Chest
Volume 132, Issue 4, October 2007, Pages 1311-1321
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TRANSLATING BASIC RESEARCH INTO CLINICAL PRACTICE
Molecular Targets in Pulmonary Fibrosis: The Myofibroblast in Focus

https://doi.org/10.1378/chest.06-2568Get rights and content

Idiopathic pulmonary fibrosis (IPF) is one of a group of interstitial lung diseases that are characterized by excessive matrix deposition and destruction of the normal lung architecture. Long-term survival of IPF patients is poor, with a 5-year survival rate of only 20%. Despite a lack of evidence-based benefit, IPF has historically been treated with corticosteroids and/or cytotoxic agents such as prednisone. Given the poor efficacy of these drugs, novel therapeutic strategies are required for the management of IPF. This demands a better understanding of the molecular mechanisms underlying the pathogenesis and progression of this disease. The primary effector cell in fibrosis is the myofibroblast; these cells are highly synthetic for collagen, have a contractile phenotype, and are characterized by the presence of α-smooth muscle actin stress fibers. They may be derived by activation/proliferation of resident lung fibroblasts, epithelial-mesenchymal differentiation, or recruitment of circulating fibroblastic stem cells (fibrocytes). From a therapeutic viewpoint, interfering with the pathways that lead to myofibroblast expansion should be of considerable benefit in the treatment of IPF. This review will highlight some of the key molecules involved in this process and the clinical trials that have ensued.

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.

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