by upregulating miR-145 and inhibiting the TGF-β1/Smad2/Smad3 pathway[J]. Acta Histochem, 2020, 122 (7): 151600. doi: 10.1016/j.acthis.2020.151600
53	ZHU Z Y , SONG Y , CHEN X M , et al. Hyperoside inhibits endometrial fibrosis and inflammation by targeting TGF-β/Smad3 signaling in intrauterine adhesion rats[J]. Rev Bras Farmacogn, 2022, 33 (1): 89- 94. doi: 10.1007/s43450-022-00283-5
54	ZHU H Y , GE T X , PAN Y B , et al. Advanced role of hippo signaling in endometrial fibrosis: implications for intrauterine adhesion[J]. Chin Med J (Engl), 2017, 130 (22): 2732- 2737. doi: 10.4103/0366-6999.218013
55	WEI C , PAN Y B , ZHANG Y L , et al. Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells[J]. Cell Death Dis, 2020, 11 (9): 755. doi: 10.1038/s41419-020-02956-2
56	XUE X , LI X L , YAO J M , et al. Transient and prolonged activation of Wnt signaling contribute oppositely to the pathogenesis of Asherman's syndrome[J]. Int J Mol Sci, 2022, 23 (15): 8808. doi: 10.3390/ijms23158808
57	MATSUZAKI S , DARCHA C . Involvement of the Wnt/β-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis[J]. PLoS One, 2013, 8 (10): e76808. doi: 10.1371/journal.pone.0076808
58	AL-HENDY A , DIAMOND M P , BOYER T G , et al. Vitamin D3 inhibits Wnt/β-catenin and mTOR signaling pathways in human uterine fibroid cells[J]. J Clin Endocrinol Metab, 2016, 101 (4): 1542- 1551. doi: 10.1210/jc.2015-3555
59	GUO Z Z , WANG Y Q , WEN X Y , et al. β-klotho promotes the development of intrauterine adhesions via the PI3K/AKT signaling pathway[J]. Int J Mol Sci, 2022, 23 (19): 11294. doi: 10.3390/ijms231911294
60	MIA M M , SINGH M K . New insights into hippo/YAP signaling in fibrotic diseases[J]. Cells, 2022, 11 (13): 2065. doi: 10.3390/cells11132065
61	ZHOU Y Y , PENG Y Y , XIA Q Q , et al. Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis[J]. Reproduction, 2021, 161 (2): 99- 109. doi: 10.1530/REP-20-0172
62	CAVALCANTE M B , SACCON T D , NUNES A D C , et al. Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice[J]. Aging (Albany NY), 2020, 12 (3): 2711- 2722.
63	YE C S , CHEN P , XU B N , et al. Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium[J]. Eur J Med Res, 2023, 28 (1): 209. doi: 10.1186/s40001-023-01180-w
64	NIGDELIOGLU R , HAMANAKA R B , MELITON A Y , et al. Transforming Growth Factor (TGF)-β promotes De Novo serine synthesis for collagen production[J]. J Biol Chem, 2016, 291 (53): 27239- 27251. doi: 10.1074/jbc.M116.756247
65	HAMANAKA R B , MUTLU G M . Metabolic requirements of pulmonary fibrosis: role of fibroblast metabolism[J]. FEBS J, 2021, 288 (22): 6331- 6352. doi: 10.1111/febs.15693
66	PHANG J M . The regulatory mechanisms of proline and hydroxyproline metabolism: recent advances in perspective[J]. Front Oncol, 2023, 12, 1118675. doi: 10.3389/fonc.2022.1118675
67	ZHAO X , KWAN J Y Y , YIP K , et al. Targeting metabolic dysregulation for fibrosis therapy[J]. Nat Rev Drug Discov, 2020, 19 (1): 57- 75. doi: 10.1038/s41573-019-0040-5
68	HWANG S , CHUNG K W . Targeting fatty acid metabolism for fibrotic disorders[J]. Arch Pharm Res, 2021, 44 (9/10): 839- 856.
69	GRANDE G , VINCENZONI F , MILARDI D , et al. Cervical mucus proteome in endometriosis[J]. Clin Proteomics, 2017, 14, 7. doi: 10.1186/s12014-017-9142-4
70	ONG G , LOGUE S E . Unfolding the interactions between endoplasmic reticulum stress and oxidative stress[J]. Antioxidants (Basel), 2023, 12 (5): 981. doi: 10.3390/antiox12050981
71	ESTORNUT C , MILARA J , BAYARRI M A , et al. Targeting oxidative stress as a therapeutic approach for idiopathic pulmonary fibrosis[J]. Front Pharmacol, 2022, 12, 794997. doi: 10.3389/fphar.2021.794997
72	GONZÁLEZ-FORURIA I , SANTULLI P , CHOUZENOUX S , et al. Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis[J]. Mol Hum Reprod, 2017, 23 (7): 488- 499. doi: 10.1093/molehr/gax028
73	WU H , XU T , CHEN T , et al. Oxidative stress mediated by the TLR4/NOX2 signalling axis is involved in polystyrene microplastic-induced uterine fibrosis in mice[J]. Sci Total Environ, 2022, 838 (Pt 2): 155825.
74	ARANGIA A , MARINO Y , FUSCO R , et al. Fisetin, a natural polyphenol, ameliorates endometriosis modulating mast cells derived NLRP-3 inflammasome pathway and oxidative stress[J]. Int J Mol Sci, 2023, 24 (6): 5076. doi: 10.3390/ijms24065076
75	BURMAN A , TANJORE H , BLACKWELL T S . Endoplasmic reticulum stress in pulmonary fibrosis[J]. Matrix Biol, 2018, 68-69, 355- 365. doi: 10.1016/j.matbio.2018.03.015
76	WISEMAN R L , MESGARZADEH J S , HENDERSHOT L M . Reshaping endoplasmic reticulum quality control through the unfolded protein response[J]. Mol Cell, 2022, 82 (8): 1477- 1491. doi: 10.1016/j.molcel.2022.03.025
77	ZHONG Q , ZHOU B Y , ANN D K , et al. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein[J]. Am J Respir Cell Mol Biol, 2011, 45 (3): 498- 509. doi: 10.1165/rcmb.2010-0347OC
78	BAEK H A , KIM D S , PARK H S , et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts[J]. Am J Respir Cell Mol Biol, 2012, 46 (6): 731- 739. doi: 10.1165/rcmb.2011-0121OC
79	TANG Y , ZHOU X P , CAO T , et al. Endoplasmic reticulum stress and oxidative stress in inflammatory diseases[J]. DNA Cell Biol, 2022, 41 (11): 924- 934. doi: 10.1089/dna.2022.0353
80	KROPSKI J A , BLACKWELL T S . Endoplasmic reticulum stress in the pathogenesis of fibrotic disease[J]. J Clin Invest, 2018, 128 (1): 64- 73. doi: 10.1172/JCI93560
81	MOHAMED A A A , YANG D Q , LIU S Q , et al. Endoplasmic reticulum stress is involved in lipopolysaccharide-induced inflammatory response and apoptosis in goat endometrial stromal cells[J]. Mol Reprod Dev, 2019, 86 (7): 908- 921. doi: 10.1002/mrd.23152
82	BAO M , FENG Q W , ZOU L P , et al. Endoplasmic reticulum stress promotes endometrial fibrosis through the TGF-β/SMAD pathway[J]. Reproduction, 2023, 165 (2): 171- 182. doi: 10.1530/REP-22-0294
83	AL-HETTY H R A K , JABBAR A D , EREMIN V F , et al. The role of endoplasmic reticulum stress in endometriosis[J]. Cell Stress Chaperones, 2023, 28 (2): 145- 150. doi: 10.1007/s12192-023-01323-2
84	BORCHERDING N , BRESTOFF J R . The power and potential of mitochondria transfer[J]. Nature, 2023, 623 (7986): 283- 291. doi: 10.1038/s41586-023-06537-z
85	LI X Y , ZHANG W , CAO Q T , et al. Mitochondrial dysfunction in fibrotic diseases[J]. Cell Death Discov, 2020, 6, 80.
86	ASSAF L , EID A A , NASSIF J . Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis[J]. Life Sci, 2022, 306, 120805. doi: 10.1016/j.lfs.2022.120805
87	SUN J , LIU C , LIU Y Y , et al. Mitophagy in renal interstitial fibrosis[J]. Int Urol Nephrol, 2024, 56 (1): 167- 179.
88	KURITA Y , ARAYA J , MINAGAWA S , et al. Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy[J]. Respir Res, 2017, 18 (1): 114. doi: 10.1186/s12931-017-0600-3

信号通路 Signaling pathway	靶向细胞 Targeted cells	调控因子 Regulators	参与纤维化的调控作用 Involved in the regulation of fibrosis	参考文献 Reference
TGF-β	上皮细胞、成纤维细胞	IL-17A、SMAD、RhoA、Ras、TAK1、P13K、mTOR	促进EMT，促进胶原蛋白和纤连蛋白的合成，促进谷氨酰胺分解	[51-53]
Hippo	成纤维细胞、肌成纤维细胞、	TAZ、YAP、Wnt、Smad	促进α-SMA和CTGF表达，调节干细胞的生长和分化，诱导COL1A1上调，调控成纤维细胞分化和ECM合成	[54, 60]
Hedgehog	基质细胞	CTGF、Gli1、Ptch1	促进肌成纤维细胞活化，诱导COL1A1、α-SMA表达	[54, 61]
PI3K/AKT	基质细胞	mTOR	促进基质细胞增殖分化、促进胶原沉积	[59, 62]
Wnt/β-Catenin	基质细胞	mTOR	促进αSMA、Col-I、FN和CTGF表达	[57-58]

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