Pathogenesis

Knowledge and understanding of idiopathic pulmonary fibrosis (IPF) pathogenesis has increased substantially in the last decade and has underpinned a fundamental change in the treatment approach for patients with IPF.10

Inflammation used to be considered the main pathological driving force in IPF and corticosteroids, in addition to cytotoxic agents, were recommended at treatment.1

Recent understanding, however, suggests the pathogenesis of IPF is driven by dysfunction and maladaptive repair of the alveolar epithelium after ongoing episodes of injury (Figure 2).11,12

Activated alveolar epithelial cells release fibrogenic growth factors that promote the migration, activation and differentiation of fibroblasts and invasive myofibroblasts, which then organise into fibroblastic foci, triggering excessive collagen production that results in architectural damage and lung scarring.11

Ultimately, healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange and finally respiratory failure and death.11,12

Schematic view of IPF pathogenesis

Figure 2. Schematic view of IPF pathogenesis.11 Repeated injuries over time lead to maladaptive repair process, characterised by alveolar epithelial cell apoptosis, proliferation and epithelium-mesenchymal cross-talk (a) and following fibroblasts, myofibroblasts proliferation and accumulation of extracellular matrix (b).
CCL2, chemokine C-C motif ligand 2; CXCL12, C-X-C motif chemokine 12; FGF, fibroblast growth factor; PAI-1, plasminogen activator inhibitor 1; PAI-2, plasminogen activator inhibitor 2; PDGF, platelet-derived growth factor; TGF-β1, Transforming Growth Factor-Beta 1; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor.

There are three pathophysiologic stages that are thought to lead to the development of pulmonary fibrosis (Figure 3).12

IPF pathogenesis can be divided into three pathophysiologic stages

Figure 3. IPF pathogenesis can be divided into three pathophysiologic stages.12

The predisposition stage includes genetic mutations/variations that predispose individuals to develop lung fibrosis, chronic epithelial cell turnover during the lifetime of an individual (which leads to shortened telomeres) and environmental exposures. These factors may lead to epithelial cell dysfunction. Not all individuals in this stage will develop clinically relevant disease; whether they do depends on the degree and duration of exposure to these factors.

In the initiation stage, molecular mediators of epithelial cell dysfunction such as ER stress; excessive TGF-β activation; and growth factor, chemokine or Wnt secretion lead to epithelial-to-mesenchymal transition, fibrocyte recruitment and fibroblast differentiation.

These lead to the progression stage, where pathologic mesenchymal cells release abnormal types and quantities of matrix proteins that remodel and scar the lung. The pathologically remodelled matrix or epigenetic changes within fibroblasts may lead to a feed-forward loop of mesenchymal cell activation and progressive fibrosis.

Find out more about the risk factors that may trigger these events
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