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Review
. 2003 Nov;201(3):343-54.
doi: 10.1002/path.1446.

Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis

Eric S White  1 , Michael H Lazar, Victor J Thannickal
Affiliations
Review

Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis

Eric S White et al. J Pathol. 2003 Nov.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, usually fatal, form of interstitial lung disease characterized by failure of alveolar re-epithelialization, persistence of fibroblasts/myofibroblasts, deposition of extracellular matrix, and distortion of lung architecture which ultimately results in respiratory failure. Clinical IPF is associated with a histopathological pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy. Therapy for this disease with glucocorticoids and other immunomodulatory agents is largely ineffective and recent trials of newer anti-fibrotic agents have been disappointing. While the inciting event(s) leading to the initiation of scar formation in UIP remain unknown, recent advances in our understanding of the mechanisms underlying both normal and aberrant wound healing have shed some light on pathogenetic mechanisms that may play significant roles in this disease. Unlike other fibrotic diseases of the lung, such as those associated with collagen vascular disease, occupational exposure, or chemotherapeutic agents, UIP is not associated with a significant inflammatory response; rather, dysregulated epithelial-mesenchymal interactions predominate. Identification of pathways crucial to fibrogenesis might offer potentially novel therapeutic targets to slow or halt the progression of IPF. This review focuses on evolving concepts of cellular and molecular mechanisms in the pathogenesis of UIP/IPF.

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Figures

Figure 1
Figure 1
Histopathology of UIP (low power). H&E-stained whole mount section of lung from a patient with IPF. Note the characteristic peripheral, subpleural location of fibrosis and honeycomb change. These changes are heterogeneous, with regions of lung parenchyma spared from fibrosis
Figure 2
Figure 2
Histopathology of UIP (higher power). A hallmark of UIP is the heterogeneity, represented by dense, acellular bundles of collagen with smooth muscle metaplasia (arrow) in close approximation to the fibroblastic focus (FF), a dense collection of fibroblasts and myofibroblasts. Cuboidal epithelial cells lining distorted airspaces (which may be undergoing apoptosis) are seen overlying the fibroblastic focus
Figure 3
Figure 3
Overview of some of the key pathogenetic mechanisms in UIP/IPF. Following an unidentified insult, alveolar epithelial cells become injured and delayed re-epithelialization leads to a denuded, disrupted basement membrane. A fibrin clot forms early and serves as a provisional matrix for the migration and proliferation of reparative type I alveolar epithelial cells. Angiogenic factors may be elaborated, leading to the formation of nascent vasculature early in the disease process. Neutrophils secrete pro-inflammatory mediators, reactive oxygen species (ROS) and MMPs, while recruited lymphocytes elaborate the Th2-type cytokines, IL-4 and IL-13. Fibroblasts migrate into the wound and produce extracellular matrix (ECM) proteins and mediators such as angiotensin II which may further promote alveolar epithelial cell apoptosis. Alveolar macrophages and epithelial cells secrete TGF-β1, which promotes myofibroblast differentiation, increases ECM production, and inhibits apoptosis of fibroblasts/myofibroblasts. As ECM deposition progresses, regression of blood vessels may occur. Reciprocal communication between alveolar epithelial cells and mesenchymal cells results in a ‘positive feedback loop’ that promotes ongoing fibrosis and destruction of alveolar architecture
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