Rethinking Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.

Keywords: Idiopathic interstitial pneumonia; Idiopathic pulmonary fibrosis; Interstitial lung disease; Usual interstitial pneumonia.

Fig. 1.

Three-stage description of the pathogenesis of IPF. In the predisposition stage, recurrent environmental insults lead, in genetically predisposed individuals, to increased turnover of alveolar type II cells, ER stress– mediated activation of UPR, apoptosis, and progressive telomere attrition. In the activation stage, accumulation of a lifetime insults leads to pathologic alterations of the lung epithelium, such as senescence reprogramming, and release of profibrotic mediators (eg, TGFβ, Wnts, and PDGFβ) by the alveolar epithelium. These mediators, either directly or indirectly via leukocytes, activate fibroblasts to deposit pathologic matrix. In the progression stage, the pathologic matrix promotes additional differentiation of fibroblasts to myofibroblasts, which deposit more matrix and further activate fibroblasts in a feed-forward loop of lung remodeling. ER, endoplasmic reticulum; PDGF, platelet-derived growth factor; TGF, transforming growth factor; UPR, unfolded protein response. (From Wolters PJ, Blackwell TS, Eickelberg O, et al. Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med. 2018;6(2):154–160. Reprinted with permission from Elsevier.)

Fig. 2.

Consideration of SLB to determine histologic features in patients with HRCT patterns of UIP and probable UIP. (Top) UIP magnified view of the left lower lobe (transverse computed tomography section) showing typical characteristics of honeycombing, consisting of clustered cystic airspaces with well-defined walls and variable diameters, seen in single or multiple layers (arrows). (Bottom) Probable UIP magnified sagittal view (reconstructed) of the right lower lobe illustrating the presence of a reticular pattern with subpleural, peripheral, and basal pre-dominance of traction bronchiolectasis that appears as tubular (arrows) or cystic (arrowhead) structures. Images reprinted from. (Reprinted from Raghu G, Remy-Jardin M, Myers J, Richeldi L, Wilson KC. The 2018 Diagnosis of Idiopathic Pulmonary Fibrosis Guidelines: Surgical Lung Biopsy for Radiological Pattern of Probable Usual Interstitial Pneumonia Is Not Mandatory. Am J Respir Crit Care Med. 2019;200(9):1089–1092; with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. All rights reserved.)

Fig. 3.

Pathobiologic features of IPF. (A) A conceptual model of the pathobiology of IPF, which is characterized by recurrent epithelial cell injury, senescent alveolar epithelial cells, profibrotic mediators leading to matrix deposition by myofibroblasts, microbiome changes, and host defense abnormalities. Potential therapeutic interventions are shown in green. Histologic features of UIP are shown in (B) at low magnification and (C) at high magnification (hematoxylin-eosin). The photomicrographs show a marked patchy fibrosis in a peripheral, lobular (paraseptal) distribution. Fibroblastic foci (asterisk) typically are a prominent (but nonspecific) feature. Absent are features that would suggest an alternative ILD, such as granulomas, hyaline membranes, organizing pneumonia, or marked inflammation. AEC, alveolar epithelial cell; CCL2, chemokine (C-C motif) ligand 2; CCR2, chemokine (C-C motif) receptor 2; CTGF, connective-tissue growth factor; CXCL12, C-X-C motif chemokine ligand 12; FGF-2, fibroblast growth factor 2; FGFR1, fibroblast growth factor receptor 1; LOXL2, lysyl oxidase–like 2; LPA, lysophosphatidic acid; LPA_1, lysophosphatidic acid receptor type 1; LPC, lysophosphatidylcholine; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; SDF-1, stromal-cell–derived factor 1; TGF-β, transforming growth factor β; TGFBR1 TGF-β receptor type 1; TIMP, tissue inhibitor of metalloproteinases; TRPV4, transient receptor potential cation channel subfamily V member 4; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. (From Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;378(19):1811–1823. Copyright © 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)