Proapoptotic Bid is required for pulmonary fibrosis

Budinger, G. R. Scott; Mutlu, Gökhan M.; Eisenbart, James; Fuller, Alyson C.; Bellmeyer, Amy; Baker, Christina M.; Wilson, Mindy S.; Ridge, Karen M.; Barrett, Terrence A.; Lee, Vivian Y.; Chandel, Navdeep S.

doi:10.1073/pnas.0507604103

Cited by 101 publications

(114 citation statements)

References 36 publications

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“…In addition to endothelin-1 induction, TGF-b1 may induce fibrosis by activating caspases that mediate cell death and apoptosis. In one study, investigators found that Bax and Bid, two apoptotic regulatory proteins suggested to mediate fibrotic responses (57,58), may be activated by TGF-b1 and may facilitate bleomycin-induced pulmonary fibrosis in mice (59). In this study, TGF-b1-mediated increases in inflammation, lung collagen content, and lung cell apoptosis were decreased significantly in both Bax-and Bid-null mice versus wild-type control mice.…”

Section: Airway Remodeling and Proliferationmentioning

confidence: 52%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

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The pathogenesis of asthma includes a complex interplay among airway inflammation, hyperresponsiveness, and remodeling. Current evidence suggests that airway structural cells, including bronchial smooth muscle cells, myofibroblasts, fibroblasts, and epithelial cells, mediate all three aspects of asthma pathogenesis. Although studies show a connection between airway remodeling and changes in bronchomotor tone, the relationship between the two remains unclear. Transforming growth factor b1 (TGF-b1), a growth factor elevated in the airway of patients with asthma, plays a role in airway remodeling and in the shortening of various airway structural cells. However, the role of TGF-b1 in mediating airway hyperresponsiveness remains unclear. In this review, we summarize the literature addressing the role of TGF-b1 in airway remodeling and shortening. Through our review, we aim to further elucidate the role of TGF-b1 in asthma pathogenesis and the link between airway remodeling and airway hyperresponsiveness in asthma and to define TGF-b1 as a potential therapeutic target for reducing asthma morbidity and mortality.

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Section: Airway Remodeling and Proliferationmentioning

confidence: 52%

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Ojiaku

Yoo

Panettieri

2017

Am J Respir Cell Mol Biol

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“…Assessment of Lung Permeability-Lung permeability was assessed using a modification of a described previously tech-nique (26). The mice were anesthetized with pentobarbital, and 125 l of fluorescein isothiocynate-dextran (molecular mass, 4,000 kDa) 0.05 g/ml (Sigma-Aldrich) was delivered into the retro-orbital plexus using a 26-gauge needle.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting-Protein immunoblotting was performed as described previously (26). The cell lysates were mixed with sample loading buffer (125 mM Tris base (pH 6.8), 4% (w/v) SDS, 20% (v/v) glycerol, 200 mM dithiothreitol, 0.02% (w/v) bromphenol blue).…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial Complex III-generated Oxidants Activate ASK1 and JNK to Induce Alveolar Epithelial Cell Death following Exposure to Particulate Matter Air Pollution

Soberanes

Urich

Baker

et al. 2009

Journal of Biological Chemistry

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122

116

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We have previously reported that airborne particulate matter air pollution (PM) activates the intrinsic apoptotic pathway in alveolar epithelial cells through a pathway that requires the mitochondrial generation of reactive oxygen species (ROS) and the activation of p53. We sought to examine the source of mitochondrial oxidant production and the molecular links between ROS generation and the activation of p53 in response to PM exposure. Using a mitochondrially targeted ratiometric sensor (Ro-GFP) in cells lacking mitochondrial DNA ( 0 cells) and cells stably expressing a small hairpin RNA directed against the Rieske iron-sulfur protein, we show that site III of the mitochondrial electron transport chain is primarily responsible for fine PM (PM 2.5 )-induced oxidant production. In alveolar epithelial cells, the overexpression of SOD1 prevented the PM 2.5 -induced ROS generation from the mitochondria and prevented cell death. Infection of mice with an adenovirus encoding SOD1 prevented the PM 2.5 -induced death of alveolar epithelial cells and the associated increase in alveolar-capillary permeability. Treatment with PM 2.5 resulted in the ROS-mediated activation of the oxidant-sensitive kinase ASK1 and its downstream kinase JNK. Murine embryonic fibroblasts from ASK1 knock-out mice, alveolar epithelial cells transfected with dominant negative constructs against ASK1, and pharmacologic inhibition of JNK with SP600125 (25 M) prevented the PM 2.5 -induced phosphorylation of p53 and cell death. We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53.Epidemiologic studies have consistently demonstrated a strong link between the daily levels of particulate matter air pollution Ͻ2.5 m in diameter (PM 2.5 ) 3 and PM Ͻ10 m in diameter (PM 10 ) and cardiopulmonary morbidity and mortality (1-3). In humans, exposure to PM 10 has been associated with an increase in mortality from ischemic cardiovascular events including stroke and myocardial infarction, an acceleration in the age-related decline in lung function in normal adults, impairment in normal lung development in children, exacerbations of asthma in children and adults, accelerated atherosclerosis in women, increased rates of lung cancer, and the development of myocardial ischemia in men with stable coronary artery disease (4 -10). The intracellular generation of reactive oxygen species (ROS) has emerged as a common mechanism by which particulates might initiate signaling pathways that end in these diverse pathologic conditions (11). We have reported that the PM-induced generation of ROS requires a functional electron transport chain, suggesting that PM might induce the inadvertent transfer of electrons from one or more sites in the electron transport chain to molecular oxygen (12).One of the mechanisms by which exposure to PM can contribute to alveolar epithelial dysfunction, lung injury an...

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“…Programmed cell death or apoptosis is a highly regulated process of cell removal in which tissue architecture is preserved and inflammation is minimized (Allen et al, 1997). To date, a considerable body of research has shown that alveolar apoptosis is a critical determinant in the pathways that initiate fibrogenesis in the lung (Adamson et al, 1988;Hagimoto et al, 1997aHagimoto et al, , 1997bRuiz et al, 2003;Budinger et al, 2006;Uhal et al, 1995 and. There are two pathways for regulating caspase activation: one is wellcharacterized and coupled to cell death receptors, and the other is initiated by events that are less clear and involve the release of mitochondrial cytochrome c. The release of cytochrome c from the mitochondria during apoptosis is regulated by members of the family of Bcl-2 related proteins.…”

Section: Discussionmentioning

confidence: 99%

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

et al. 2007

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-Although paraquat (PQ) is widely known to induce pulmonary fibrosis, the molecular mechanisms are poorly understood. Therefore, to bring a new dimension to the elucidation of the mechanisms, we conducted microarray experiments to investigate the expression profiles of 1,090 genes in the lungs during the progressive phase of PQ-induced pulmonary fibrosis in rats. After several s.c. injections of PQ, rats were divided into a fibrogenic group and a non-fibrogenic group. Time-course gene expression analysis of the fibrogenic group showed altered gene regulation throughout the experimental period. The expression levels of many cell membrane channel, transporter, and receptor genes were substantially altered. These genes were classified into two categories: polyamine transporter-and electrolyte/fluid balance-related genes. Moreover, comparative analysis of the fibrogenic and the non-fibrogenic group revealed 36 genes with significantly different patterns of expression, including the pro-apoptotic gene Bad. This indicates that Bad is a key factor in apoptosis and that apoptosis provides a major turning point in PQ-induced pulmonary fibrosis. Notably, subtypes of transforming growth factor (TGF)-β genes that are considered to play a pivotal role in fibrogenesis showed no differences in expression between the two groups, though TGF-β3 was markedly induced in both groups. These results provide novel and extensive insights into the molecular mechanisms that lead to pulmonary fibrosis after exposure to PQ.

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Proapoptotic Bid is required for pulmonary fibrosis

Cited by 101 publications

References 36 publications

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

Mitochondrial Complex III-generated Oxidants Activate ASK1 and JNK to Induce Alveolar Epithelial Cell Death following Exposure to Particulate Matter Air Pollution

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

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