Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation

Kim, So Ri; Kim, Dong Im; Kang, Moon Gi; Lee, Kyung Sun; Park, Seung Yong; Jeong, Jae Seok; Lee, Yong Chul

doi:10.1016/j.jaci.2013.08.041

Cited by 124 publications

(153 citation statements)

References 66 publications

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“…All three major UPR pathways in ER stress are engaged with glucose (Oyadomari et al, 2008) Rutkowski et al, 2008) metabolism. Our results showed that most genes involved in ER stress significantly increased with LPS treatment, and the CHOP protein also significantly increased, which is consistent with most ER stress reports (Kaplowitz et al, 2007;Kozlov et al, 2009;Kim et al, 2013). The GRP78/bip protein significantly decreased, rather than increased, which may suggest that ER stress cannot be resolved because this requires an increase in functional UPR responsive proteins, especially GRP78/bip (Kozlov et al, 2009).…”

Section: Discussionsupporting

confidence: 87%

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Sun

Huang

Yin

et al. 2016

Animal

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Most previous studies on the effects of lipopolysaccharide (LPS) in pigs focused on the body's immune response, and few reports paid attention to body metabolism changes. To better understand the glucose metabolism changes in skeletal muscle following LPS challenge and to clarify the possible mechanism, 12 growing pigs were employed. Animals were treated with either 2 ml of saline or 15 µg/kg BW LPS, and samples were collected 6 h later. The glycolysis status and mitochondrial function in the longissimus dorsi (LD) muscle of pigs were analyzed. The results showed that serum lactate content and NADH content in LD muscle significantly increased compared with the control group. Most glycolysis-related genes expression, as well as hexokinase, pyruvate kinase and lactic dehydrogenase activity, in LD muscle was significantly higher compared with the control group. Mitochondrial complexes I and IV significantly increased, while mitochondrial ATP concentration markedly decreased. Significantly increased calcium content in the mitochondria was observed, and endoplasm reticulum (ER) stress has been demonstrated in the present study. The results showed that LPS treatment markedly changes glucose metabolism and mitochondrial function in the LD muscle of pigs, and increased calcium content induced by ER stress was possibly involved. The results provide new clues for clarifying metabolic diseases in muscle induced by LPS.Keywords: lipopolysaccharide, mitochondria, glycolysis, pig, inflammation ImplicationsSkeletal muscle is the primary tissue responsible for wholebody energy metabolism. In the current study, we designed the experiment to investigate the effect of lipopolysaccharide (LPS) treatment on muscle energy metabolism in pigs. The results indicated that LPS treatment significantly changed glycolysis level and mitochondrial function in the longissimus dorsi (LD) muscle of pigs, and increased calcium content induced by endoplasm reticulum stress was possibly involved. Understanding these underlying mechanisms may provide new therapeutic strategies for treating metabolic diseases induced by LPS in muscle.

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Section: Discussionsupporting

confidence: 87%

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Sun

Huang

Yin

et al. 2016

Animal

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“…PBA has been shown to ameliorate several diseases, including cystic fibrosis, diabetes, and colitis, by reducing ER stress (8)(9)(10)(11). In particular, two recent reports showed that PBA administration alleviates ER stress and reduces lipopolysaccharide (LPS)-induced lung inflammation (47) and colitis in mice (12). Based on these studies, we investigated whether one of the mechanisms by which PBA reduces intestinal inflammation in Salmonella-induced colitis was the reduction of ER stress during infection.…”

Section: Resultsmentioning

confidence: 99%

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

et al. 2016

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c Sodium phenylbutyrate (PBA) is a derivative of the short-chain fatty acid butyrate and is approved for treatment of urea cycle disorders and progressive familial intrahepatic cholestasis type 2. Previously known functions include histone deacetylase inhibitor, endoplasmic reticulum stress inhibitor, ammonia sink, and chemical chaperone. Here, we show that PBA has a previously undiscovered protective role in host mucosal defense during infection. Administration of PBA to Taconic mice resulted in the increase of intestinal Lactobacillales and segmented filamentous bacteria (SFB), as well as an increase of interleukin 17 (IL-17) production by intestinal cells. This effect was not observed in Jackson Laboratory mice, which are not colonized with SFB. Because previous studies showed that IL-17 plays a protective role during infection with mucosal pathogens, we hypothesized that Taconic mice treated with PBA would be more resistant to infection with Salmonella enterica serovar Typhimurium (S. Typhimurium). By using the streptomycin-treated mouse model, we found that Taconic mice treated with PBA exhibited significantly lower S. Typhimurium intestinal colonization and dissemination to the reticuloendothelial system, as well as lower levels of inflammation. The lower levels of S. Typhimurium gut colonization and intestinal inflammation were not observed in Jackson Laboratory mice. Although PBA had no direct effect on bacterial replication, its administration reduced S. Typhimurium epithelial cell invasion and lowered the induction of the proinflammatory cytokine IL-23 in macrophage-like cells. These effects likely contributed to the better outcome of infection in PBA-treated mice. Overall, our results suggest that PBA induces changes in the microbiota and in the mucosal immune response that can be beneficial to the host during infection with S. Typhimurium and possibly other enteric pathogens. S odium 4-phenylbutyrate (phenylbutyric acid [PBA]) is related to the short-chain fatty acid (SCFA) butyrate, differing by the presence of a phenyl group at the 4 position. PBA is an orphan drug, originally approved for urea cycle disorders (1) and subsequently approved for progressive familial intrahepatic cholestasis type 2 (2). The compound has been used in preclinical and clinical studies as a treatment for a variety of diseases, including other urea cycle disorders (3), spinal muscular atrophy (4), homozygous ␤-thalassemia (5), and cancer (6). Additionally, PBA was shown to be effective in the treatment of neurodegenerative diseases, including Parkinson's disease (7).Recent studies have revealed that PBA also plays a role in the reduction of endoplasmic reticulum (ER) stress caused by the unfolded protein response (UPR), thereby suppressing oxidative stress in several animal models (8-11), including in a mouse colitis model (12). In vitro studies further demonstrated that PBA can suppress the activity of nuclear factor B (NF-B), suggesting anti-inflammatory properties for the compound (13). Moreover, administration of PBA w...

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“…4‐phenylbutyrate (4‐PBA) and tauroursodeoxycholic acid (TUDCA) are chemical chaperones which promote correct folding in the ER that have been used widely in animal models of ER stress. 4‐PBA reduced ER stress, inflammation and fibrosis in the bleomycin model in mice,84 attenuated symptoms of asthma in the house dust mite allergen model in mice90 and also reduced ER stress and autophagy in LPS‐induced acute lung injury 104. Similarly, TUDCA has also been demonstrated to alleviate ER stress and associated pathology in the bleomycin fibrosis model and in asthma models in mice 83, 92.…”

Section: Therapeutic Approaches To Resolve Oxidative and Er Stress Inmentioning

confidence: 97%

“…Genetic predisposition has also linked asthma and ER stress via the ORMLD3 gene which encodes a protein that modulates function of the sarcoendoplasmic reticulum Ca 2+ ATPase pump (SERCA) that regulates ER vs cytosolic Ca 2+ concentrations, and thereby modulates protein folding and Ca 2+ ‐signalling 12, 88, 89. Studies of ER stress in the human disease are rather limited but there is evidence of ER stress in both cells sampled by bronchiolar lavage and in peripheral blood leucocytes 90. A range of animal models of allergy and asthma have also implicated ER stress in the pathophysiology of these conditions 90, 91, 92, 93, 94, 95, 96.…”

Section: Oxidative and Er Stress In Chronic Inflammatory And Mucopurumentioning

confidence: 99%

“…Studies of ER stress in the human disease are rather limited but there is evidence of ER stress in both cells sampled by bronchiolar lavage and in peripheral blood leucocytes 90. A range of animal models of allergy and asthma have also implicated ER stress in the pathophysiology of these conditions 90, 91, 92, 93, 94, 95, 96. Airway goblet cell hyperplasia and mucus hypersecretion are characteristics of most forms of asthma and the increased biosynthetic load in these cells may be principal drivers of ER stress, as may the ROS/RNS released by phagocytes, particularly in neutrophilic disease.…”

Section: Oxidative and Er Stress In Chronic Inflammatory And Mucopurumentioning

confidence: 99%

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Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

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Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation

Cited by 124 publications

References 66 publications

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

Oxidative and endoplasmic reticulum stress in respiratory disease

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