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TRANSLATING BASIC RESEARCH INTO CLINICAL PRACTICEMolecular Targets in Pulmonary Fibrosis: The Myofibroblast in Focus
Section snippets
Current Therapy
Historically, IPF was believed to result mainly from chronic inflammation, leading to persistent epithelial and vascular injury and activation/expansion of the lung mesenchyme. Established treatments based on this assumption involve the use of antiinflammatory or immunosuppressive drugs such as prednisone, azathioprine, or cyclophosphamide.1 Unfortunately, none of these agents have been shown to unequivocally alter the inflammatory process in IPF or reduce severity or progression of the
TGF-β
As mentioned previously, there is overwhelming evidence for a pathogenic role for TGF-β in IPF disease progression. This cytokine can drive EMT, fibroblast-to-myofibroblast differentiation, and is the most potent inducer of ECM production characterized to date. As a result, there is considerable optimism that drugs targeting TGF-β will be of benefit in IPF. One caveat to this approach is that TGF-β has an important role in regulating inflammation and acts as a tumor suppressor in certain
Wnt Signaling
The canonical Wnt signaling pathway involves the binding of Wnt proteins (cysteine-rich secreted glycoproteins) to frizzled-cell surface receptors or low-density lipoprotein coreceptors. A detailed description of this pathway is beyond the scope of this review (see Morrisey53 and Kikuchi et al54 for more information), but, briefly, it results in the inhibition of glycogen synthase kinase-3β and the consequent hypophosphorylation of β-catenin; this cytoskeletal protein can then translocate to
Anticoagulants
In 2005, Kubo et al57 published the results of a nonblinded, randomized trial of 56 patients with IPF administered prednisolone alone or prednisolone plus anticoagulation (oral warfarin for outpatients or low-molecular-weight heparin for hospitalized patients). These investigators reported a significant increase in survival in the anticoagulant group, with 63% survival at 3 years in the anticoagulant group vs 35% in the nonanticoagulant group. Both groups had a comparable incidence of acute
Conclusions and Future Directions
This review has outlined a few of the key molecular targets in pulmonary fibrosis that are intimately involved with fibroblast/myofibroblast recruitment, expansion, and differentiation; further understanding of how these molecules interact will undoubtedly bring novel therapeutic targets into focus. A brief perusal of the literature would reveal that there are many more potential targets that are the subject of current research; well over a thousand papers describe experiments in the bleomycin
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The authors declare that they have no conflicting financial interests.