Friday, 6th December 2019

Molecular Pathophysiology of Fibrosis

Lab 103 Santiago Lamas grupo


Santiago Lamas




Research summary:

Our laboratory is interested in the molecular mechanisms leading to fibrogenesis in human pathology. Fibrosis is the final common pathway for many organ diseases including diabetic kidney disease, liver cirrhosis, scleroderma, myocardial sclerosis and idiopathic or inflammatory-mediated pulmonary fibrosis. Evolving from a long-standing interest in the vascular wall and redox biology we have now focused our efforts on understanding how the process of fibrogenesis takes place with an emphasis on the role of microRNAs and their regulation by redox signals in processes such as epithelial to mesenchymal transition, TGF-b signaling and fibroblast to myofibroblast transformation. We employ cellular and animal models for lung, skin and kidney fibrosis. We plan to decipher not only the profile of microRNAs involved in fibrogenesis but also the link between the underlying metabolic cellular changes occurring in the fibrotic process and the triggering of specific redox responses leading to the expression of microRNAs relevant for fibrogenesis.



Animal model in lung fibrosis. Intratracheal administration of the antibiotic bleomycin to mice promotes the development of a progressive lung fibrosis phenotype characterized by the loss of the typical alveolar architecture of the lung and extensive accumulation of extracellular matrix components as assessed by histological examination with hematoxilin and eosin (H&E) and Masson´s trichome histological staining, respectively.



Recent publications:

  • PriceNL*, MiguelV*, DingW, SinghAK, MalikS, Rotllan N, Moshnikova A, Toczek J, Zeiss C, Sadeghi M, Arias Rueda N, Baldán A, Andreev O, Rodriguez-Puyol D,Bahal R, Reshetnyak YK, Suárez Y, Fernández-Hernando C*, Lamas S*. Genetic deficiency and pharmacological inhibition of miR-33 enhances renal fatty acid oxidation and attenuates kidney fibrosis. Accepted for publication in JCI Insight
  • Fierro-FernándezM,MiguelV, Márquez-ExpósitoL, Nuevo-TapiolesC, HerreroJI, Blanco-RuizE, TituañaJ, CastilloC, CannataP, MonsalveM, Ruiz-OrtegaM, RamosR, Lamas SMiR-9-5p protects from kidney fibrosis by metabolic reprogramming. Accepted for publication in The FASEB Journal.
  • Rodriguez P, Sassi Y, Troncone L, Benard L, Ishikawa K, Gordon RE, Lamas S, Laborda J, Hajjar RJ, Lebeche D. Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis. Eur Heart J. 2018 Apr. 13.                                                                             
  • Espinosa-Díez C, Miguel V, Vallejo S, Sánchez FJ, Sandoval E, Blanco E, Cannata P, Peiró C, Sánchez-Ferrer CF, Lamas S. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol. 2018 Apr. 14:88-99.
  • Miguel V, Cui JY, Daimiel L, Espinosa-Díez C, Fernández-Hernando C, Kavanagh TJ, Lamas SThe Role of MicroRNAs in Environmental Risk Factors, Noise-Induced Hearing Loss, and Mental Stress. Antioxid Redox Signal.  2018 Mar. 20;28(9):773-79
  • Espinosa-Díez C, Miguel V, Vallejo S, Sánchez FJ, Sandoval E, Blanco E, Cannata P, Peiró C, Sánchez-Ferrer CF, Lamas S. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol. 2017; 14:88-99.
  • Lamas S, Michel T. Introduction to Special Issue "Redox regulation of cardiovascular signaling in health and disease". Free Radic Biol Med. 2017; 109:1-3.
  • Daiber A, Steven S, Weber A, Shuvaev VV, Muzykantov VR, Laher I, Li H, Lamas S, Münzel T. Targeting vascular (endothelial) dysfunction. 2017; 174(12):1591-1619.
  • Miguel V, Busnadiego O, Fierro-Fernández M, Lamas S. Protective role for miR-9-5p in the fibrogenic transformation of human dermal fibroblasts. Fibrogenesis Tissue Repair. 2016; 9:7.
  • Fierro-Fernández M, Busnadiego  O, Sandoval P, Espinosa-Diez C, Blanco-Ruiz E, Rodriguez M, Pian H, Ramos R, López-Cabrera M, García-Bermejo ML, Lamas S. miR-9-5p suppresses pro-fibrogenic transformation of fibroblast  and prevents organ fibrosis by targeting NOX4 and  TGFBR2. Embo Reports 2015 16 (10):1358-77.
  • Sánchez-Gómez  FJ, Calvo  E, Bretón-Romero R, Fierro-Fernández M, Anilkumar N, Shah AM, Schröder K, Brandes RP, Vázquez J, Lamas S. NOX-4-dependent hydrogen peroxide  promotes shear stress-induced  SHP2 sulfenylation and eNOS activation. Free Radic Biol Med 2015, 89: 419-430
  • Espinosa-Díez C, Fierro-Fernández M, Sánchez-Gómez F, Rodríguez-Pascual F, Alique M, Ruiz Ortega M, Beraza N, Martínez-Chantar ML, Fernández-Hernando C, Lamas  S. Targeting  of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces  Glutthione Biosynthesis  and Promotes  TGF-b-Dependent Fibrogenesis . Antioxid Redox Signal 2014
  • Bretón-Romero R, Acín-Perez R, Rodríguez-Pascual F, Martínez-Molledo M, Brandes RP, Rial E, Enríquez JA, Lamas S. Laminar shear stress regulates mitochondrial dynamics, bioenergetics responses and PRX3 activation in endothelial cells. Biochim Biophys Acta. 1843 (11): 2403-13.
  • Busnadiego O, Loureiro-Álvarez J, Sandoval P, Lagares D, Dotor J, Pérez-Lozano ML, López-Armada MJ, Lamas S, López-Cabrera M, Rodríguez-Pascual F. A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis. J Am Soc Nephrol. 2015, 26 (1): 173-82.
  • P Hernasanz Agustin; A Izquierdo Alvarez; F Javier Sánchez Gómez; E Ramos; T Villa Piña; S Lamas; A Bogdanova; A Martínez Ruiz. Acute hypoxia produces a superoxide burst in cells.Free Radical Biology & Medicine.  201471, pp. 146 -156.
  • R Bretón Romero; S Lamas. Hydrogen peroxide signaling in vascular endothelial cells.Redox Biol. 2014 2, pp. 529 - 534.
  • Sánchez-Gómez FJ,; Espinosa-Díez C,; Dubey M,; Dikshit M; Lamas S. S-glutathionylation: relevance in diabetes and potential role as a biomarker. Biol. Chem.
  • Olmos Y,; Sánchez-Gómez FJ,; Wild B; García-Quintans N,; Cabezudo S; Lamas S,; Monsalve M.SirT1 Regulation of Antioxidant Genes Is Dependent on the Formation of a FoxO3a/PGC-1# Complex. Antioxid Redox Signal, 2013 19(13): 1507-21.Martínez-Ruiz A; Araújo IM,; Izquierdo-Álvarez A,; Hernansanz-Agustín P; Lamas S,; Serrador JM. Specificity in S-Nitrosylation: A Short-Range Mechanism for NO Signaling?. Antioxid Redox Signal 
  • Laares, D., Busnadiego, O., García-Fernández, R.A., Lamas, S, and Rodríguez-Pascual, F. (2012) Adenoviral gene transfer of endothelin-1 in the lung induces pulmonary fibrosis through the activation of focal adhesion kinase. Am J Respir Cell Mol Biol. 47(6):834-42.
  • Martínez-Acedo, P., Núñez, E., Gómez, F.J., Moreno, M., Ramos, E., Izquierdo-Álvarez, A., Miró-Casas, E., Mesa, R., Rodríguez, P., Martínez-Ruiz, A., Dorado, D.G., Lamas, S, and Vázquez, J. (2012) A novel strategy for global analysis of the dynamic thiol redox proteome. Mol Cell Proteomics. 11(9):800-13.
  • Rodríguez-Pascual, F., Busnadiego, O., Lagares, D., and Lamas, S. (2011) Role of endothelin in the cardiovascular system. Pharmacol Res, 63(6):463-472.
  • Martínez-Ruiz, A., Cadenas, S., and Lamas, S. (2011) Nitric oxide signaling: classical, less classical, and nonclassical mechanisms. Free Radic Biol Med. 51(1):17-29.
  • Loureiro, J., Aguilera, A., Selgas, R., Sandoval, P., Albar-Vizcaíno, P., Pérez-Lozano, M.L., Ruiz-Carpio, V., Majano, P.L., Lamas, S., Rodríguez-Pascual, F., Borras-Cuesta, F., Dotor, J., and López-Cabrera, M. (2011) Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage. J Am Soc Nephrol 22(9):1682-1695.


Doctoral Thesis:

Veronica Miguel.(2019). The Metabolic Basis  of Renal Fibrosis: Role of microRNAs and insight from genetic models targeting lipid metabolism. Director: Santiago Lamas.

M. Cristina  Espinosa Diez (2015). Papel de la g-glutamilcistein ligasa en modelos de daño vascular y fibrótico e implicación de miR-433 en la sintesis de  glutation. Director: Santiago Lamas

M. Ángeles Higueras López (2014). Fisiología y Fisiopatología de DLK-1 en el Endotelio Vascular. Universidad Complutense de Madrid. Directores: Santiago Lamas y Patricia Rodríguez

Rosa Bretón Romero (2013). Redox Signaling Responses to Laminar Shear Stress in vascular endothelial cells. Universidad Autónoma de Madrid. Director:Santiago Lamas

David Lagares Salto (2012) Implicaciones Fisiopatológicas y Terapeuticas del eje TGF-beta/ET-1 y la Quinasa de Adhesión Focal en los procesos Fibróticos. Universidad Autónoma de Madrid. Directores: Santiago Lamas Peláez y Fernando Rodríguez Pascual.


European Application "Compounds for prevention and/or treatment of fibrotic diseases" Application No/Patent No 14382239.3-1401

International application  201031547 “Uso de Dlk1 como inhibidor de angiogénesis”, Dec 2011.

 Other activities:

.Organización de actividades I + D:

  • Workshop "Redox Biology as a major drive to the undestandidng of pathophysiology : Contibutions from the CONSOLREDOX network". Salamanca. Abril 2018
  • "Redox signaling and oxidative stress in health and disease IV Spanish and Portuguese meeting on free radicals" Valencia. Junio 2012
  • "Workshop on Gasotransmitters in health and disease" Madrid. Enero 2012
  • "XVII Simposio Internacional del Instituto "Reina Sofía" de Investigaciones Nefrológicas". Noviembre 2011
  • "Current Trends In Biomedicine. Molecular and Cellular Bases of Redox Signaling and Oxidative Stress: Implications in Biomedicine". Universidad Internacional de Andalucía. Simposium Internacional Baeza. Noviembre 2011
  • Curso de Verano "La fibrosis tisular en la enfermedad humana". Fundación General de la Universidad de Álcala de Henares. Septiembre 2012.


 Associate editor of the Redox Biology magazine


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