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Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34.

Sun Y, Ito S, Nishio N, Tanaka Y, Chen N, Liu L, Isobe K - Oxid Med Cell Longev (2015)

Bottom Line: Here we investigated the effects of GADD34 on acrolein-induced lung injury.Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice.Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan ; Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.

ABSTRACT
Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.

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Related in: MedlinePlus

Low level of pulmonary inflammation in GADD34-knockout mice induced by acrolein. Lungs were collected from wild-type and GADD34-knockout mice at days 7 and 28 after 5 μmol/kg acrolein instillation. (a) Alveolar macrophages as F4/80highCD11c+ and (b) neutrophils as Gr-1+CD11b+ were confirmed by FACS. (c) The expression of phospho-NF-κB p65. (d) The expressions of macrophage type I markers, TNFα, IL-6, and Irf5, and macrophage type II markers, Arg-1, Mrc-2, and Retnla, were analyzed by quantitative real-time PCR. (e) Wild-type and GADD34-knockout mice macrophages were cultured in 12-well plastic plates and stimulated with 10 μM acrolein for 12 and 24 h. Supernatants were taken and IL-6 expression was analyzed by ELISA. Data shown are the mean ratios ± SE of three separate experiments. Data are represented as means ± s.e.m. *P < 0.05, **P < 0.01.
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fig4: Low level of pulmonary inflammation in GADD34-knockout mice induced by acrolein. Lungs were collected from wild-type and GADD34-knockout mice at days 7 and 28 after 5 μmol/kg acrolein instillation. (a) Alveolar macrophages as F4/80highCD11c+ and (b) neutrophils as Gr-1+CD11b+ were confirmed by FACS. (c) The expression of phospho-NF-κB p65. (d) The expressions of macrophage type I markers, TNFα, IL-6, and Irf5, and macrophage type II markers, Arg-1, Mrc-2, and Retnla, were analyzed by quantitative real-time PCR. (e) Wild-type and GADD34-knockout mice macrophages were cultured in 12-well plastic plates and stimulated with 10 μM acrolein for 12 and 24 h. Supernatants were taken and IL-6 expression was analyzed by ELISA. Data shown are the mean ratios ± SE of three separate experiments. Data are represented as means ± s.e.m. *P < 0.05, **P < 0.01.

Mentions: We have demonstrated that the acrolein-induced lung injury is accompanied by inflammatory response. To investigate whether GADD34 affects the pathologies of pulmonary inflammatory responses, the mice were instilled with acrolein for 7 or 28 days to generate acute inflammation. The increase of F4/80highCD11c+ macrophages was lower in GADD34-knockout mice than those in wild-type mice (Figure 4(a)). However, the GR-1+CD11b+ neutrophils migration was not observed at 7 or 28 days after acrolein treatment both in wild-type and in GADD34-knockout mice. (Figure 4(b)). Acrolein-induced lung damage may promote lung inflammation through NF-κB signaling. A sizable NF-κB response with phosphorylation of p65 on Ser536 was observed in wild-type mice, whereas this response was lowered in GADD34-knockout mice (Figure 4(c)).


Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34.

Sun Y, Ito S, Nishio N, Tanaka Y, Chen N, Liu L, Isobe K - Oxid Med Cell Longev (2015)

Low level of pulmonary inflammation in GADD34-knockout mice induced by acrolein. Lungs were collected from wild-type and GADD34-knockout mice at days 7 and 28 after 5 μmol/kg acrolein instillation. (a) Alveolar macrophages as F4/80highCD11c+ and (b) neutrophils as Gr-1+CD11b+ were confirmed by FACS. (c) The expression of phospho-NF-κB p65. (d) The expressions of macrophage type I markers, TNFα, IL-6, and Irf5, and macrophage type II markers, Arg-1, Mrc-2, and Retnla, were analyzed by quantitative real-time PCR. (e) Wild-type and GADD34-knockout mice macrophages were cultured in 12-well plastic plates and stimulated with 10 μM acrolein for 12 and 24 h. Supernatants were taken and IL-6 expression was analyzed by ELISA. Data shown are the mean ratios ± SE of three separate experiments. Data are represented as means ± s.e.m. *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: Low level of pulmonary inflammation in GADD34-knockout mice induced by acrolein. Lungs were collected from wild-type and GADD34-knockout mice at days 7 and 28 after 5 μmol/kg acrolein instillation. (a) Alveolar macrophages as F4/80highCD11c+ and (b) neutrophils as Gr-1+CD11b+ were confirmed by FACS. (c) The expression of phospho-NF-κB p65. (d) The expressions of macrophage type I markers, TNFα, IL-6, and Irf5, and macrophage type II markers, Arg-1, Mrc-2, and Retnla, were analyzed by quantitative real-time PCR. (e) Wild-type and GADD34-knockout mice macrophages were cultured in 12-well plastic plates and stimulated with 10 μM acrolein for 12 and 24 h. Supernatants were taken and IL-6 expression was analyzed by ELISA. Data shown are the mean ratios ± SE of three separate experiments. Data are represented as means ± s.e.m. *P < 0.05, **P < 0.01.
Mentions: We have demonstrated that the acrolein-induced lung injury is accompanied by inflammatory response. To investigate whether GADD34 affects the pathologies of pulmonary inflammatory responses, the mice were instilled with acrolein for 7 or 28 days to generate acute inflammation. The increase of F4/80highCD11c+ macrophages was lower in GADD34-knockout mice than those in wild-type mice (Figure 4(a)). However, the GR-1+CD11b+ neutrophils migration was not observed at 7 or 28 days after acrolein treatment both in wild-type and in GADD34-knockout mice. (Figure 4(b)). Acrolein-induced lung damage may promote lung inflammation through NF-κB signaling. A sizable NF-κB response with phosphorylation of p65 on Ser536 was observed in wild-type mice, whereas this response was lowered in GADD34-knockout mice (Figure 4(c)).

Bottom Line: Here we investigated the effects of GADD34 on acrolein-induced lung injury.Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice.Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan ; Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.

ABSTRACT
Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.

Show MeSH
Related in: MedlinePlus