Innovative approaches to the therapy of fibrosis.
OBJECTIVE
The lung in systemic sclerosis (scleroderma) is susceptible to fibrosis and the ensuing respiratory insufficiency contributes to significant morbidity and mortality in this disease. The lack of effective therapies for pulmonary fibrosis has spurred a re-evaluation of pathobiological paradigms and therapeutic strategies in scleroderma-associated interstitial lung disease and in idiopathic pulmonary fibrosis. The purpose of this review is to examine emerging new therapeutic targets that modulate pro-fibrotic phenotypes of tissue-resident cells and the associated aberrant tissue remodeling responses in fibrotic disorders.


RESULTS
Progressive forms of tissue fibrosis, including scleroderma, are characterized by an accumulation of activated mesenchymal cells and their secreted extracellular matrix proteins in association with dysrepair of epithelial and endothelial cells. Recent studies suggest that emergence of cellular phenotypes that perpetuate loss of cellular homeostasis is characteristic of many fibrosis-related clinical syndromes.


CONCLUSIONS
Therapeutic strategies that modulate the fate/phenotype of reparative structural cells, including epithelial, endothelial, and mesenchymal cells, offer new opportunities for the development of more effective drugs for the treatment of fibrosis.
de Andrade
Joao A
JA
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, USA. joao@uab.edu
Thannickal
Victor J
VJ
D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology; D051523:Fibroblast Growth Factor 7 / Q000502:physiology; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D015398:Signal Transduction; D033581:Stem Cell Transplantation
D039561:Eukaryotic Initiation Factor-4E; C496453:FGF7 protein, human; C066855:HGF protein, human; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D051523:Fibroblast Growth Factor 7; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human