Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a life-threatening condition, with a median survival of <3 yrs. The pathophysiology is not fully understood, but chronic injury of alveolar epithelial type II cells (AECII) is considered key. In IPF, disturbed folding and processing of surfactant proteins and impaired DNA repair may represent underlying reasons for maladaptive endoplasmic reticulum stress responses, increased reactive oxygen species production and/or DNA damage. Excessive AECII apoptosis occurs, leading to permanently perturbed epithelial homeostasis. The role of secondary hits also becomes evident. These may aggravate the disease and result in increased epithelial turnover, exhausting the regenerative capacity of progenitors and disturbing epithelial-mesenchymal interactions. Fibroblast proliferation, transdifferentiation and matrix deposition may be mediated through various mechanisms including epithelial-mesenchymal transition, fibrocyte invasion or expansion of a local fibroblast population. Treatment modalities aiming to attenuate epithelial injury are currently in early pre-clinical development and may reach the clinical arena in only a few years. Meanwhile, novel drugs acting on highly activated fibroblasts such as pirfenidone, an anti-fibrotic drug authorised for IPF in the European Union, or BIBF 1120, a novel triple-kinase inhibitor (blocking vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor) currently under clinical investigation, seem to attenuate the progression of IPF.

Figure 1.

Possible mechanisms of famillial idiopathic interstitial pneumonia leading to lung fibrosis involves apoptosis caused mainly through chronic endoplasmic reticulum (ER) stress. Telomere mutations may primarily cause DNA damage once telomeres have been substantially shortened. SP-A/C: surfactant protein A/C; SFTPA/C: surfactant protein A/C gene; TR: telomerase RNA-component; TERT: telomerase reverse transcriptase.

Figure 2.

Surfactant protein (SP)-C mutations lead to protein misfolding. Pathomechanism of c.460+1G>A mutation, leading to alternate splicing of the SP-C mRNA and deletion of exon 4, and resultant production of a defective proprotein foreshortened by 37 amino acids. The mutated proSP-C protein cannot be folded and processed to its mature form, and so accumulates with the healthy SP-C proprotein. The deposition of unfolded aggregated surfactant proteins seems to cause chronic alveolar epithelial type II cell injury and eventually lung fibrosis [26].

Figure 3.

The cyctoprotective endoplasmic reticulum (ER) stress mechanism [32]. BiP: immunoglobulin heavy chain-binding protein / 78 kDa glucose-regulated protein; IRE1: inositol-requiring protein 1; ATF: activating transcription factor; PERK: protein kinase R-like endoplasmic reticulum kinase; eIF: elongation initiation factor; XBP1: X-box binding protein 1; ERAD: ER-associated protein degradation; ROS: reactive oxygen species.

Figure 4.

Maladaptive endoplasmic reticulum (ER) stress. This process generally helps the cell to survive, but if stress is overwhelming or prolonged, the cell will be driven to apoptosis. a) Prolonged activation of inositol-requiring protein (IRE)1 may promote apoptosis. b) Pathways through which prolonged activation of C/EBP homologous protein (CHOP) may promote apoptosis. XBP-1: X-box binding protein-1; TRAF2: tomour necrosis factor (TNF) receptor-associated factor 2; AIP1: ASK1-interacting protein 1; ASK1: apoptosis signal-regulating kinase 1; P-JNK: phosphorylated c-Jun N-terminal kinase; Bax: apoptosis regulator Bax; Bak: Bcl-2 homologous antagonist/killer; RIDD: regulated IRE1 dependent decay; ATF-4: activating transcription factor 4; ERO1α: ER oxidoreductin-1α; IP3R: inositol 1,4,5-triphosphate (Ip3) receptor; STAT: signal transducer and activator of transcription; Fas: TNF ligand superfamily member 6/Fas antigen ligand; NOx: nitric oxide; ROS: reactive oxygen species; GADD34: growth arrest and DNA damage-inducible protein GADD34; DR5: death receptor 5; TRB 3: Tribbles homolog 3; Bcl-2: B-cell lymphoma 2/apoptosis regulator Bcl-2; Bim: Bcl-2 like protein 11/Bcl2-interacting mediator of cell death; OMM: outer mitochondrial membrance. Reproduced from [33] with permission from the publisher.

Figure 5.

Hyperplastic alveolar epithelial type II cells show severe endoplasmic reticulum stress and consecutive apoptosis. Representative immunohistochemistry for a, d) pro-surfactant protein C, b) cleaved caspase 3, c) C/EBP homologous protein, e) activating transcription factor (ATF)-6 and f) ATF-4 in serial sections of idiopathic pulmonary fibrosis lung tissue. Scale bars=50 µm. Reproduced from [10] with permission from the publisher.

Figure 6.

a) Healthy alveolar epithelial cells type II (AECII) and b) Hermansky–Pudlak syndrome-associated interstitial pneumonia (HPSIP) AECII. Disturbed intracellular surfactant transport in AECII occurs. The mature forms of surfactant proteins are blocked inside the late lysosomal compartment of the cell, but not primarily in the endoplasmic reticulum (ER) or Trans-golgi. The AECIIs become swollen due to the accumulation of the mature surfactant proteins, which in turn causes lysosomal stress reactions through activation of cathepsin D, glycerol ceramides and eventually C/EBP homologous protein (CHOP). GlCcer: glucosylceramides; LB: lamellar bodies; MVB: multivesicular bodies; PL: phospholipids; SP: surfactant protein; TM: tubular myelin; ULV: unilamellar vesicles.

Figure 7.

Current therapeutic approaches targeting profibrotic signalling pathways. Those pathways potentially leading to fibrosis have been used to develop targeted therapies for idiopathic pulmonary fibrosis treatment. Some potential therapies, which have had success in other disease areas, have failed. For example, tumour necrosis factor (TNF)-α blockers (e.g. etanercept) have been shown to be ineffective, and it appears that there is no significant role for agents that act on the endothelin pathway (e.g. bosentan). Therapies targeting anti-fibrotic and growth factor pathways are currently being developed. TGF-β: transforming growth factor-β; PGE₂: prostaglandin E₂; PDGF: platelet-derived growth factor; CTGF: connective tissue growth factor; TF: transcription factor; HGF: hepatocyte growth factor; TIMP: tissue inhibitor of metalloproteinases; PAI-1: plasminogen activator inhibitor-1; uPA: urokinase-type plasminogen activator; MMP: matrix metalloproteinases; ROS: reactive oxygen species; TH2: T-helper 2 cell; IL: interleukin; IFN: interferon. Reproduced from [48] with permission from the publisher.