Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment

Khalil, Nasreen; O’Connor, Robert

doi:10.1503/cmaj.1030055

Cited by 85 publications

(74 citation statements)

References 83 publications

(141 reference statements)

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“…These changes result from injury to the cellular components of the alveolar walls, as a result of the accumulation of inflammatory cells in the lesion (2,3). The alveolar macrophages play a central role in this process by releasing chemokines that amplify the inflammation by recruiting other inflammatory cells such as mast cells, neutrophils, and lymphocytes (4 -6).…”

Section: Diopathic Pulmonary Fibrosis (Ipf)mentioning

confidence: 99%

Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis

Matsuyama

Watanabe

Shirahama

et al. 2005

The Journal of Immunology

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Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. We previously reported the functional expression of DDR1 on human monocyte-derived macrophages in vitro; however, information regarding its role in diseases is limited. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease, and the lesions contain an abundance of collagen. In this study, we examined DDR1 expression on bronchoalveolar lavage fluid (BALF) cells and investigated its functionality using samples obtained from 28 IPF patients, 13 chronic obstructive pulmonary disease patients, and 14 healthy volunteers. The DDR1 expression level in CD14-positive BALF cells was higher in IPF patients than in chronic obstructive pulmonary disease patients or healthy volunteers. The predominant isoform was DDR1b in the IPF group, while DDR1a was predominant in the other two groups. Using immunohistochemical analysis, we also detected DDR1 expression on infiltrating inflammatory cells in the IPF lesion. In IPF patients, DDR1 activation induced the production of MCP-1, IL-8, MIP-1 α, and matrix metalloproteinase-9 (MMP-9) from CD14-positive BALF cells in a p38 MAPK-dependent manner. In contrast, DDR1 activation of CD14-positive BALF cells in the other groups did not induce the production of these chemokines or MMP-9. These chemokines and MMP-9 contribute to the development of IPF and, therefore, we suggest that DDR1 might be associated with the pathogenesis of IPF in the tissue microenvironment.

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Section: Diopathic Pulmonary Fibrosis (Ipf)mentioning

confidence: 99%

Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis

Matsuyama

Watanabe

Shirahama

et al. 2005

The Journal of Immunology

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“…2C). Bleomycin-induced pulmonary fibrosis protected tumor cells from immune surveillance by secreting high levels of TGF-h1 that increased the number of CD4 IPF is the most common type and afflicts >5 million patients worldwide, with a median survival of 3 to 5 years after diagnosis, and yet there is no effective treatment (39). A few growth factors Figure 6.…”

Section: Discussionmentioning

confidence: 99%

Naringenin: A Potential Immunomodulator for Inhibiting Lung Fibrosis and Metastasis

et al. 2009

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Patients with idiopathic pulmonary fibrosis have a high incidence of lung cancer and a worse prognosis for clinical treatment. A few molecules with antifibrosis properties have been shown promoting cancer progression in clinical trials. The objective of this study was to determine whether there is a similar tendency in mice as in human beings and whether these mice models may be used to find new therapeutic agents with antifibrotic properties but not cancer-promoting properties. We used bleomycin to induce pulmonary fibrosis in mice with or without naringenin treatment and measured the immune-associated lymphocytes and their secreted cytokines using flow cytometry and ELISA from lung tissue. Both passive and spontaneous metastatic models in bleomycin-treated C57BL/6 and BALB/c mice were used to test the hypothesis that mice with pulmonary fibrosis could have an increased risk of lung cancer and associated cancer progression. Here, we show that mice with lung fibrosis challenged using tumors show an increased incidence of lung metastasis and shorter life spans compared with the mice without lung fibrosis. A fibrotic environment in the lung results in increased abundance of transforming growth factor-B1 and CD4 + CD25 + Foxp3 + regulatory T cells and a decreased proportion of activated effector T cells. This grave immunosuppressive environment favors tumor localization and growth. Naringenin significantly reduces lung metastases in mice with pulmonary fibrosis and increases their survival by improving the immunosuppressive environment through down-regulating transforming growth factor-B1 and reducing regulatory T cells. Naringenin could be an ideal therapeutic agent in the treatment of both cancer and fibrosis. [Cancer Res 2009;69(7):3205-12]

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“…28,29 However, in IPF, because of the release of fibrogenic cytokines such as tumor necrosis factor (TNF)-␣, 30,31 interleukin (IL)-1, 31 and basic fibroblast growth factor, 32 these myofibroblasts are differentiated and activated. 3 An in vitro study showed that the primary cultures of fibroblasts from IPF patients contain significantly greater numbers of myofibroblasts than the cultures from patients without pulmonary fibrosis. 4,28 In addition, fibroblasts from IPF patients have been reported to be more resistant to apoptosis than those from patients without pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…2 In these processes, the release of fibrogenic cytokines may result in fibroblast proliferation and migration to various sites in the lung, followed by differentiation of the fibroblast phenotype. 3,4 This differentiation of fibroblasts is considered key to the chronic nature of IPF, and several reports suggest that fibroblasts in IPF appear to be more resistant to apoptosis, 5,6 a process that is important in both the pathogenesis and resolution of pulmonary fibrotic lesions. 7 However, the cellular mechanisms specifically involved in fibroblast apoptosis have not been completely elucidated.…”

mentioning

confidence: 99%

RETRACTED: Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis

Matsuyama

Watanabe

Shirahama

et al. 2006

The American Journal of Pathology

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Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-B activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-B nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-B inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well. (Am J Pathol

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Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment

Cited by 85 publications

References 83 publications

Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis

Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis

Naringenin: A Potential Immunomodulator for Inhibiting Lung Fibrosis and Metastasis

RETRACTED: Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis

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