Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls.
The currently accepted approach to treatment of idiopathic pulmonary fibrosis (IPF) is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in IPF aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor (TGF)-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.
Ask
Kjetil
K
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8N 3Z5.
Martin
Gail E M
GE
Kolb
Martin
M
Gauldie
Jack
J
D002986:Clinical Trials as Topic; D055513:Connective Tissue Growth Factor; D000068800:Etanercept; D005109:Extracellular Matrix / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors; D007074:Immunoglobulin G / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor; D000068800:Etanercept