The pathogenesis of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an appalling prognosis. The failure of anti-inflammatory therapies coupled with the observation that deranged epithelium overlies proliferative myofibroblasts to form the fibroblastic focus has lead to the emerging concept that IPF is a disease of deregulated epithelial-mesenchymal crosstalk. IPF is triggered by an as yet unidentified alveolar injury that leads to activation of transforming growth factor-β (TGF-β) and alveolar basement membrane disruption. In the presence of persisting injurious pathways, or disrupted repair pathways, activated TGF-β can lead to enhanced epithelial apoptosis and epithelial-to-mesenchymal transition (EMT) as well as fibroblast, and fibrocyte, transformation into myofibroblasts which are resistant to apoptosis. The resulting deposition of excess disrupted matrix by these myofibroblasts leads to the development of IPF.

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

“…CIPF shares several clinical features with human IPF (Corcoran et al, 1999;Lobetti et al, 2001;Heikkilä et al, 2011); however, there are minor histopathological differences between these entities (Syrjä et al, 2013). In human IPF, chronic alveolar epithelial cell injuries and subsequent dysregulated tissue repair are considered to be the main pathological processes involved in the pathogenesis of this fibroproliferative disease (Coward et al, 2010;Raghu et al, 2011). The mechanisms of repair initiated by a tissue injury are complex and are determined by the presence of biological mediators such as growth factors and chemokines, which coordinate most aspects of the inflammatory and subsequent repair responses.…”

Neonatal Hyperoxia Increases Sensitivity Of Adult Mice To Bleomycin-Induced Lung Fibrosis

“…Because these lesions are often patchy, lacking inflammation, and refractory to conventional anti-inflammatory strategies, the concept that IPF is an inflammatory-mediated lung disease has now shifted to considering it a disease of repetitive epithelial injury with impaired repair. Despite the overt lack of inflammation in fibrosis, inflammation clearly contributes to disease progression, as reviewed by Coward and colleagues (36). The recruitment of granulocytes, monocytes, and circulating fibrocytes after injury is thought to be beneficial because they release factors that enhance the expression of the vascular endothelial growth factor, keratinocyte growth factor, and TGF-b1 required for appropriate repairs of the injured lung.…”

Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP

“…There is extensive ongoing investigation into the molecular mechanisms leading to the development of fibrosis that are beyond the scope of this review, and these are summarized elsewhere. 18,19 Although inflammation is no longer considered the primary event in the development of UIP, it is important to remember that some degree of inflammation does occur as a secondary phenomenon, and it may further drive the development of fibrosis.…”

“…This observation along with recognition of the importance of fibroblast foci in diagnosing UIP led to the current theory that acute lung injury is the primary event in the pathogenesis of UIP. 2,18,19 Fibroblast foci are small aggregates of fibroblasts and myofibroblasts that are present within myxoid stroma along the interstitium (Figure 8). 2 The spindle-shaped cells are arranged in layers parallel to the long axis of the alveolar septa beneath an epithelial lining composed of either hyperplastic type 2 pneumocytes or ciliated bronchiolar epithelium.…”