Molecular basis of organ fibrosis: Potential therapeutic approaches

Abstract

Fibrosis, a non-physiological wound healing in multiple organs, is associated with end-stage pathological symptoms of a wide variety of vascular injury and inflammation related diseases. In response to chemical, immunological and physical insults, the body's defense system and matrix synthetic machinery respond to healing the wound and maintain tissue homeostasis. However, uncontrolled wound healing leads to scarring or fibrosis, a pathological condition characterized by excessive synthesis and accumulation of extracellular matrix proteins, loss of tissue homeostasis and organ failure. Understanding the actual cause of pathological wound healing and identification of igniter(s) of fibrogenesis would be helpful to design novel therapeutic approaches to control pathological wound healing and to prevent fibrosis related morbidity and mortality. In this article, we review the significance of a few key cytokines (TGF-β, IFN-γ, IL-10) transcriptional activators (Sp1, Egr-1, Smad3), repressors (Smad7, Fli-1, PPAR-γ, p53, Klotho) and epigenetic modulators (acetyltransferase, methyltransferases, deacetylases, microRNAs) involved in major matrix protein collagen synthesis under pathological stage of wound healing, and the potentiality of these regulators as therapeutic targets for fibrosis treatment. The significance of endothelial to mesenchymal transition (EndMT) and senescence, two newly emerged fields in fibrosis research, has also been discussed.

Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

“…In previous studies in normal kidney or following ureteral obstructive kidney disease, the glomerulus was not a significant target for intracellular uptake, but in mice with early Alport nephropathy, glomerular podocytes, function (9). Therefore, unlike transcription factors, individual miRNAs are readily targetable with oligonucleotides in both animals and humans (10,11).…”

Myocardin-related Transcription Factor Regulates Nox4 Protein Expression

“…Organ fibrosis is a dysregulated form of tissue repair in response to chronic injury, characterized by excessive extracellular matrix deposition and the consequent loss of tissue architecture, which ultimately leads to organ failure (1,2). Fibroproliferative diseases, including renal, hepatic, pulmonary, and cardiovascular fibrosis, and systemic sclerosis are thought to contribute to 45% of all deaths in the Western world (2).…”

La transition épithélio-mésenchymateuse et la fibrose du transplant rénal

“…De même, A. Vongwiwatana a comparé dix biopsies de greffons rénaux dont la fonction se dégradait à des biopsies d'allogreffes dont la fonction restait stable. Les greffons fibreux se caractérisaient par une perte de marqueurs épithéliaux (E-cadhérine, cytokératine) dans les cellules épithéliales tubulaires, associée à l'expression de marqueurs mésenchymateux, de médicaments, et sa détection pourrait être utile au diagnostic précoce de fibrose [28][29][30]. Toutefois, ces approches thérapeutiques sont actuellement cantonnées aux modèles in vitro et chez l'animal.…”