Pathophysiology of peritoneal inflammation and fibrosis (PERINFIB)

Research summary:

Used to treat advanced chronic kidney disease, peritoneal dialysis (PD) consists of using the peritoneum as a semipermeable membrane across which diffusion and ultrafiltration take place. During PD, the peritoneum is exposed to bio-incompatible solutions that cause inflammation, angiogenesis and fibrosis, resulting in membrane failure. Our group has shown that mesothelial cells undergo an epithelial-mesenchymal transition (EMT) in response to the peritoneal insult (Figure 1). During the last 16 years, there have been reports in the literature that mesothelial EMT (also termed Mesothelial to Mesenchymal Transition, MMT) is a good marker for membrane failure and a therapeutic target for preventing PD-induced fibrosis and/or angiogenesis.

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Figure 1. In the peritoneum new fibroblast-like cells arise from local conversion of mesothelial cells (MCs) by epithelial to mesenchymal transition (EMT) during peritoneal dialysis. Trans-differentiated MCs invade the submesothelial stroma, where they participate in the fibrotic and angiogenic processes, which ultimately lead to peritoneal ultrafiltration failure.

Recently, we considered whether the EMT plays a role in other peritoneal pathologies such as peritoneal metastasis and post-surgical adhesions. Peritoneal metastasis is a complication of abdominal carcinomas (e.g. ovarian carcinoma) for which there is no effective therapy. Progression of the metastatic implants is affected by Carcinoma-Associated Fibroblasts (CAFs), which can derive from several cell types. We have shown in human peritoneal implant biopsies that a subpopulation of CAFs derives from mesothelial cells through EMT. Our results also suggest that this EMT renders the peritoneum more receptive to implantation of tumor cells, contributes to the growth and vascularization of secondary tumors and that EMT is a therapeutic target in peritoneal carcinomatosis (Figure 2).

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Figure 2. Peritoneal dissemination is a frequent metastatic route for cancers of the ovary and gastrointestinal tract. We have shown that in peritoneal metastatic implants a sub-population of carcinoma-associated fibroblasts (CAFs) derives from mesothelial cells through mesothelial to mesenchymal transition (MMT). Moreover, MMT promotes the adhesion and invasion of tumor cells.

Adhesions are areas of fibrotic tissue that bind tissues and organs that would normally not be connected, and can be seriously life-threatening. Most adhesions are post-surgical. Histological analysis of human post-surgical adhesions has demonstrated that the mesothelial cells adjacent to the fibrotic tissue show signs of an EMT, suggesting that this could be an initial step in their development. The physiopathological processes involved in their formation remain unknown. Recent results have shown that mechanical injury is the main inducer of EMT during the formation of adhesions. Consequently, molecules involved in mechano-transduction, such as caveolin 1 (CAV-1), could play a role in the modulation of mechanical EMT and adhesion formation (Figure 3).

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Figure 3. a) Peritoneal adhesion experiments, based on ischemic buttons, showed that Cav-1 KO mice have increased capacity to develop adhesions compared with WT mice. b) Immunohistochemical analysis, on serial sections of peritoneal biopsies, showed that Cav-1 KO mice have exacerbated signs of mesothelial to mesenchymal transition, as demonstrated by the co-expression of cytokeratin and a-SMA in stromal fibroblast-like cells.

The aim of our work is to expand the knowledge of the pathological implications of the EMT of mesothelial cells and the molecular mechanisms that regulate this process, and to identify molecular targets for the design of therapeutic strategies, with possible applications in diseases associated with peritoneal fibrosis/angiogenesis, and in peritoneal metastasis.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Arriero PaisEva María4064707evaapais(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Carrero LiroaJavier4064707jcarrero(at)cbm.csic.esTitulado Doctor FC2
Kopytina Valeriia4064707vkopytina(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
López CabreraManuel4064604/4707mlcabrera(at)cbm.csic.esE. Investigadores Científicos de Organismos Públicos
Pascual AntónLucía4064707lucia.pascual(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1

Relevant publications:

  • Raby AC, González-Mateo GT, Williams A, Topley N, Fraser D, López-Cabrera M, Labéta MO. Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution-induced fibrosis. Kidney Int. 2018 Aug;94(2): 346-362
  • Horejs CM, St-Pierre JP, Ojala JRM, Steele JAM, da Silva PB, Rynne-Vidal A, Maynard SA, Hansel CS, Rodríguez-Fernández C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, López-Cabrera M, Stevens MM. Preventing tissue fibrosis by local biomaterials-interfacing of specific cryptic extracellular matrix information. Nat Commun.  2017 Jun 8;8:15509.
  • Rynne-Vidal A, Au-Yeung CL, Jiménez-Heffernan JA, Pérez-Lozano ML, Cremades-Jimeno L, Bárcena C, Cristóbal-García I, Fernández-Chacón C, Yeung TL, Mok SC, Sandoval P, López-Cabrera M. Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer J Pathol. 2017 Jun;242(2):140-151.
  • Liappas G, González-Mateo GT, Sánchez-Díaz R, Lasarte S, Matesanz-Marín A, Zur R, Ferrantelli E, García Ramírez L Aguilera A, Fernández-Ruiz E, Beelen RHJ, Selgas R, Sánchez-Madrid F, Martín P, López-Cabrera M. Immune-regulatory molecule CD69 controls peritoneal fibrosis. J Am Soc Nephrol. 2016 Dec;27(12):3561-3576.
  • Sandoval P, Jiménez-Heffernan JA, Guerra-Azcona G, Pérez-Lozano ML, Rynne-Vidal A, Martín P, Coronado MJ, Dotor J, Aguilera A, López-Cabrera M. Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions. J Pathology 2016 May;239(1): 48-59. doi: 10.1002/path.4695.
  • Strippoli R, Loureiro J, Moreno V, Benedicto I, Pérez Lozano ML, Barreiro O, Pellinen T, Minguet S, Foronda M, Osteso MT, Calvo E, Vázquez J, López-Cabrera M, Del Pozo MA. Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis. EMBO Mol Med. 2014 Dec 30;7(1): 102-23.
  • Sandoval P, Jiménez-Heffernan JA, Rynne-Vidal A, Pérez-Lozano ML, Gilsanz A, Ruiz-Carpio V, Reyes R, García-Bordas J, Stamatakis K, Dotor J, Majano PL, Fresno M, Cabañas C, López-Cabrera M. Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial to mesenchymal transition in peritoneal metastasis. J Pathology. 2013 Dec;231(4): 517-531.
  • Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-Vizcaíno P, Pérez-Lozano ML, Ruíz-Carpio V, Majano PL, Lamas S, Rodríguez-Pascual F, Borras-Cuesta F, Dotor J, López Cabrera M. Blocking TGF-β1 Protects the Peritoneal Membrane from Dialysate-Induced Damage. J Am Soc Nephrol. 2011 Sep;22(9): 1682-1695.
  • Aroeira LS, Lara-Pezzi E, Loureiro J, Aguilera A, Ramírez-Huesca M, González-Mateo G, Pérez-Lozano ML, Albar-Vizcaíno P, Bajo MA, del Peso G, Sánchez-Tomero JA, Jiménez-Heffernan JA, Selgas R and López-Cabrera M. Cyclooxygenase-2 Mediates Dialysate Induced Alterations of the Peritoneal Membrane. J Am Soc Nephrol. 2009 Mar;20(3): 582-592.
  • Yáñez-Mó M, Lara-Pezzi E, Selgas R, Ramírez-Huesca M, Domínguez-Jiménez C, Jiménez-Heffernan JA, Aguilera A, Sánchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sánchez-Madrid F, and López-Cabrera M. Peritoneal dialysis and epithelial-mesenchymal transition of mesothelial cells. N Engl J Med. 2003 Jan 30;348(5): 403-413.

Doctoral theses:

  • Guadalupe Tirma González Mateo (2011). Caracterización y modulación de la inflamación peritoneal para limitar la fibrosis causada por el líquido de diálisis: modelo de ratón. Universidad Complutense de Madrid. Director: Manuel López Cabrera y Rafael Selgas Gutiérrez.
  • Ignacio Benedicto Español (2011). Interrelación entre proteínas asociadas a uniones intercelulares estrechas, polaridad de los hepatocitos y el virus de la hepatitis C. Universidad Autónoma de Madrid. Directores: Manuel López Cabrera y Pedro Lorenzo Majano Rodríguez.
  • Jesús Loureiro Álvarez (2011). Transición epitelio-mesenquimal como diana terapéutica en modelos experimentales de diálisis peritoneal. Universidad Autónoma de Madrid. Director: Manuel López Cabrera.

Patents:

  • Inventors: Manuel López-Cabrera, Abelardo Aguilera, Rafael Selgas, Jutta Passlick-Deetjen, Janine Buechel, Sonja Steppan. Title: Method and kit for diagnosing epithelial to mesenchymal transition of the peritoneum. German Patent Number: DE 102015115158.8. (Granted). Date of Priority: 09/09/2015. Date of granting: 13/07/2017. International applications: PCT/EP2016/071149 WO2017042253 (A1). Extended Countries: USA patent: US 2018/0246098 A1, China patent: CN108449998 (A)-2018-08-24
  • Inventors: Abelardo Aguilera, Manuel López-Cabrera, Rafael Selgas, Jutta Passlick-Deetjen, Janine Büchel, Sonja Stephan. Title: Pharmaceutical Compositions Containing Steviosides. Application Number: Priority application EP 14 191 301.2. Date of Priority: October 31st, 2014. International applications: PCT/EP2015/074955 WO2016066672 (A1). Extended Countries: USA patent: US 2017/0304335 A1

Participación en proyectos financiados por la Unión Europea:

  • TÍTULO DEL PROYECTO: Identification and Management of Patients at Risk – Outcome and Vascular Events in Peritoneal Dialysis (Acrómimo: IMPROVE-PD).
    • TIPO DE CONTRATO: H2020-MSCA-ITN-2018 (Marie S-Curie Innovative Training Networks) (Grant # 812699)
    • ADMINISTRACIÓN FINANCIADORA: EUROPEAN UNION
    • ENTIDADES PARTICIPANTES: 11 grupos de investigación procedentes de siete países europeos.
    • DURACIÓN,  DESDE: 2018             HASTA: 2022
    • INVESTIGADOR COORDINADOR:  Manuel López Cabrera (CSIC)
    • Total Financiación: 4.021.380 Euros.

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