New Insights into the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis: A Potential Role for Stem Cells in the Lung Parenchyma and Implications for Therapy

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal form of interstitial lung disease. It is characterized by injury with loss of lung epithelial cells and abnormal tissue repair, resulting in replacement of normal functional tissue, abnormal accumulation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and distortion of lung architecture which results in respiratory failure. Despite improvements in the diagnostic approach to IPF and active research in recent years, the molecular mechanisms of the disease remain poorly understood. This highly lethal lung disorder continues to pose major clinical challenges since an effective therapeutic regimen has yet to be identified and developed. For example, a treatment modality has been based on the assumption that IPF is a chronic inflammatory disease, yet most available anti-inflammatory drugs are not effective in treating it. Hence researchers are now focusing on understanding alternative underlying mechanisms involved in the pathogenesis of IPF in the hope of discovering potentially new pharmaceutical targets. This paper will focus on lung tissue repair, regeneration, remodeling, and cell types that may be important to consider in therapeutic interventions and includes a more detailed discussion of the potential targets of current therapeutic attack in pulmonary fibrosis. The discovery that adult bone marrow stem cells can contribute to the formation of differentiated cell types in other tissues, especially after injury, implies that they have the potential to participate in tissue remodeling, and perhaps regeneration. The current promise of the use of adult stem cells for tissue regeneration, and the belief that once irreversibly damaged tissue could be restored to a normal functional capacity using stem cell-based therapy, suggests a novel approach for treatment of diverse chronic diseases. However this optimism is tempered by current evidence that the pathogenesis of pulmonary fibrosis may involve the recruitment of bone marrow-derived fibroblasts, which are the key contributors to the pathogenesis of this chronic progressive disorder. Nevertheless, stem cell-related therapies are widely viewed as promising treatment options for patients suffering from various types of pulmonary diseases. Gender mismatched bone marrow or lung transplant recipients serve as natural populations in which to study the role of bone marrow-derived stem cells in recovery from pulmonary diseases. Understanding the mechanism of recruitment of stem cells to sites of injury, and their involvement in tissue repair, regeneration, and remodeling may offer a novel therapeutic target for developing more effective treatments against this fatal disorder. This article reviews the new concepts in the pathogenesis, current and future treatment options of pulmonary fibrosis, and the recent advances regarding the roles of stem cells in lung tissue repair, regeneration, and remodeling.

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced alveolar epithelial to mesenchymal transition

“…In contrast, we found that AGE inhibited TGF-β-induced ERK1/2 and SMAD2 phosphorylation, and increased SMAD7 expression, which was suppressed by TGF-β. TGF-β induces the alveolar EMT in human lung epithelial cells via a SMAD2-or SMAD3-dependent pathway (Yao et al, 2004;Kasai et al, 2005;Hackett et al, 2009) and is considered to be an important step toward fibroblastic foci formation in IPF (Thannickal et al, 2004;Gharaee-Kermani et al, 2007). SMAD7 inhibits TGF-β signaling through competitive binding to type 1 receptors, and it inhibits the activation of SMAD2/3 (Li et al, 2003).…”

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

“…Fibrosis is analogous to abnormal wound healing occurring during tissue response due to chronic and sustained injury, microtrauma, oxidative stress, endogenous or exogenous insults, autoimmunity, and other factors. This process affects multiple organs in localized, multifocal, or disseminated forms, in conditions such as systemic sclerosis, liver cirrhosis, progressive kidney disease, cardiovascular disease, pulmonary fibroses, macular degeneration, and muscle dystrophies (Willis et al 2006, Gharaee-Kermani et al 2007, Henderson & Iredale 2007. Although chronic inflammation usually precedes fibrosis, it is neither necessary nor sufficient to trigger it, and as a result anti-inflammatory agents are usually not effective against fibrosis.…”

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

“…Recent attention has focused on ECM components and mesenchymal cell phenotypes as being critical to the development of fibrosis (1,2). The ECM is a highly dynamic complex that varies in composition according to its tissue localization and physiologic circumstances.…”