Pathogenesis of idiopathic pulmonary fibrosis and therapeuthic perspectives

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterized by an accumulation of myofibroblasts in the alveolar wall, aberrant matrix deposition and subsequent distortion of the normal lung architecture. According to the predominant pathogenic hypothesis a recurrent injury to alveolar epithelium might lead to an aberrant fibroproliferative response although is still debated whether pulmonary fibrosis could instead be the result of a chronic inflammatory process. The "PANTHER" study has recently solved this debate showing that patients treated with prednisone, azathioprine and NAC had an increased risk of death and hospitalization as compared with placebo. The failure of this anti-inflammatory and immunosuppressive treatment has indirectly provided evidence that inflammation is not a predominant feature in the pathogenesis of IPF. According to the current pathogenic hypothesis, IPF is instead the result of a chronic damage of the alveolar epithelium followed by activation of fibroblasts, abnormal tissue repair and impairment of the alveolar structure. This has recently led to the development and then to the clinical approval of molecules such as pirfenidone that mainly acts inhibiting fibroblast activation and TGF-beta expression. More recently, IPF was assimilated to a neoproliferative disorder based on the evidence that a number of pathogenic features of IPF are shared with cancer. Genetic and epigenetic changes, delayed apoptosis and altered response to regulatory signals by myofibroblasts, reduced cellular communications and abnormal activation of specific signalling pathways have been shown to unambiguously mark both IPF and cancer. Tyrosine kinases (TKs) are key mediators of signalling pathways involved in regulation of normal cellular processes whose aberrant activity plays an important role in the development, progression and spread of several types of cancer. More recently, the activity of these receptors has also been related to wound healing and fibrogenesis. The antifibrotic profile of the multiple inhibitors of tyrosine kinase receptors (TKR) has been evaluated on fibroblasts in vitro and more interestingly in vivo in a rat model of bleomycin-induced fibrosis. The contemporary inhibition of PDGFR, VEGFR and FGFR resulted in significant attenuation of fibrosis suggesting a novel therapeutic approach for the treatment of IPF. Based on these observations TKR inhibitors have been proposed, and used as potential targets for the treatment of both cancer and IPF. The vision of IPF as a cancer-like disease may satisfy the need for a better understanding of the pathogenesis of IPF exploiting the great deal of knowledge that cancer biology may evoke. The recognition of common pathogenic pathways between the two diseases may stimulate new clinical trials with cancer drugs and hopefully with combination or different lines of drugs as already experimented in oncology. Moreover, the concept of IPF as a cancer-like disorder may ameliorate the attention given to this dreadful disease at a public, political and healthcare level.