Expression of Apoptotic and Antiapoptotic Markers in Epithelial Cells in Idiopathic Pulmonary Fibrosis

Plataki, Maria; Koutsopoulos, Anastassios V; Darivianaki, Katherine; Delides, G; Siafakas, Nikolaos M.; Bouros, Demosthenes

doi:10.1378/chest.127.1.266

Cited by 211 publications

(164 citation statements)

References 30 publications

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“…An important question is why Elovl6 À / À mice manifest pulmonary fibrosis at baseline and are highly susceptible to BLM compared with WT mice. One possible explanation is that Elovl6 deletion per se causes apoptosis of alveolar epithelial cells and/or induces TGF-b1 production in these cells, given that apoptosis and TGF-b1 production in alveolar epithelial cells largely contributes to the development of fibrosis [4][5][6][7][8][9] . Hence, we compared fluorescent TUNEL staining and caspase 3 activity between WT or Elovl6 À / À lungs before and after BLM instillation.…”

Section: Blm Treatment Decreases Elovl6 Expression In the Lungmentioning

confidence: 99%

“…The role of alveolar epithelial cell apoptosis during fibrosis has been extensively studied. For example, Plataki et al 4 showed that the apoptosis promoting factors, p53, p21, Bax and caspase 3 were upregulated in bronchial and alveolar epithelial cells in lung specimens taken by biopsy in IPF patients, and TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end-labelling) was positive in alveolar epithelial cells of all IPF patients. Likewise, Kuwano et al 5 demonstrated that caspase inhibitor protected progression of fibrosis in the rodent model.…”

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confidence: 99%

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Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6 À / À ) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6 À / À mice, resulting in induction of apoptosis, TGF-b1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.

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Section: Blm Treatment Decreases Elovl6 Expression In the Lungmentioning

confidence: 99%

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confidence: 99%

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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“…More recently, increased apoptosis of type II AECs has been demonstrated both in areas of IPF/UIP that appear histologically normal, without established fibrosis (19), and in epithelial cells overlying myofibroblasts (20). Increased expression of proapoptotic proteins and decreased expression of antiapoptotic proteins has also been reported (21). Thus, there is increasing evidence that at least certain subpopulations of AECs in IPF/UIP are undergoing apoptosis in association with inadequate or dysfunctional reparative responses of the alveolar and bronchiolar epithelium.…”

Section: Apoptosis Of Aecs In Ipf What Is the In Vivo Evidence For Apmentioning

confidence: 99%

“…Both the intrinsic (25) and extrinsic pathways (26-28) have been implicated (Figure 1). Type II AECs express high levels of p53 in association with DNA strand breaks in patients with IPF (21,29). p53 is a key regulator of the checkpoint response that typically mediates cell cycle arrest, DNA repair, and apoptosis in response to DNA damage.…”

Section: What Are the Cellular And Molecular Mechanisms For Injury/apmentioning

confidence: 99%

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Thannickal

Horowitz

2006

Proceedings of the American Thoracic Society

324

272

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Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive fibrosing disease of the lung of unknown etiology. Significant progress has been made in recent years in elucidating key aspects of the pathobiology of IPF. Insights into disease pathogenesis have come from studies of cell biology, growth factor/cytokine signaling, animal models of pulmonary fibrosis, and human IPF cells and tissue. A consistent finding in the ultrastructural pathology of IPF is alveolar epithelial cell injury and apoptosis. Another consistent finding in the histopathology of human IPF, described as usual interstitial pneumonia, is the accumulation of aggregates of myofibroblasts in fibroblastic foci. The extent or profusion of fibroblastic foci in lung biopsies is strongly correlated with increased mortality in patients with IPF. There is emerging evidence that myofibroblasts in IPF/usual interstitial pneumonia, both in the in vivo microenvironment and during the process of differentiation in vitro, acquire resistance to apoptosis. Here, we review the current evidence and mechanisms for this apparent "apoptosis paradox" in the pathogenesis of IPF.

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“…The mean linear intercept (Lm) was calculated from the number of fields examined (N), the length of the line used (L), and the number of intercepts (m), derived from the formula: Lm = N × L/m. The tissue embedded by OCT (Sakura, Japan) was frost sectioned for immunostaining as an established procedure (Yaguchi et al 1998;Plataki et al 2005). Goat polyclonal antibody against mouse MMP-12 (1:500; Abcam, USA) was labeled with rabbit anti-goat IgG/FITC.…”

Section: Histology and Immunostainingmentioning

confidence: 99%

Disruption of Plasminogen Activator Inhibitor-1 Gene Enhances Spontaneous Enlargement of Mouse Airspace with Increasing Age

Zhao

Xiao

et al. 2010

Tohoku J. Exp. Med.

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Plasminogen activator inhibitor-1 (PAI-1) is the most effective protease inhibitor in the fibrinolysis system, and plays an important role in the remodeling of the extracellular matrix. We therefore explored whether PAI-1 is involved in the change of lung structure with increasing age. PAI-1 gene knockout mice and wild-type mice were sacrificed at age 3 weeks, 3 months, 6 months and 15 months for histopathology analysis, and assessed the relationship between PAI-1 and the change in lung structure with age. Six-month-old mice were chosen for further studies. Elastin in the lung was detected using Weigert staining. We measured the expression of matrix metalloproteinase-12 (MMP-12) that is a major protease in elastin degradation by real time PCR and immunostaining. Transforming growth factor-β 1 (TGF-β 1) expression was measured by western blot analysis. PAI-1 gene knockout mice showed significant increases in alveolar size with increasing age and damaged alveolar structure at the age of 15 months, compared with wild-type mice. At the age of 6 months, elastin protein was decreased in the lungs of PAI-1 gene knockout mice. PAI-1 null mice had higher MMP-12 mRNA expression, and lower expression level of active TGF-β 1 in the lung. Taken together, these results indicate that the emphysema-like change attributed to PAI-1 deficiency might be facilitated with increased MMP-12 expression that accelerates elastin degradation in mice lungs, and TGF-β 1 might be involved in the modulation of this process.

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Expression of Apoptotic and Antiapoptotic Markers in Epithelial Cells in Idiopathic Pulmonary Fibrosis

Cited by 211 publications

References 30 publications

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Disruption of Plasminogen Activator Inhibitor-1 Gene Enhances Spontaneous Enlargement of Mouse Airspace with Increasing Age

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