Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway

Wallach-Dayan, Shulamit B.; Izbicki, Gabriel; Cohen, Pazit Y.; Gerstl-Golan, Regina; Fine, Alan; Breuer, Raphael

doi:10.1152/ajplung.00300.2004

Cited by 179 publications

(159 citation statements)

References 50 publications

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“…In addition, in concert with the abundant evidence indicating that ROS is central to BLM-induced pulmonary fibrosis 25,[36][37][38] , our study demonstrate that alveolar type II epithelial cells in Elovl6 À / À mice produce more ROS than those in WT mice as assessed by staining with antibody against nitrotyrosine. These results help explain why Elovl6 À / À mice are more susceptible to BLM-induced pulmonary fibrosis.…”

Section: Blm Treatment Decreases Elovl6 Expression In the Lungsupporting

confidence: 78%

“…We demonstrated that Elovl6 deficiency resulted in exacerbation of pulmonary fibrosis in mice when they are exposed to BLM. A number of evidence established that BLM induced apoptosis in the alveolar epithelial and endothelial cells [25][26][27] , which has a key role in the initiation and progression of pulmonary fibrosis 28 . Indeed, we found the induction of apoptosis and caspase 3 activation in the lung from Elovl6 À / À mice, and confirmed them in Elovl6-kockdown LA-4 cells.…”

Section: Blm Treatment Decreases Elovl6 Expression In the Lungmentioning

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 Lungsupporting

confidence: 78%

Section: Blm Treatment Decreases Elovl6 Expression In the Lungmentioning

confidence: 99%

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

et al. 2013

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“…Apoptosis of pulmonary endothelial and epithelial cell plays an important role in the initiation and progression of pulmonary fibrosis (2,9,11,32), and the mechanism of bleomycininduced apoptosis in lung cells has been a critical topic for pulmonary fibrosis research (17,18,28,30). The major finding of this study is that, in primary pulmonary endothelial cells, bleomycin induces early activation of the extrinsic apoptotic pathway, but not of the intrinsic apoptotic pathway.…”

Section: Discussionmentioning

confidence: 77%

“…However, cell culture experiments using primary rat lung epithelial cells and transformed mouse lung epithelial (MLE) cells provided evidence for activation of the intrinsic pathway of apoptosis by bleomycin in a c-Jun NH 2 -terminal kinase-(JNK) dependent manner (17). In a separate report, also using MLE, bleomycin was shown to activate caspase-8, suggesting the involvement of the extrinsic pathway of apoptosis (28).…”

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confidence: 99%

Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

Mungunsukh

Griffin

Lee

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis in humans and is commonly used to induce experimental pulmonary fibrosis in rodents. In cell culture, bleomycin causes single- and double-stranded DNA breaks and produces reactive oxidative species, both of which require iron (Fe2+) and O2. The mechanism of bleomycin-induced apoptosis is controversial due to its complexity. We investigated bleomycin apoptotic signaling events in primary pulmonary endothelial cells. Time course experiments revealed that bleomycin induced apoptosis within 4 h. Caspase-8, the initiator caspase for the extrinsic pathway, was activated within 2 h and preceded activation of the effector caspases-3 and -6 (4 h). Caspase-9, the initiator of the intrinsic pathway and release of cytochrome c from the mitochondria were not detected at these time points. Bleomycin induced the expression of Bcl-2 and Bcl-xL, Bcl-2 family member proteins that protect cells from the mitochondria-dependent intrinsic apoptosis. Real-time quantitative RT-PCR results demonstrated that, at 4–8 h, bleomycin induced expression of TNF and TNF receptor family genes known to induce the extrinsic apoptotic pathway. Silencing of the death receptor adaptor protein Fas-associated death domain by short interfering RNA significantly reduced bleomycin-induced apoptosis. Apoptosis was also abrogated by caspase-8 inhibition, but only slightly reduced by caspase-3 inhibition. Together, these data suggest that bleomycin initiates apoptosis via the extrinsic pathway.

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“…2,3 In addition, the oxidative effects of bleomycin in vitro have also been well described. 4,5 In contrast to intratracheal administration of bleomycin, repeated subcutaneous administrations result in a systemic exposure, and cause distal fibrosis that develops in parallel with mild inflammation. 6 The mechanisms behind these events are unknown, although it is likely that the endothelial niche is involved as previous studies have described systemic bleomycin administration (albeit at a higher dose) to result in capillary damage.…”

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confidence: 99%

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

Andersson-Sjöland

Karlsson

Rydell‐Törmänen

2016

Laboratory Investigation

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Pulmonary fibrosis is a grave diagnosis with insidious progression, generally considered as a consequence of aberrant epithelial wound healing and excessive scarring. This process is commonly modeled in animals by local bleomycin administration, resulting in peribronchial inflammation and subsequent fibrosis. We have previously described initiation and early development of distal pulmonary fibrosis following repeated subcutaneous bleomycin injections (systemic administration). The aim of this study was to identify mechanisms for the development of pulmonary fibrosis, which we hypothesize is related to endothelial stress and activation. Bleomycin was administered subcutaneously 3 times/ week during 0.33-4w, and parenchymal alterations were studied. In addition, we used microvascular endothelial cells to investigate effects of bleomycin in vitro. Our results confirmed that systemic administration of bleomycin exerts oxidative stress indicated by an increase in Sod1 at 0.33, 1, and 4w (Po0.05). Endothelial cells were activated (increased CD106 expression) from 1w and onwards (Po0.05), and p21 expression was increased 2-3 times throughout the study (Po0.05) as were the number of β-catenin-positive nuclei (Po0.001). Wnt3a was increased at 0.33, 1, and 4w (Po0.01) and Wnt5a from 1w and onwards (Po0.001). The present study suggests that bleomycin-induced reactive oxygen species (ROS) causes DNA stress affecting the endothelial niche, initiating repair processes including Wnt signaling. The repeated systemic administrations disrupt a normally fine-tuned balance in the Wnt signaling. In addition, pericyte differentiation was affected, which may have significant effects on fibrosis due to their ability to differentiate into myofibroblasts. We conclude that the endothelial niche may have an important role in the development of pulmonary fibrosis and warrants further investigations.

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Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway

Cited by 179 publications

References 50 publications

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

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

Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

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