P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis
Abstract
:1. Introduction
2. Results
2.1. P2X7 Expression Is Increased in Intestinal Resections from CD Patients
2.2. Lack of P2X7 Receptor Exacerbates Intestinal Fibrosis
2.3. Lack of P2X7 Increases the Inflammatory Status and Alters the Macrophage Phenotype in Intestinal Mucosa
2.4. P2X7 Regulates the Expression of Col1a1 in Human Intestinal Fibroblasts
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Isolation of Primary Human Intestinal Fibroblasts
4.3. Mice
4.4. Induction of Intestinal Fibrosis
4.5. Induction of Chronic DSS Colitis
4.6. Cell Culture
4.7. Small Interfering (siRNA) Transfection
4.8. Protein Extraction and Western Blot Analysis
4.9. RNA Isolation and Real-Time Quantitative PCR (RT–qPCR)
4.10. Hematoxylin–Eosin Staining
4.11. Sirius Red Staining
4.12. Immunofluorescence
4.13. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
- Yoo, J.H.; Holubar, S.; Rieder, F. Fibrostenotic strictures in Crohn’s disease. Intest. Res. 2020, 18, 379–401. [Google Scholar] [CrossRef] [PubMed]
- Holvoet, T.; Devriese, S.; Castermans, K.; Boland, S.; Leysen, D.; Vandewynckel, Y.P.; Devisscher, L.; Van den Bossche, L.; Van Welden, S.; Dullaers, M.; et al. Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor. Gastroenterology 2017, 153, 1054–1067. [Google Scholar] [CrossRef] [PubMed]
- Solitano, V.; Dal Buono, A.; Gabbiadini, R.; Wozny, M.; Repici, A.; Spinelli, A.; Vetrano, S.; Armuzzi, A. Fibro-Stenosing Crohn’s Disease: What Is New and What Is Next? J. Clin. Med. 2023, 12, 3052. [Google Scholar] [CrossRef] [PubMed]
- Lin, S.N.; Mao, R.; Qian, C.; Bettenworth, D.; Wang, J.; Li, J.; Bruining, D.H.; Jairath, V.; Feagan, B.G.; Chen, M.H.; et al. Development of antifibrotic therapy for stricturing Crohn’s disease: Lessons from randomized trials in other fibrotic diseases. Physiol. Rev. 2022, 102, 605–652. [Google Scholar] [CrossRef] [PubMed]
- Longhi, M.S.; Moss, A.; Jiang, Z.G.; Robson, S.C. Purinergic signaling during intestinal inflammation. J. Mol. Med. 2017, 95, 915–925. [Google Scholar] [CrossRef] [PubMed]
- Kopp, R.; Krautloher, A.; Ramirez-Fernandez, A.; Nicke, A. P2X7 Interactions and Signaling—Making Head or Tail of It. Front. Mol. Neurosci. 2019, 12, 183. [Google Scholar] [CrossRef] [PubMed]
- Cao, F.; Hu, L.Q.; Yao, S.R.; Hu, Y.; Wang, D.G.; Fan, Y.G.; Pan, G.X.; Tao, S.S.; Zhang, Q.; Pan, H.F.; et al. P2X7 receptor: A potential therapeutic target for autoimmune diseases. Autoimmun. Rev. 2019, 18, 767–777. [Google Scholar] [CrossRef] [PubMed]
- Zhang, R.; Li, N.; Zhao, M.; Tang, M.; Jiang, X.; Cai, X.; Ye, N.; Su, K.; Peng, J.; Zhang, X.; et al. From lead to clinic: A review of the structural design of P2X7R antagonists. Eur. J. Med. Chem. 2023, 251, 115234. [Google Scholar] [CrossRef]
- Pelegrin, P. P2X7 receptor and the NLRP3 inflammasome: Partners in crime. Biochem. Pharmacol. 2021, 187, 114385. [Google Scholar] [CrossRef]
- Di Virgilio, F.; Dal Ben, D.; Sarti, A.C.; Giuliani, A.L.; Falzoni, S. The P2X7 Receptor in Infection and Inflammation. Immunity 2017, 47, 15–31. [Google Scholar] [CrossRef]
- Zhou, J.; Tian, G.; Quan, Y.; Li, J.; Wang, X.; Wu, W.; Li, M.; Liu, X. Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1beta Pathway. Oxid. Med. Cell. Longev. 2020, 2020, 7956274. [Google Scholar] [CrossRef] [PubMed]
- Mezzaroma, E.; Toldo, S.; Farkas, D.; Seropian, I.M.; Van Tassell, B.W.; Salloum, F.N.; Kannan, H.R.; Menna, A.C.; Voelkel, N.F.; Abbate, A. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc. Natl. Acad. Sci. USA 2011, 108, 19725–19730. [Google Scholar] [CrossRef] [PubMed]
- Tung, H.C.; Lee, F.Y.; Wang, S.S.; Tsai, M.H.; Lee, J.Y.; Huo, T.I.; Huang, H.C.; Chuang, C.L.; Lin, H.C.; Lee, S.D. The Beneficial Effects of P2X7 Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis. PLoS ONE 2015, 10, e0124654. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.; Yu, W.; Cui, H.; Wang, Y.; Zhang, L.; Han, F.; Huang, T. P2X7 blockade attenuates mouse liver fibrosis. Mol. Med. Rep. 2014, 9, 57–62. [Google Scholar] [CrossRef] [PubMed]
- Goncalves, R.G.; Gabrich, L.; Rosario, A., Jr.; Takiya, C.M.; Ferreira, M.L.; Chiarini, L.B.; Persechini, P.M.; Coutinho-Silva, R.; Leite, M., Jr. The role of purinergic P2X7 receptors in the inflammation and fibrosis of unilateral ureteral obstruction in mice. Kidney Int. 2006, 70, 1599–1606. [Google Scholar] [CrossRef] [PubMed]
- Solini, A.; Iacobini, C.; Ricci, C.; Chiozzi, P.; Amadio, L.; Pricci, F.; Di Mario, U.; Di Virgilio, F.; Pugliese, G. Purinergic modulation of mesangial extracellular matrix production: Role in diabetic and other glomerular diseases. Kidney Int. 2005, 67, 875–885. [Google Scholar] [CrossRef]
- Riteau, N.; Gasse, P.; Fauconnier, L.; Gombault, A.; Couegnat, M.; Fick, L.; Kanellopoulos, J.; Quesniaux, V.F.; Marchand-Adam, S.; Crestani, B.; et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 2010, 182, 774–783. [Google Scholar] [CrossRef] [PubMed]
- Moncao-Ribeiro, L.C.; Faffe, D.S.; Santana, P.T.; Vieira, F.S.; da Graca, C.L.; Marques-da-Silva, C.; Machado, M.N.; Caruso-Neves, C.; Zin, W.A.; Borojevic, R.; et al. P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica. PLoS ONE 2014, 9, e110185. [Google Scholar] [CrossRef]
- Gentile, D.; Natale, M.; Lazzerini, P.E.; Capecchi, P.L.; Laghi-Pasini, F. The role of P2X7 receptors in tissue fibrosis: A brief review. Purinergic Signal. 2015, 11, 435–440. [Google Scholar] [CrossRef]
- Cheng, N.; Zhang, L.; Liu, L. Understanding the Role of Purinergic P2X7 Receptors in the Gastrointestinal System: A Systematic Review. Front. Pharmacol. 2021, 12, 786579. [Google Scholar] [CrossRef]
- Ohbori, K.; Fujiwara, M.; Ohishi, A.; Nishida, K.; Uozumi, Y.; Nagasawa, K. Prophylactic Oral Administration of Magnesium Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through a Decrease of Colonic Accumulation of P2X7 Receptor-Expressing Mast Cells. Biol. Pharm. Bull. 2017, 40, 1071–1077. [Google Scholar] [CrossRef] [PubMed]
- Jooss, T.; Zhang, J.; Zimmer, B.; Rezzonico-Jost, T.; Rissiek, B.; Felipe Pelczar, P.; Seehusen, F.; Koch-Nolte, F.; Magnus, T.; Zierler, S.; et al. Macrophages and glia are the dominant P2X7-expressing cell types in the gut nervous system-No evidence for the role of neuronal P2X7 receptors in colitis. Mucosal Immunol. 2023, 16, 180–193. [Google Scholar] [CrossRef] [PubMed]
- Neves, A.R.; Castelo-Branco, M.T.; Figliuolo, V.R.; Bernardazzi, C.; Buongusto, F.; Yoshimoto, A.; Nanini, H.F.; Coutinho, C.M.; Carneiro, A.J.; Coutinho-Silva, R.; et al. Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn’s disease. Inflamm. Bowel Dis. 2014, 20, 444–457. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Dejanovic, D.; Zangara, M.T.; Chandra, J.; McDonald, C.; Rieder, F. Mouse Models of Intestinal Fibrosis. Methods Mol. Biol. 2021, 2299, 385–403. [Google Scholar]
- Ortiz-Masia, D.; Gisbert-Ferrandiz, L.; Bauset, C.; Coll, S.; Mamie, C.; Scharl, M.; Esplugues, J.V.; Alos, R.; Navarro, F.; Cosin-Roger, J.; et al. Succinate Activates EMT in Intestinal Epithelial Cells through SUCNR1: A Novel Protagonist in Fistula Development. Cells 2020, 9, 1104. [Google Scholar] [CrossRef] [PubMed]
- Schuler, C.; Foti, F.; Perren, L.; Mamie, C.; Weder, B.; Stokmaier, M.; de Valliere, C.; Heuchel, R.; Ruiz, P.A.; Rogler, G.; et al. Deletion of Smad7 Ameliorates Intestinal Inflammation and Contributes to Fibrosis. Inflamm. Bowel Dis. 2023, 29, 647–660. [Google Scholar] [CrossRef] [PubMed]
- Da Silva Watanabe, P.; Cavichioli, A.M.; D’Arc de Lima Mendes, J.; Aktar, R.; Peiris, M.; Blackshaw, L.A.; de Almeida Araujo, E.J. Colonic motility adjustments in acute and chronic DSS-induced colitis. Life Sci. 2023, 321, 121642. [Google Scholar] [CrossRef] [PubMed]
- Jiang, S.; Zhang, Y.; Zheng, J.H.; Li, X.; Yao, Y.L.; Wu, Y.L.; Song, S.Z.; Sun, P.; Nan, J.X.; Lian, L.H. Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation. Pharmacol. Res. 2017, 117, 82–93. [Google Scholar] [CrossRef]
- Zhang, Y.; Jin, Q.; Li, X.; Jiang, M.; Cui, B.W.; Xia, K.L.; Wu, Y.L.; Lian, L.H.; Nan, J.X. Amelioration of Alcoholic Liver Steatosis by Dihydroquercetin through the Modulation of AMPK-Dependent Lipogenesis Mediated by P2X7R-NLRP3-Inflammasome Activation. J. Agric. Food Chem. 2018, 66, 4862–4871. [Google Scholar] [CrossRef]
- Pereira, J.M.S.; Barreira, A.L.; Gomes, C.R.; Ornellas, F.M.; Ornellas, D.S.; Miranda, L.C.; Cardoso, L.R.; Coutinho-Silva, R.; Schanaider, A.; Morales, M.M.; et al. Brilliant blue G, a P2X7 receptor antagonist, attenuates early phase of renal inflammation, interstitial fibrosis and is associated with renal cell proliferation in ureteral obstruction in rats. BMC Nephrol. 2020, 21, 206. [Google Scholar] [CrossRef]
- Henderson, N.C.; Rieder, F.; Wynn, T.A. Fibrosis: From mechanisms to medicines. Nature 2020, 587, 555–566. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.; Lin, S.; Brown, J.M.; van Wagoner, D.; Fiocchi, C.; Rieder, F. Novel mechanisms and clinical trial endpoints in intestinal fibrosis. Immunol. Rev. 2021, 302, 211–227. [Google Scholar] [CrossRef] [PubMed]
- Xia, G.Q.; Fang, Q.; Cai, J.N.; Li, Z.X.; Zhang, F.Z.; Lv, X.W. P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis. J. Clin. Transl. Hepatol. 2022, 10, 1205–1212. [Google Scholar] [CrossRef] [PubMed]
- Le Dare, B.; Victoni, T.; Bodin, A.; Vlach, M.; Vene, E.; Loyer, P.; Lagente, V.; Gicquel, T. Ethanol upregulates the P2X7 purinergic receptor in human macrophages. Fundam. Clin. Pharmacol. 2019, 33, 63–74. [Google Scholar] [CrossRef] [PubMed]
- Qin, J.; Zhang, X.; Tan, B.; Zhang, S.; Yin, C.; Xue, Q.; Zhang, Z.; Ren, H.; Chen, J.; Liu, M.; et al. Blocking P2X7-Mediated Macrophage Polarization Overcomes Treatment Resistance in Lung Cancer. Cancer Immunol. Res. 2020, 8, 1426–1439. [Google Scholar] [CrossRef] [PubMed]
- Li, R.; Shang, Y.; Hu, X.; Yu, Y.; Zhou, T.; Xiong, W.; Zou, X. ATP/P2X7r axis mediates the pathological process of allergic asthma by inducing M2 polarization of alveolar macrophages. Exp. Cell Res. 2020, 386, 111708. [Google Scholar] [CrossRef] [PubMed]
- Wan, P.; Liu, X.; Xiong, Y.; Ren, Y.; Chen, J.; Lu, N.; Guo, Y.; Bai, A. Extracellular ATP mediates inflammatory responses in colitis via P2 x 7 receptor signaling. Sci. Rep. 2016, 6, 19108. [Google Scholar] [CrossRef]
- Marques, C.C.; Castelo-Branco, M.T.; Pacheco, R.G.; Buongusto, F.; do Rosario, A., Jr.; Schanaider, A.; Coutinho-Silva, R.; de Souza, H.S. Prophylactic systemic P2X7 receptor blockade prevents experimental colitis. Biochim. Biophys. Acta 2014, 1842, 65–78. [Google Scholar] [CrossRef]
- Oliveira, S.D.; Nanini, H.F.; Savio, L.E.; Waghabi, M.C.; Silva, C.L.; Coutinho-Silva, R. Macrophage P2X7 receptor function is reduced during schistosomiasis: Putative role of TGF- beta1. Mediators Inflamm. 2014, 2014, 134974. [Google Scholar] [CrossRef]
- Gadeock, S.; Tran, J.N.; Georgiou, J.G.; Jalilian, I.; Taylor, R.M.; Wiley, J.S.; Sluyter, R. TGF-beta1 prevents up-regulation of the P2X7 receptor by IFN-gamma and LPS in leukemic THP-1 monocytes. Biochim. Biophys. Acta 2010, 1798, 2058–2066. [Google Scholar] [CrossRef]
- Steiner, C.A.; Cartwright, I.M.; Taylor, C.T.; Colgan, S.P. Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis. Am. J. Physiol. Cell Physiol. 2022, 323, C866–C878. [Google Scholar] [CrossRef] [PubMed]
- Flores-Munoz, C.; Maripillan, J.; Vasquez-Navarrete, J.; Novoa-Molina, J.; Ceriani, R.; Sanchez, H.A.; Abbott, A.C.; Weinstein-Oppenheimer, C.; Brown, D.I.; Cardenas, A.M.; et al. Restraint of Human Skin Fibroblast Motility, Migration, and Cell Surface Actin Dynamics, by Pannexin 1 and P2X7 Receptor Signaling. Int. J. Mol. Sci. 2021, 22, 1069. [Google Scholar] [CrossRef] [PubMed]
- Eser, A.; Colombel, J.F.; Rutgeerts, P.; Vermeire, S.; Vogelsang, H.; Braddock, M.; Persson, T.; Reinisch, W. Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn’s Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study. Inflamm. Bowel Dis. 2015, 21, 2247–2253. [Google Scholar] [CrossRef] [PubMed]
- Cosin-Roger, J.; Canet, F.; Macias-Ceja, D.C.; Gisbert-Ferrandiz, L.; Ortiz-Masia, D.; Esplugues, J.V.; Alos, R.; Navarro, F.; Barrachina, M.D.; Calatayud, S. Autophagy Stimulation as a Potential Strategy Against Intestinal Fibrosis. Cells 2019, 8, 1078. [Google Scholar] [CrossRef] [PubMed]
- Macias-Ceja, D.C.; Ortiz-Masia, D.; Salvador, P.; Gisbert-Ferrandiz, L.; Hernandez, C.; Hausmann, M.; Rogler, G.; Esplugues, J.V.; Hinojosa, J.; Alos, R.; et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 2019, 12, 178–187. [Google Scholar] [CrossRef] [PubMed]
- Bauset, C.; Lis-Lopez, L.; Coll, S.; Gisbert-Ferrandiz, L.; Macias-Ceja, D.C.; Seco-Cervera, M.; Navarro, F.; Esplugues, J.V.; Calatayud, S.; Ortiz-Masia, D.; et al. SUCNR1 Mediates the Priming Step of the Inflammasome in Intestinal Epithelial Cells: Relevance in Ulcerative Colitis. Biomedicines 2022, 10, 532. [Google Scholar] [CrossRef] [PubMed]
- Obermeier, F.; Hausmann, M.; Kellermeier, S.; Kiessling, S.; Strauch, U.G.; Duitman, E.; Bulfone-Paus, S.; Herfarth, H.; Bock, J.; Dunger, N.; et al. IL-15 protects intestinal epithelial cells. Eur. J. Immunol. 2006, 36, 2691–2699. [Google Scholar] [CrossRef]
CD | Non-IBD | ||
---|---|---|---|
Number of patients | 25 | 15 | |
Age | Mean | 47 | 66 |
Interval | (30–70) | (37–80) | |
Gender | Male | 9 | 6 |
Female | 16 | 9 | |
CD phenotype | B2 or stricturing | 15 | - |
B3 or penetrant | 10 | - | |
Concomitant Medication | Azathioprine | 16 | - |
Methotrexate | 5 | - | |
6-Mercaptopurine | 3 | - | |
Biological Therapy (anti-TNFα) | 24 | - |
Antibody | Supplier | Dilution (μL) |
---|---|---|
COLLAGEN 1 | Ab34710; Abcam | 1:1000 |
P2X7 | Ab93354; Abcam | 1:1000 |
GAPDH | G9545-200UL; Sigma | 1:15,000 |
Gene | Sense (5′–3′) | Antisense (3′–5′) | Fragment’s Size (bp) |
---|---|---|---|
a-SMA | GCTTCCCTGAACACCACCCA | ACAGAGCCCAGAGCCATTGT | 131 |
COL1A1 | GGAGCAGACGGGAGTTTCTC | CCGTTCTGTACGCAGGTGAT | 252 |
COL3A1 | CGCCCTCCTAATGGTCAAGG | TTCTGAGGACCAGTAGGGCA | 161 |
COL4A1 | CCGGATCACATTGACATGAAACC | TGGAAACCAGTCCATGCTCG | 236 |
COL5A1 | CCTGACAAGAAGTCCGAAGGG | GCGTCCACATAGGAGAGCAG | 107 |
COL5A2 | TGGTGCTGAAAGAAGAGCCC | TCTGACAAGGGGCAGGTTTC | 281 |
COL6A3 | GGCCGTCTTTTGCCTCTTTC | TGTTCCTCTCCAATGGTCCAAG | 132 |
P2X7 | TGCCGAAAACTTCACTGTGC | ATGCCCATTATTCCGCCCTG | 209 |
TGF B | AGCAACAATTCCTGGCGATAC | CGGTAGTGAACCCGTTGATG | 202 |
VIMENTIN | ATGAAGGAGGAAATGGCTCGTC | GGGTATCAACCAGAGGGAGTGAA | 196 |
Gene | Sense (5′–3′) | Antisense (3′–5′) | Fragment’s Size (bp) |
---|---|---|---|
Arg | GTGGGGAAAGCCAATGAAGAG | TCAGGAGAAAGGACACAGGTTG | 232 |
Ccr7 | CTCTCCACCGCCTTTCCTG | ACCTTTCCCCTACCTTTTTATTCCC | 125 |
Cd11c | TCTTCTGCTGTTGGGGTTTG | CAGTTGCCTGTGTGATAGCC | 204 |
Cd16 | GAAGGGGAAACCATCACGCT | GCAAACAGGAGGCACATCAC | 293 |
Cd206 | TGTGGAGCAGATGGAAGGTC | TGTCGTAGTCAGTGGTGGTTC | 201 |
Cd86 | GCACGGACTTGAACAACCAG | CCTTTGTAAATGGGCACGGC | 194 |
Col1a1 | CAGGCTGGTGTGATGGGATT | AAACCTCTCTCGCCTCTTGC | 317 |
Cox-2 | CCCGGACTGGATTCTATGGTG | TTCGCAGGAAGGGGATGTTG | 153 |
E-cadherine | AACCCAAGCACGTATCAGGG | ACTGCTGGTCAGGATCGTTG | 142 |
F480 | TGTCTGAAGATTCTCAAAACATGGA | TGGAACACCACAAGAAAGTGC | 211 |
Fizz1 | CGTGGAGAATAAGGTCAAGGAAC | CAACGAGTAAGCACAGGCAG | 212 |
Il10 | GGACAACATACTGCTAACCGAC | CCTGGGGCATCACTTCTACC | 110 |
Il13 | GCCAAGATCTGTGTCTCTCCC | ACTCCATACCATGCTGCCG | 106 |
Il1b | TGCCACCTTTTGACAGTGATG | ATGTGCTGCTGCGAGATTTG | 136 |
Il6 | GAGTCCTTCAGAGAGATACAGAAAC | TGGTCTTGGTCCTTAGCCAC | 150 |
Il8 | CTGCTGGCTGTCCTTAACC | TCTGTTGCAGTAAATGGTCTCG | 150 |
iNos | CGCTTGGGTCTTGTTCACTC | GGTCATCTTGTATTGTTGGGCTG | 222 |
Mmp2 | GCCAACTACAACTTCTTCCCC | CAAAAGCATCATCCACGGTTTC | 112 |
P2x7 | TAGGTGAGGGTTTGCTGTGG | ATGCCTTTGACCTTGGTGTG | 281 |
Snail1 | ATGCACATCCGAAGCCACAC | GGTCAGCAAAAGCACGGTTG | 148 |
Snail2 | GAAGCCCAACTACAGCGAAC | ATAGGGCTGTATGCTCCCGA | 123 |
Tgf-β | GCGGACTACTATGCTAAAGAGG | TCAAAAGACAGCCACTCAGG | 295 |
Tnf-a | GATCGGTCCCCAAAGGGATG | GGTGGTTTGTGAGTGTGAGGG | 86 |
Vimentin | GCTCCTACGATTCACAGCCA | CGTGTGGACGTGGTCACATA | 190 |
Ym1 | AGAAGCAATCCTGAAGACACC | GCATTCCAGCAAAGGCATAG | 205 |
Epithelium (E) | Infiltration (I) | ||
---|---|---|---|
0 | Normal morphology | 0 | No infiltrate |
1 | Loss of epithelial cells | 1 | Infiltrate around crypt basis |
2 | Loss of epithelial cell in large areas | 2 | Infiltrate reaching to L. muscularis mocusae |
3 | Loss of crypts | 3 | Extensive infiltration reaching the L. muscularis mucosae and thickening of the mucosa with abundant oedema |
4 | Loss of crypts in large areas | 4 | Infiltration of the L. submucosa |
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Lis-López, L.; Bauset, C.; Seco-Cervera, M.; Macias-Ceja, D.; Navarro, F.; Álvarez, Á.; Esplugues, J.V.; Calatayud, S.; Barrachina, M.D.; Ortiz-Masià, D.; et al. P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis. Int. J. Mol. Sci. 2023, 24, 12936. https://doi.org/10.3390/ijms241612936
Lis-López L, Bauset C, Seco-Cervera M, Macias-Ceja D, Navarro F, Álvarez Á, Esplugues JV, Calatayud S, Barrachina MD, Ortiz-Masià D, et al. P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis. International Journal of Molecular Sciences. 2023; 24(16):12936. https://doi.org/10.3390/ijms241612936
Chicago/Turabian StyleLis-López, Lluis, Cristina Bauset, Marta Seco-Cervera, Dulce Macias-Ceja, Francisco Navarro, Ángeles Álvarez, Juan Vicente Esplugues, Sara Calatayud, Maria Dolores Barrachina, Dolores Ortiz-Masià, and et al. 2023. "P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis" International Journal of Molecular Sciences 24, no. 16: 12936. https://doi.org/10.3390/ijms241612936