Research activities

Molecular and genetic dissection of pathogenetic mechanisms in the development of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal lung disorder of unknown aetiology. At present there are no proven therapies for IPF. Current research indicates that the mechanisms driving IPF reflect abnormal, deregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of pro-inflammatory and pro-fibrogenic factors. In order to further dissect pathogenetic mechanisms of pulmonary fibrosis, we are utilizing the animal model of bleomycin-induced pulmonary inflammation and fibrosis to address the possible involvement of various mediators through genetic modifications, expression profiling and translational research. Along these lines, we have suggested a role for Hypoxia-inducible factor-1 in disease pathogenesis and we have underlined the importance of epithelial apoptosis in initiating the pathological cascade leading to the development of pulmonary fibrosis. Epithelial apoptosis was shown to rely on epithelial cytoskeletal architecture mediated by gelsolin, an actin-binding protein. Moreover, we have distinguished the role of transmembrane and soluble TNF, suggesting that soluble TNF secreted from apoptosing epithelial cells, mediates the transition from pulmonary inflammation to fibrosis contrary to the beneficial role of transmembrane TNF. Most importantly, we have recently shown a pivotal role for ATX in disease pathogenesis and suggested ATX as a likely therapeutic target, currently in phase 2 clinical trials. Current efforts are focusing on the role of phospholipid homeostasis in IPF pathogenesis, as well as other pulmonary pathophysiological disorders. In the same context, we are currently co-editing, together with distinguished colleagues, a special research topic on “Pulmonary Fibrosis” at Frontiers in Medicine.

 

Indicative selected publications

  • Oikonomou N., Harokopos V., Zalevsky J., Valavanis C., Kotanidou A., Szymkowski D.E., Kollias G. and, Aidinis V., 2006, "Soluble TNF Mediates the Transition from Pulmonary Inflammation to Fibrosis.", PLoS One, 2006 Dec 27, e108 [PubMed]. 
  • Tzouvelekis A, Harokopos V, Paparountas T, Oikonomou N, Chatziioannou A, Vilaras G, Tsiambas E, Karameris A, Bouros D and Aidinis V., 2007, "Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis", Am J Respir Crit Care Med, 176(11) :1108-19 [Pubmed] 
  • Oikonomou N, Thanassopoulou A, Tzouvelekis A, Harokopos V, Paparountas T, Nikitopoulou I, Witke W, Karameris A, Kotanidou A, Bouros D, and Aidinis V., 2009, "Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis.", Thorax. , 64(6): 467-75 [Pubmed]. 
  • Mouratis MA, Aidinis V. 2011, "Modeling pulmonary fibrosis with bleomycin.", Curr Opin Pulm Med., 2011 Sep; 17(5):355-61. [PubMed]. 
  • Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V. 2012, "Pulmonary Autotaxin Expression Contributes to the Pathogenesis of Pulmonary Fibrosis.", Am J Respir Cell Mol Biol, 2012 Jun 28 [PubMed]. 

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The role of ATX and LPA signalling in embryonic development, pathophysiology and cancer

Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely present in biological fluids, including blood. It is a plasma lysophospholipase D (lysoPLD) considered to be responsible for the majority of lysophosphatidic acid (LPA) production in the blood and at sites of inflammation. In turn, LPA is a bioactive lysophospholipid that evokes a great variety of cellular responses in almost all cell types, including cell migration, proliferation and survival. ATX and LPA signaling was shown from our group to be necessary for embryonic development, since complete genetic deletion of ATX from mice resulted to embryonic lethality, attributed to aberrant circulation and failure of neural tube closure. ATX was originally isolated from the supernatant of melanoma cells as an autocrine mobility stimulation factor; since, its role in carcinogenesis was well established and we are currently examining its role in various forms of cancer. However, high ATX expression has been discovered in non-malignant tissues such as the frontal cortex of Alzheimer-like dementia patients, the cerebrospinal fluid of multiple sclerosis patients, and as reported more recently from our group the arthritic synovium and the fibrotic lung, suggesting a possible involvement of ATX in chronic inflammatory disorders. On going genetic and pharmacological studies aim to establish ATX as a therapeutic target in chronic inflammatory disorders and cancer, to identify regulatory mechanisms of ATX expression and to examine its role in phospholipid homeostasis.

 

Indicative selected publications

  • Fotopoulou S, Oikonomou N, Grigorieva E, Nikitopoulou I, Paparountas T, Thanassopoulou A, Zhao Z, Xu Y, Kontoyiannis DL, Remboutsika E, Aidinis V 2010, "ATX expression and LPA signalling are vital for the development of the nervous system.", Dev Biol., Mar 15;339(2) , :451-64 [PubMed].
  • Nikitopoulou I, Oikonomou N, Karouzakis E, Sevastou I, Nikolaidou-Katsaridou N, Zhao Z, Mersinias V, Armaka M, Xu Y, Masu M, Mills GB, Gay S, Kollias G, Aidinis V. 2012, "Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis.", J Exp Med., 2012 May 7; 209(5):925-33. Epub 2012 Apr 9. [PubMed].
  • Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V. 2012, "Pulmonary Autotaxin Expression Contributes to the Pathogenesis of Pulmonary Fibrosis.", Am J Respir Cell Mol Biol, 2012 Jun 28 [PubMed].
  • Kaffe E, Katsifa A, Xylourgidis N, Ninou I, Zannikou M, Harokopos V, Foka P, Dimitriadis A, Evangelou K, Moulas AN, Georgopoulou U, Gorgoulis VG, Dalekos GN, Aidinis V. 2016, "Hepatocyte Autotaxin expression promotes liver fibrosis and cancer", Hepatology, 2016 Dec 16. [PubMed].

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Older interests

 

B.S.R.C. "Alexander Fleming"
34 Fleming Street, 16672 Vari, Greece
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