Determinants of initiation and progression of idiopathic pulmonary fibrosis

University of Rochester School of Medicine, Rochester, NY 14642, USA.
Respirology (Impact Factor: 3.35). 10/2009; 14(7):917-33. DOI: 10.1111/j.1440-1843.2009.01624.x
Source: PubMed


IPF is a devastating disease with few therapeutic options. The precise aetiology of IPF remains elusive. However, our understanding of the pathologic processes involved in the initiation and progression of this disease is improving. Data on the mechanisms underlying IPF have been generated from epidemiologic investigations as well as cellular and molecular studies of human tissues. Although no perfect animal model of human IPF exists, pre-clinical animal studies have helped define pathways which are likely important in human disease. Epithelial injury, fibroblast activation and repetitive cycles of injury and abnormal repair are almost certainly key events. Factors which have been associated with initiation and/or progression of IPF include viral infections, abnormal cytokine, chemokine and growth factor production, oxidant stress, autoimmunity, inhalational of toxicants and gastro-oesophageal reflux disease. Furthermore, recent evidence identifies a role for a variety of genetic and epigenetic abnormalities ranging from mutations in surfactant protein C to abnormalities in telomere length and telomerase activity. The challenge remains to identify additional inciting agents and key dysregulated pathways that lead to disease progression so that we can develop targeted therapies to treat or prevent this serious disease.

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    • "PF can be caused by systemic diseases (such as rheumatoid arthritis and sarcoidosis), exposure to environmental agents (asbestos, silica), chemicals (chemotherapy drugs including bleomycin, busulfan, carmustine and chlorambucil), or radiation therapy [1], [3]. Idiopathic pulmonary fibrosis (IPF), in which the cause is unknown, is the worst form of lung scarring, with a median survival time of 2.9 years and no effective treatments [1]. "
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    ABSTRACT: Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001), and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases.
    No preview · Article · May 2013 · PLoS ONE
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    • "There is growing evidence for abnormalities in DNA methylation in fibroblasts in other chronic fibrotic diseases, such as are observed in the lung and kidney.[101102] A recent study demonstrated epigenetic silencing of Thy- 1 by DNA hypermethylation specifically within fibroblast foci in patients with IPF, suggesting that this may be an important mechanism for pathogenetic fibroblast alterations since absence of Thy-1 correlates with a pro-fibrotic phenotype.[103] "
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    ABSTRACT: Experimental data indicate that the adventitial compartment of blood vessels, in both the pulmonary and systemic circulations, like the connective tissue stroma in tissues throughout the body, is a critical regulator of vessel wall function in health and disease. It is clear that adventitial cells, and in particular the adventitial fibroblast, are activated early following vascular injury, and play essential roles in regulating vascular wall structure and function through production of chemokines, cytokines, growth factors, and reactive oxygen species (ROS). The recognition of the ability of these cells to generate and maintain inflammatory responses within the vessel wall provides insight into why vascular inflammatory responses, in certain situations, fail to resolve. It is also clear that the activated adventitial fibroblast plays an important role in regulating vasa vasorum growth, which can contribute to ongoing vascular remodeling by acting as a conduit for delivery of inflammatory and progenitor cells. These functions of the fibroblast clearly support the idea that targeting chemokine, cytokine, adhesion molecule, and growth factor production in activated fibroblasts could be helpful in abrogating vascular inflammatory responses and thus in ameliorating vascular disease. Further, the recent observations that fibroblasts in vascular and fibrotic diseases may maintain their activated state through epigenetic alterations in key inflammatory and pro-fibrotic genes suggests that current therapies used to treat pulmonary hypertension may not be sufficient to induce apoptosis or to inhibit key inflammatory signaling pathways in these fibroblasts. New therapies targeted at reversing changes in the acetylation or methylation status of key transcriptional networks may be needed. At present, therapies specifically targeting abnormalities of histone deacytelase (HDAC) activity in fibroblast-like cells appear to hold promise.
    Full-text · Article · Mar 2012
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    • "In contrast to the idiopathic form of PF, there are many known causes such as exposure to respirable particles and toxicants, viral infections, oxidative stress, and gastroesophageal reflux disease that have been shown to initiate an inflammatory response and may induce events associated with PF [10]. Once respired particles and/or pathogens arrive inside the alveoli, they are engulfed by alveolar macrophages, which play an important role in the recognition, uptake, and clearance of particles from the lungs [11]. "
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    ABSTRACT: Pulmonary fibrosis is a progressive, disabling disease with mortality rates that appear to be increasing in the western population, including the USA. There are over 140 known causes of pulmonary fibrosis as well as many unknown causes. Treatment options for this disease are limited due to poor understanding of the molecular mechanisms of the disease progression. However, recent progress in inflammasome research has greatly contributed to our understanding of its role in inflammation and fibrosis development. The inflammasome is a multiprotein complex that is an important component of both the innate and adaptive immune systems. Activation of proinflammatory cytokines following inflammasome assembly, such as IL-1β and IL-18, has been associated with development of PF. In addition, components of the inflammasome complex itself, such as the adaptor protein ASC have been associated with PF development. Recent evidence suggesting that the fibrotic process can be reversed via blockade of pathways associated with inflammasome activity may provide hope for future drug strategies. In this paper we will give an introduction to pulmonary fibrosis and its known causes. In addition, we will discuss the importance of the inflammasome in the development of pulmonary fibrosis as well as discuss potential future treatment options.
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