Coming to "Grp(s)" with Senescence in the Alveolar Epithelium.

According to the current paradigm of idiopathic pulmonary fibrosis (IPF) pathogenesis, injury to and dysfunction of the lung epithelium play a major role in driving the disease process (1). Over the past two decades, studies of families with PF implicated rare mutations in genes related to surfactant biology as monogenic causes of PF (2), and subsequent work from multiple groups has indicated that at least a subset of surfactant protein mutations lead to misfolding of the proprotein, leading to endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) (3–5). Although surfactant protein mutations appear to be rare causes of adult PF, evidence of UPR activation in the lung epithelium is a common, if not ubiquitous, feature of IPF lungs (6, 7). Studies using several different pharmacologic UPR inducers and transgenic mouse models have demonstrated links between UPR activation, epithelial cell death by apoptosis or necroptosis (4, 5, 8, 9), and chronic inflammation (10). Conceptually, these studies suggest that high-level expression of misfolded proteins can overwhelm ER chaperone function, promoting a proinflammatory epithelial cell phenotype and premature death of the alveolar epithelium. Consistent with this hypothesis, global haploinsufficiency for the ER chaperone Grp78 (glucose-related peptide 78, also known as the immunoglobulin heavy-chain chaperone protein, Bip) appears to worsen experimental fibrosis (11). However, a clear understanding of the mechanisms linking lung epithelial UPR activation to parenchymal fibrosis has remained frustratingly elusive.

In this issue of the Journal, Borok and colleagues (pp. 198–211) provide new insights into the mechanisms through which the ER chaperone Grp78 plays a homeostatic role in the lung epithelium and protects against alveolar inflammation and fibrosis (12). Focusing specifically on the role of Grp78 in type II alveolar epithelial (AT2) cells, the authors generated novel tamoxifen-inducible, AT2-cell–specific, Grp78-deficient mouse models. By day 14 after tamoxifen administration, these mice developed patchy histologic fibrosis, increased lung collagen content, and reduced lung compliance. Consistent with the authors’ hypothesis, deletion of Grp78 in AT2 cells led to evidence of downstream UPR activation, including increased levels of Grp94 and Chop, and increased apoptosis in the lung epithelium. In most mice, by 90 days after tamoxifen treatment, there was resolution of injury and fibrosis. Lineage-tracing studies indicated that epithelial repair was mediated primarily by mobilization and proliferation of unlabeled (i.e., Grp78-competent) cells. This finding suggested a potential role of Grp78 in the regulation of AT2 progenitor potential.

The authors hypothesized that rather than being a direct effect of Grp78, this process could be mediated by UPR-driven induction of senescence. Using an elegant precision-cut lung-slice model, they demonstrated that mitigation of ER stress and apoptosis/senescence through administration of TUDCA, a pan-caspase inhibitor, and dasatinib/quercetin, respectively, led to enhanced resolution of hallmarks of fibrotic change and senescence. Although a protective role for TUDCA was previously demonstrated in mice (13), remarkably, these observations were also recapitulated in slices from human IPF lungs, suggesting that targeting these pathways may be an avenue for possible therapeutic intervention.

As the authors note, the impact of the Sftpc-CreER transgenic construct introduces complexity into interpretation of these studies. As demonstrated in the study, this construct leads to a functionally SP-C null allele, and therefore all Grp78-deficient mice were either haploinsufficient for SP-C or were SP-C null. It is difficult to ascertain how this impacts the findings. Loss or reduction of a highly expressed and processed protein may have reduced the burden on the ER quality-control systems and potentially mitigated the phenotypic severity and/or persistence to some degree. Conversely, prior work indicates that SP-C null mice have exaggerated injury responses and delayed injury repair (14). Regardless of these complexities, the net effect of simultaneously modulating levels of SP-C and Grp78 clearly alters the balance of the ER stress response in AT2 cells, leading to a profibrotic state.

Notably, it is becoming increasingly evident that the UPR pathway likely plays a significant role outside of the alveolar compartment in the context of fibrosis. For example, it was recently demonstrated that the UPR-regulated transcription factor XBP1 is critical for regulation of airway mucus secretion (15), and transgenic mice overexpressing Muc5b in the secretory cells appear to have increased fibrotic susceptibility in experimental models (16). A link between the UPR and senescence in the airway epithelium has not yet been established; however, several recent reports have described the presence of senescent basal-like cells in IPF lungs (17, 18), raising the possibility that this mechanism could play a broader role in the pathologic remodeling of the fibrotic lung epithelium.

This study has several significant implications. First, it adds to the growing body of evidence that widespread injury to AT2 cells is sufficient to trigger an acute inflammatory and fibrotic response in mice (10, 19–23). One question that has remained unresolved is why only a subset of models of AT2 injury lead to significant fibrosis; for example, LPS and influenza are both capable of causing severe alveolar injury but only minimal parenchymal fibrosis. This study suggests that the induction of a senescent phenotype in surviving AT2 cells may be one of the critical mechanisms that promote parenchymal fibrosis. Second, and perhaps more importantly, this work provides tantalizing evidence that alveolar epithelial senescence actively inhibits the resolution of fibrosis in a therapeutically targetable manner. Although further studies are clearly required to better elucidate the underlying mechanism, this finding suggests that cross-talk between the senescent epithelium and local mesenchymal populations is a central driver of lung fibrosis. With a growing understanding of the pathobiology linking epithelial senescence to fibrosis, there is reason to be optimistic that future therapies targeting senescence and its paracrine consequences in the lung epithelium will be able to improve outcomes for patients with PF.