Idiopathic Pulmonary Fibrosis: Pathobiology of Novel Approaches to Treatment

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The pathogenesis of IPF: shifting paradigms

Understanding of the mechanisms involved in the pathogenesis of IPF has greatly evolved during the past 2 to 3 decades. The realization, as outlined in the first American Thoracic Society/European Respiratory Society (ATS/ERS) consensus statement, that IPF is an entity distinct from the other idiopathic interstitial pneumonias, has been an important contributor to this evolution.2 Clearer case definition coupled with the advent of high-resolution CT—which has enabled accurate, noninvasive,

Treatment development challenges: an embarrassment of riches but a lack of tools

Even a cursory review of the IPF literature discloses that a vast number of mediators, growth factors, cytokines, and signaling pathways are differentially regulated in IPF lung compared with normal control lung. This should, however, come as no surprise given the complexity, pleiotropism, and biologic redundancy that characterize the normal wound healing response. One of the major challenges confronting IPF researchers is separating key initiating events and pathways integral to the

The IPF treatment landscape: past and present

The belief that the development and progression of IPF were driven by uncontrolled inflammation underpins what has, until only recently, been the standard therapeutic approach for IPF. Even now, prednisolone, either alone, or in combination with azathioprine, is widely used as first-line treatment of many patients with IPF. Yet there is a lack of robust trial evidence to support this approach and evidence that there is predates the current classification of IPF.23 Clinical experience indicates

What can be learnt from IPF trail failures?

During the past decade, several potential treatments of IPF have failed to show efficacy in phase III clinical trials. It is worth considering these agents for the insights they provide into the pathogenetic processes in IPF. Interferon gamma-1b was the first compound to be tested in a true randomized placebo controlled trial in IPF.1 The rationale underlying the use of interferon gamma-1b in IPF was the observation that there exists an imbalance between profibrotic TH2 cytokines and

Emerging treatment targets in IPF

Several novel therapies targeting a variety of pathways important in wound healing are in early-phase trials in patients with IPF. Many more compounds are in the preclinical development phase. The remainder of this article considers potential therapeutic targets in IPF with particular reference to those being explored in currently active clinical trials programs (overviewed in Fig. 2).

Summary

IPF is a complex disease characterized by abnormalities in multiple pathways involved in the normal wound healing response. Better understanding of the pathobiology of the disease has led to a dramatic increase in the past decade in the number of clinical trials of novel therapies for IPF. With the recent licensing of pirfenidone in Europe, India, and Japan, these trials are beginning to result in the availability of treatments proved to alter the progression of the disease. Even so,

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      α-SMA and fibronectin expression were raised in the BLM-challenged groups compared with the control group, while the GHK-Cu treatment inhibited this BLM-induced increase in the α-SMA and fibronectin level in pulmonary fibrosis (Fig. 4), indicating a protective role for GHK-Cu against EMT progression in pulmonary fibrosis. We evaluated the oxidative stress level in this study by detecting the ROS/NO, MDA and GSH levels in the lung tissue due to the crucial role of oxidative stress in the development of pulmonary fibrosis (Fig. 5A, B, C) [28]. MDA is an oxidative stress-induced lipid peroxidation index, while GSH is a critical antioxidant and is related to the prevention of the oxidative stress induced injury.

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      The gradual loss of lung function can only be treated with lung transplantation, highlighting the necessity of finding other treatment options for this disease. Although the etiology of the disease is not known, injury to the lung alveolar epithelial cells seems to be the primary event which results in excessive ECM disposition and fibrosis due to the imbalance between the profibrotic and antifibrotic events [120]. Increase of CTGF levels in fibroblasts of bleomycin-induced mouse model of fibrosis indicates a potential role of CTGF in pathology of IPF [121].

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      In this study, influence of TGF-β1 alone on EMT and permeability in A549, NCI-H441, and Calu-3 cells were evaluated. Although TGF-β1 is most important factor for development of IPF (Coward, Saini, & Jenkins, 2010; Fernandez & Eickelberg, 2012), other growth factors and cytokines such as platelet-derived growth factor, connective tissue growth factor, and interleukin-13 are also involved in the development of pulmonary fibrosis (Harari & Caminati, 2010; Maher, 2012). Therefore, to establish a better in vitro model of respiratory epithelial cells that accurately reflects IPF, it might be necessary to investigate the influence of these growth factors and cytokines on the characteristics of respiratory epithelial cells.

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      Recent clinical trials have therefore shifted their focus from antiinflammatory and immunosuppressant compounds to molecules targeting components of the wound healing cascade and fibrogenesis. Nonetheless, despite this shift, results have been mostly disappointing, probably because of the plethora of mediators and signalling pathways likely to be involved in IPF pathogenesis (Maher, 2012). As such, the only care options which are endorsed by current evidence-based guidelines are oxygen therapy, pulmonary rehabilitation, lung transplantation and enrolment in clinical trials (Raghu et al., 2011).

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    Disclosures: I am in receipt of an unrestricted academic industry grant from GlaxoSmithKline (GSK). In the past 3 years I have received advisory board or consultancy fees from Actelion, Boheringer Ingleheim, GSK, Respironics, and Sanofi-Aventis.

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