Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by chronic progressive parenchymal lung fibrosis. Although extensive researches for IPF pathogenesis have been reported for several decades, the precise mechanisms are still unknown and the specific treatments for elimination of fibrosis and prolongation of survival are also still unknown. The role of inflammation as initial insult of lung fibrosis is still debating by controversial results of animal model experiments. The recent proposed mechanism for IPF is a dysregulation of epithelial-mesenchymal interactions which have critical role in tissue repair process and fibrosis. This hypothesis suggests impaired communications between epithelium and mesenchymal cells in terms of abnormal proliferation of mesenchymal cells instead of normal proliferation of epithelium. At recent, epithelial mesenchymal transition is regarded as an important source of myofiborblast which are major cells producing extracellular matrix. Classical treatment agents including steroid are already known to be ineffective in treatment of IPF, and also, IFN- one of newly emerging drug, is proved to be ineffective in treatment of IPF. Now new drugs involved in the molecular levels of signal transduction of fibrotic pathway, inhibition of various growth factors (TGF, CTGF, VEGF), and direct inhibition of fibrotic cytokines are under investigated in animal experiments and human clinical studies. Further studies should be focused on the evaluation of precipitating factors, genetic markers, drugs for inhibiting specific molecules responsible for lung fibrosis, and agents for controlling ECM precipitation.
References
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Table 1.
Trial | Phase | Patient numbers | Design | Endpoints |
---|---|---|---|---|
Antibody for MCP-1 | II | 120 | Randomized, double-blind, placebo-controlled | Efficacy |
Pirfenidone | III | 750 | Open label, uncontrolled | Adverse events or death |
Ambrisentan (ARTEMIS) | III | 600 | Randomized, double-blind, placebo-controlled | Death or disease progression |
Bosentan (BUILD3) | III | 600 | Open-label | Long term safety and tolerability |
PDL, AZA, NAC* (PANTHER) | III | 390 | Randomized, double-blind, placebo-controlled | PDL+AZA+NAC, NAC alone, placebo Change of FVC |
Pirfenidone | II | 090 | Open label, uncontrolled | Adverse events |
Sildenafil (STEP-IPF) | III | 170 | Randomized, double-blind, placebo-controlled | 6-min walk distance |
Sildenafil | IV | 050 | Randomized, double-blind, placebo-controlled | 6-min walk distance |
Pirfenidone | III | 400 | Randomized, double-blind, placebo-controlled | Change of FVC |
Bosentan | IV | 050 | Randomized, open-label | 6-min walk distance |
Angiokinase inhibitor | II | 400 | Randomized, double-blind, placebo-controlled | Change of FVC |
Zileuton | II | 140 | Randomized, open-label | LTB4 in BAL flluid |
Table 2.
Trial | Phase | Patient numbers | Primary endpoints Results |
---|---|---|---|
Thaliomide | II | 119 | Safety, feasibility and efficacy, Not reported |
Imatinib mesylate | II/III | 120 | Progression (FVC change), Not reported |
NAC* (INFIGENIA) | III | 184 | VC and DLCO Favor results |
Bosentan (BUILD-1) | II/III | 158 | 6-min walk distance, No significant effect |
Etanercept | II | 188 | Safety and efficacy, No significant effect |
Aerosol IFN | I/II | 115 | Safety and efficacy, Not reported |