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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.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.

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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GADD34 mediates acrolein-caused lung injury. The wild-type and GADD34-knockout mice were intranasally instilled by 1 and 5 μmol/kg acrolein. The mice were treated daily for 5 d/week for up to 28 days and then were sacrificed at 7 and 28 days. (a) The whole lungs of wild-type and GADD34-knockout mice were photographed at days 7 and 28. (b) H&E staining of lung tissue. Scale bar: 50 μm. Analysis of alveolar length determined by mean linear intercepts (n = 5 to 7 mice in each group) and the number of alveolar macrophages in wild-type and GADD34-knockout mice (n = 4 mice in each group). (c) Lungs stained for epithelial type II cells (ProSpC green), nuclei (DAPI blue), and the number of epithelial type II-positive cells in wild-type and GADD34-knockout mice (10 fields, n = 4). Scale bar: 50 μm. *P < 0.05, **P < 0.01. Data are represented as means ± s.e.m. (d) Levels of ROS production in the lung of wild-type and GADD34-knockout mice were measured by DCFH-DA after acrolein treated.
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fig3: GADD34 mediates acrolein-caused lung injury. The wild-type and GADD34-knockout mice were intranasally instilled by 1 and 5 μmol/kg acrolein. The mice were treated daily for 5 d/week for up to 28 days and then were sacrificed at 7 and 28 days. (a) The whole lungs of wild-type and GADD34-knockout mice were photographed at days 7 and 28. (b) H&E staining of lung tissue. Scale bar: 50 μm. Analysis of alveolar length determined by mean linear intercepts (n = 5 to 7 mice in each group) and the number of alveolar macrophages in wild-type and GADD34-knockout mice (n = 4 mice in each group). (c) Lungs stained for epithelial type II cells (ProSpC green), nuclei (DAPI blue), and the number of epithelial type II-positive cells in wild-type and GADD34-knockout mice (10 fields, n = 4). Scale bar: 50 μm. *P < 0.05, **P < 0.01. Data are represented as means ± s.e.m. (d) Levels of ROS production in the lung of wild-type and GADD34-knockout mice were measured by DCFH-DA after acrolein treated.

Mentions: Our previous studies have demonstrated that intranasal instillation of acrolein (5 μmol/kg) induced lung damage and hemorrhage [8]. We examined whether GADD34-knockout mice showed same phenotypes by intranasal instillation of acrolein. Although acrolein administration caused serious alveolar structure destruction, such as airspace enlargement, and hemorrhaging in the lung of wild-type mice, GADD34 deficiency decreased the lung injury with preserved alveolar structure, no significant hemorrhaging, and sparse accumulation of intra-alveolar macrophages at 7 and 28 days (Figures 3(a) and 3(b)). The numbers of type II epithelial cells were significantly reduced in wild-type mice compared to GADD34-knockout mice (Figure 3(c)). In addition, higher level of ROS production was detected in wild-type mice than GADD34-knockout mice (Figure 3(d)). These results collectively indicated that GADD34 might play a crucial role in the pathogenesis of experimental acrolein-induced pulmonary injury.


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)

GADD34 mediates acrolein-caused lung injury. The wild-type and GADD34-knockout mice were intranasally instilled by 1 and 5 μmol/kg acrolein. The mice were treated daily for 5 d/week for up to 28 days and then were sacrificed at 7 and 28 days. (a) The whole lungs of wild-type and GADD34-knockout mice were photographed at days 7 and 28. (b) H&E staining of lung tissue. Scale bar: 50 μm. Analysis of alveolar length determined by mean linear intercepts (n = 5 to 7 mice in each group) and the number of alveolar macrophages in wild-type and GADD34-knockout mice (n = 4 mice in each group). (c) Lungs stained for epithelial type II cells (ProSpC green), nuclei (DAPI blue), and the number of epithelial type II-positive cells in wild-type and GADD34-knockout mice (10 fields, n = 4). Scale bar: 50 μm. *P < 0.05, **P < 0.01. Data are represented as means ± s.e.m. (d) Levels of ROS production in the lung of wild-type and GADD34-knockout mice were measured by DCFH-DA after acrolein treated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: GADD34 mediates acrolein-caused lung injury. The wild-type and GADD34-knockout mice were intranasally instilled by 1 and 5 μmol/kg acrolein. The mice were treated daily for 5 d/week for up to 28 days and then were sacrificed at 7 and 28 days. (a) The whole lungs of wild-type and GADD34-knockout mice were photographed at days 7 and 28. (b) H&E staining of lung tissue. Scale bar: 50 μm. Analysis of alveolar length determined by mean linear intercepts (n = 5 to 7 mice in each group) and the number of alveolar macrophages in wild-type and GADD34-knockout mice (n = 4 mice in each group). (c) Lungs stained for epithelial type II cells (ProSpC green), nuclei (DAPI blue), and the number of epithelial type II-positive cells in wild-type and GADD34-knockout mice (10 fields, n = 4). Scale bar: 50 μm. *P < 0.05, **P < 0.01. Data are represented as means ± s.e.m. (d) Levels of ROS production in the lung of wild-type and GADD34-knockout mice were measured by DCFH-DA after acrolein treated.
Mentions: Our previous studies have demonstrated that intranasal instillation of acrolein (5 μmol/kg) induced lung damage and hemorrhage [8]. We examined whether GADD34-knockout mice showed same phenotypes by intranasal instillation of acrolein. Although acrolein administration caused serious alveolar structure destruction, such as airspace enlargement, and hemorrhaging in the lung of wild-type mice, GADD34 deficiency decreased the lung injury with preserved alveolar structure, no significant hemorrhaging, and sparse accumulation of intra-alveolar macrophages at 7 and 28 days (Figures 3(a) and 3(b)). The numbers of type II epithelial cells were significantly reduced in wild-type mice compared to GADD34-knockout mice (Figure 3(c)). In addition, higher level of ROS production was detected in wild-type mice than GADD34-knockout mice (Figure 3(d)). These results collectively indicated that GADD34 might play a crucial role in the pathogenesis of experimental acrolein-induced pulmonary injury.

Bottom Line: Here we investigated the effects of GADD34 on acrolein-induced lung injury.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.

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