Idiopathic pulmonary fibrosis : new concepts in pathogenesis and implications for drug therapy

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic 'reaction' patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in T(H)1/T(H)2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.

Figure 1

Idiopathic interstitial pneumonias (IIPs) represent an overlapping spectrum of inflammatory and fibrotic tissue reactions or histopathologic patterns in response to an “unknown” injury. At one end of the spectrum are IIPs marked predominantly by diffuse inflammatory cell infiltration; these IIPs tend to be more responsive to anti-inflammatory and immunosuppressive drug therapy. At the other end of the spectrum are IIPs characterized by fibrosis with minimal inflammation; these disease processes tend to have poor responses to currently available pharmacologic agents. Host factors (such as age and genetic polymorphisms) in combination with environmental factors (such as exposure to infectious agents and cigarette smoke) likely determine the resulting histopathological reaction patterns. DIP, desquamative interstitial pneumonia; RB-ILD, respiratory bronchiolitis associated-interstitial lung disease; COP, cryptogenic organizing pneumonia; NSIP, non-specific interstitial pneumonia; AIP, acute interstitial pneumonia; UIP, usual interstitial pneumonia.

Figure 2

The pathogenesis of IPF is complex and three major hypotheses or paradigms for the pathogenesis of IPF have emerged: dysregulated epithelial-mesenchymal interactions, aberrant angiogenesis and the TH₁/TH₂ cytokine imbalance. Epithelial-mesenchymal interactions between altered epithelial and mesenchymal phenotypes results in dysregulated interactions between these cellular compartments. In response to an unknown stimulus, alveolar epithelial cells in IPF develop a phenotype characterized by increased apoptosis, dysregulated proliferation, impaired regeneration/differentiation and perhaps impaired migration. Alveolar epithelial cells elaborate increased TGF-β1 and endothelin-1 along with decreased levels of PGE₂. Mesenchymal cells in this alveolar microenvironment acquire a contractile, synthetically active myofibroblast phenotype. Myofibroblasts retain the capacity to proliferate and are resistant to apoptosis while secreting large amounts of extracellular matrix proteins, soluble growth factors/cytokines and extracellular oxidants. Soluble mediators and the insoluble matrix elaborated by these myofibroblasts may, in turn, lead to aberrant reepithelialization that perpetuates a feed-forward cycle. IPF fibroblasts/myofibroblasts and alveolar epithelial cells contribute to an imbalance in angiogenic chemokines that may promote neovascularization and aberrant angiogenesis in IPF. A “shift” in the host immune response, favoring a TH₂ cytokine profile, has been postulated to contribute to initiation and/or progression of IPF.