Pulmonary fibrosis: patterns and perpetrators (original) (raw)
Pathologic hallmarks of UIP/IPF are the destruction of basement membrane and presence of hyperplastic alveolar epithelial cells (38). This has been suggested to create an environment of “frustrated” re-epithelialization (refs. 39, 40, and Figure 5). There are a number of mediators important in regulating epithelial-mesenchymal crosstalk during alveolar development that are expressed in IPF (41, 42). Among these are the morphogenic cytokines of the TGF-β superfamily (activin, bone morphogenetic protein 4 [BMP4] and BMP7, and perhaps most importantly, TGF-β1), Wnt/β-catenin, and sonic hedgehog (Shh). In addition, several tyrosine kinase signaling pathways including those downstream of FGFs, VEGF, PDGF, epithelial growth factor, and keratinocyte growth factor mediate epithelial-mesenchymal interactions, but their precise role in IPF is unknown. Despite the fact that there is a relative paucity of data directly implicating these pathways in the pathogenesis of pulmonary fibrosis, several clinical trials studying the utility of tyrosine kinase inhibitors in the treatment of fibrotic lung disease have been undertaken. A clinical trial evaluating the efficacy of imatinib in IPF failed to demonstrate an impact on disease over the course of one year of treatment (43). Interestingly, a Phase II trial evaluating a triple tyrosine kinase inhibitor with effects on FGF, VEGF, and PDGF showed promise (44, 45), and Phase III trials are underway (46).
Proposed mechanisms of severe lung fibrosis. Injured AEC2s attempting to repair damage release growth factors, cytokines, coagulants, and other substances. These factors promote mesenchymal expansion and activation, leading to the accumulation of matrix-producing and invasive fibroblasts/myofibroblasts. Figure adapted with permission from the American Journal of Respiratory Cell and Molecular Biology (2).
There are a number of studies evaluating Wnt/β-catenin signaling in animal models of pulmonary fibrosis (47–49). Furthermore, increased expression of several components of the Wnt signaling pathway as well as downstream targets have been demonstrated in IPF (50). The challenges to sorting out the role of Wnt/β-catenin signaling in pulmonary fibrosis derive from the protean expression of the pathway and the lack of AEC2-specific targeting approaches to interrogate the functional significance following lung injury.
In addition to mediators of lung development that may be implicated in fibrogenesis, studies investigating the pathogenesis of non-infectious lung injury have identified other salient pathways. Following lung injury, a constellation of events is set into place as the lung attempts to limit the extent of damage and restore functional integrity. Epithelial cells and innate immune cells (particularly macrophages) are the first responders charged with assessing the severity of the insult and mounting a host response. Diffuse alveolar damage occurs at focal sites of injury, with hyaline membrane formation and a fibronectin-rich provisional matrix as the coagulation cascade is locally activated in the context of increased alveolar permeability. The coagulation cascade has been suggested as a therapeutic target in IPF (51, 52), but a recent trial evaluating Coumadin (warfarin) was terminated for lack of efficacy (25, 53). However, more directed approaches such as targeting factor Xa, which has been shown to be expressed in IPF tissue and may contribute to TGF-β activation through interaction with the PAR-1 receptor, could be more fruitful (52).
The interplay between epithelial cells and macrophages in orchestrating the recruitment of fibroblasts is an area of active investigation. Both populations are capable of releasing a variety of mediators that have chemotactic properties for fibroblasts (54–56), but the relative contributions of these cell types has been difficult to discern. Recently, lysophosphatidic acid (LPA) has been shown to be present following lung injury, and its cognate receptor, LPAR1, is necessary for the recruitment of fibroblasts to the lung and the development of fibrosis following lung injury (55). Based on these data, an antagonist of LPAR1 is in early clinical development for IPF (57).
As noted above, activation of TGF-β is undoubtedly a critical ingredient for fibrogenesis. Several studies have suggested that fibrosis is abrogated in the absence of TGF-β signaling in the epithelium (58, 59). The integrin αvβ6 has been shown to be upregulated on epithelium following lung injury and to be necessary for activation of latent TGF-β (60). Anti-β6 antibodies are being studied in a Phase II clinical trial for IPF (52, 61). The precise and fundamental signals generated by epithelium that promote mesenchymal expansion have not been elucidated, but a recent study in acute kidney injury suggested that epithelial cell cycle arrest may generate signals that promote fibrosis (62). Interestingly, this process appeared to be mediated by JNK, and fibrosis was abated with a JNK inhibitor. Of note, a JNK inhibitor is in clinical development for IPF (63, 64).