The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops

Abstract

Pulmonary fibrosis is a devastating, progressive disease and carries a prognosis worse than most cancers. Despite ongoing research, the mechanisms that underlie disease pathogenesis remain only partially understood. However, the self-perpetuating nature of pulmonary fibrosis has led several researchers to propose the existence of pathological signalling loops. According to this hypothesis, the normal wound-healing process becomes corrupted and results in the progressive accumulation of scar tissue in the lung. In addition, several negative regulators of pulmonary fibrosis are downregulated and, therefore, are no longer capable of inhibiting these feed-forward loops. The combination of pathological signalling loops and loss of a checks and balances system ultimately culminates in a process of unregulated scar formation. This review details specific signalling pathways demonstrated to play a role in the pathogenesis of pulmonary fibrosis. The evidence of detrimental signalling loops is elucidated with regard to epithelial cell injury, cellular senescence and the activation of developmental and ageing pathways. We demonstrate where these loops intersect each other, as well as common mediators that may drive these responses and how the loss of pro-resolving mediators may contribute to the propagation of disease. By focusing on the overlapping signalling mediators among the many pro-fibrotic pathways, it is our hope that the pulmonary fibrosis community will be better equipped to design future trials that incorporate the redundant nature of these pathways as we move towards finding a cure for this unrelenting disease.

FIGURE 1

Overview of the interaction among various feed-forward loops involved in pulmonary fibrosis whereby all pathways to the development of the disease.

FIGURE 2

Recurrent epithelial injury leads to chronic activation of transforming growth factor-β₁ (TGF-β₁) and Wingless/Integrase-1 (Wnt) signalling cascades. The activation of TGF-β₁ can suppress negative regulators of the Wnt pathway and ultimately activate Wnt signalling. Activation of Wnt signalling also propagates TGF-β₁ signalling. This, coupled with chronic epithelial damage, further drives this cycle to result in pathological, unresolving wound healing. DKK1: Dickkopf-1

FIGURE 3

Signalling cartoon of the interaction among transforming growth factor-β₁ (TGF-β₁), epithelial–mesenchymal transition (EMT), epithelial injury, oxidative stress, telomere attrition and senescence. Red boxes depict pro-fibrotic pathways and green boxes indicate anti-fibrotic ones. TGFBR2: transforming growth factor-β receptor-2; PTEN: phosphatase and tensin homolog; JAK: Janus-activated kinase; p38 MAPK: p38 mitogen-activated kinase; PI3K: phosphatidylinositol-3 kinase; AMPK: 5′-AMP activated kinase; mTOR: mammalian target of rapamycin; AP-1: activator protein-1; SIRT: sirtuin protein family; VEGF: vascular endothelial growth factor; SASP: senescence-associated secretory phenotype.