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PULMONARY FIBROSIS
Coordinator
Dr. María Molina
Cell plasticity and microenvironment in lung fibrosis: looking for
its regulation as a potential treatment
Idiopathic pulmonary Fibrosis (IPF) is the most lethal interstitial lung disease (ILD), with no effective treatment and a mean survival of 2-4 years from the diagnosis . The histological defined pattern is the usual interstitial pneumonia (UIP), characterized by the loss of epithelial structures, interstitial collagenized fibrosis, microscopic honeycombing, and focal areas of “fibroblast foci” . The current pathogenic hypothesis
posited epithelial injury and impaired wound repair as the etiology of fibrosis . The initial cause is unknown, but genetic factors have been found to be associated such as telomerase gene mutations, which imply an impaired cell turnover and aging . IPF is characterized by a reactive stroma surrounding the altered alveolar epithelial units that exhibits a spatial accumulation of fibroblasts and myofibroblasts . The imbalance between the increase of pro-fibrotic growth factors, such as transforming growth factor beta1 (TGF-β1), angiotensin-II (ANGII), or reactive oxygen species (ROS), and the decrease of anti-fibrotic mediators such as prostaglandin-E2 (PGE-2), enhance the perpetuation of the process . Despite advances in the knowledge of fibrotic pathogenesis, the complex and potentially therapeutically relevant relationship and interactions between the containing cells and ECM remain poorly understood .
CELL REGENERATING ANSWER TO TISSUE DAMAGE.
Pneumocyte loss is followed by attempted tissue regeneration and exaggerated release of molecular signals triggering fibroblast proliferation and migration . The increased activation of the Wnt-pathway signalling in IPF is directly related to abnormal myofibroblast activity and epithelial-mesenchymal transition (EMT) . They have been a number of studies characterising population of stem cells in lung, as well as markers of EMT and MET and their implication in the fibrotic process . So far, though, LRSC’s of whatever origin have not been characterized in human diseased lungs . On the other hand, in animal model, introduction of MSCs into the lungs ameliorates bleomycin injury since a BM-MSCs subpopulation provides protection from lung injury . These data suggest that different MSCs subpopulations can significantly modulate the onset of a fibrogenic response .
INTERSTITIAL HALLMARKS OF THE ALTERED WOUND HEALING IN IPF..
Progressive tissue distortion and hardening in fibrosis have been associated with abnormal wound healing . Thus, in normal physiological conditions our organism can repair epithelial injury by forming a provisional structure generated by ECM protein deposition, fibroblast proliferation and transient myofibroblast activation . Completion of injury repair is followed by degradation of the provisional ECM and apoptosis of myofibroblasts . In pathologic conditions, some glycoprotein ECM components remain increased, collagen I and III are not degraded; myofibroblasts evade apoptosis and develop dysfunctional repair mechanisms . The contributions of the different environmental alterations during dysfunctional repair to tissue scar are likely to depend on the particular disease and organ, and overall remain poorly understood . Our group has recently demonstrated abnormally high levels of ECM components in IPF lungs that are implicated in tissue remodelling (cell adhesion, fibroblast migration) . Myofibroblasts are interstitial key effector cells in pulmonary fibrosis that can be derived from resident fibroblasts undergoing fibroblast-to-myofibroblast transformation (FMT), alveolar epithelial-to-mesenchymal transition (EMT), mesenchymal stem cells (MSCs) or even endothelial cells (EnMT) . FMT is characterized by a dramatic increase in wound ECM components including collagens and glycoproteins . Extracellular microenvironment can regulate FMT and EMT . Based on these observations it is tempting to speculate that there is a positive feedback loop between cell
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