Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2

Wang, Xingqi; Nelson, Amy; Weiler, Zachary M.; Patil, Amol; Satô, Tadashi; Kanaji, Nobuhiro; Nakanishi, Masayoshi; Michalski, Joel; Farid, Maha; Basma, Hesham; LeVan, Tricia D.; Miller‐Larsson, Anna; Wieslander, Elisabet; Muller, Kai Christian; Holz, Olaf; Magnussen, H; Rabe, Klaus F.; Liu, Xiangde; Rennard, Stephen I.

doi:10.2147/jir.s43736

Cited by 8 publications

(6 citation statements)

References 29 publications

(40 reference statements)

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“…In various experimental conditions budesonide was previously shown to inhibit mediators relevant to O 3 -induced airway changes such as IL-6 (63), CCL11 (64), CXCL2 mRNA in the lung (65) and IL-13-induced ex vivo airway hyperreactivity (66), while CCL20 was actually stimulated by budesonide in asthmatic airway epithelial cells (67) and there is no data in the literature on the effects of budesonide on IL-23p19. O 3 upregulated BAL IL-6, CXCL2, and CCL20 in a budesonide-resistant manner and reversed the inhibitory effects of budesonide on CCL11, IL-13, and IL-23p19 expression in mice sensitized and challenged with Af .…”

Section: Discussionmentioning

confidence: 99%

Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice

Flayer

Hwang

et al. 2019

Front. Immunol.

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Inhaled glucocorticoids form the mainstay of asthma treatment because of their anti-inflammatory effects in the lung. Exposure to the air pollutant ozone (O3) exacerbates chronic airways disease. We and others showed that presence of the epithelial-derived surfactant protein-D (SP-D) is important in immunoprotection against inflammatory changes including those induced by O3 inhalation in the airways. SP-D synthesis requires glucocorticoids. We hypothesized here that O3 exposure impairs glucocorticoid responsiveness (including SP-D production) in allergic airway inflammation. The effects of O3 inhalation and glucocorticoid treatment were studied in a mouse model of allergic asthma induced by sensitization and challenge with Aspergillus fumigatus (Af) in vivo. The role of O3 and glucocorticoids in regulation of SP-D expression was investigated in A549 and primary human type II alveolar epithelial cells in vitro. Budesonide inhibited airway hyperreactivity, eosinophil counts in the lung and bronchoalveolar lavage (BAL) and CCL11, IL-13, and IL-23p19 release in the BAL of mice sensitized and challenged with Af (p < 0.05). The inhibitory effects of budesonide were attenuated on inflammatory changes and were completely abolished on airway hyperreactivity after O3 exposure of mice sensitized and challenged with Af. O3 stimulated release of pro-neutrophilic mediators including CCL20 and IL-6 into the airways and impaired the inhibitory effects of budesonide on CCL11, IL-13 and IL-23. O3 also prevented budesonide-induced release of the immunoprotective lung collectin SP-D into the airways of allergen-challenged mice. O3 had a bi-phasic direct effect with early (<12 h) inhibition and late (>48 h) activation of SP-D mRNA (sftpd) in vitro. Dexamethasone and budesonide induced sftpd transcription and translation in human type II alveolar epithelial cells in a glucocorticoid receptor and STAT3 (an IL-6 responsive transcription factor) dependent manner. Our study indicates that O3 exposure counteracts the effects of budesonide on airway inflammation, airway hyperreactivity, and SP-D production. We speculate that impairment of SP-D expression may contribute to the acute O3-induced airway inflammation. Asthmatics exposed to high ambient O3 levels may become less responsive to glucocorticoid treatment during acute exacerbations.

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Section: Discussionmentioning

confidence: 99%

Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice

Flayer

Hwang

et al. 2019

Front. Immunol.

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“…One potential explanation was that, somehow, pulmonary inflammation was “spilling over” into the systemic circulation[ 21 ]. Considering budesonide could attenuate the release and expression of IL-6 and IL-8 in bronchial epithelial cells[ 22 ] and block the release of cytokines and MMPs in COPD lung fibroblasts[ 23 ], it’s plausible that Bud/Form reduced systemic inflammation through attenuating airway and pulmonary inflammation in COPD. In addition, as IL-6 is a major signaling cytokine for CRP expression and other acute-phase proteins by hepatocytes[ 24 ], it’s possible that Bud/Form downregulated IL-6 production in the airways[ 22 ], which then reduced CRP expression by the liver.…”

Section: Discussionmentioning

confidence: 99%

Long-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D

et al. 2017

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BackgroundThe systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted.MethodsEligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), and white blood cell (WBC).ResultsAfter 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-α, Fib and WBC levels.ConclusionsA long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone.

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“…Nevertheless, treatments that restore HDAC2 may be clinically feasible in reducing cigarette smoke (CS)-induced inflammatory responses. 9 …”

Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Acupuncture Treatment on Airway Smooth Muscle in a Rat Model of Smoke-Induced Chronic Obstructive Pulmonary Disease

Tang

et al. 2016

Acupunct Med

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BackgroundChronic obstructive pulmonary disease (COPD) is one of the most common lung diseases. It is a chronic inflammatory process characterised by airway obstruction and progressive lung inflammation, associated with difficulty breathing and insensitivity to corticosteroid therapy. Although there is some preliminary evidence to suggest a beneficial effect of acupuncture on COPD, its mechanism of action has not been investigated. Our aim was to examine the anti-inflammatory effects of acupuncture in a rat model of COPD induced by exposure to cigarette smoke (CS).MethodsSixty Sprague–Dawley rats were exposed to the smoke of 15 cigarettes for 1 h/day, 6 days/week for 3 months to induce COPD and treated with acupuncture at BL13 (Feishu), BL23 (Shenshu) and Dingchuan (COPD+Acupuncture, n=15), sham acupuncture (COPD+Sham, n=15) or left untreated (n=15). Exposed rats were compared with controls not exposed to CS (control, n=15). Pulmonary function was measured, and tumour necrosis factor-α (TNF-α) and interleukin-8 (IL-8) levels were determined in bronchoalveolar lavage fluid by ELISA. Histone deacetylase 2 (HDAC2) protein and mRNA expression were examined in lung tissue and in bronchus.ResultsAcupuncture treatment appeared to protect pulmonary function and reduce the COPD-induced inflammatory response by decreasing cell inflammation and the production of TNF-α and IL-8. Acupuncture also enhanced HDAC2 mRNA and protein expression, suggesting a possible direct effect on protein structure through post-translational modifications.ConclusionsOur results suggest that acupuncture regulates inflammatory cytokines and contributes to lung protection in a rat model of smoke-induced COPD by modulating HDAC2.

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Anti-inflammatory effects of budesonide in human lung fibroblasts are independent of histone deacetylase 2

Cited by 8 publications

References 29 publications

Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice

Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice

Long-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D

Long-Term Effects of Acupuncture Treatment on Airway Smooth Muscle in a Rat Model of Smoke-Induced Chronic Obstructive Pulmonary Disease

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