Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice - PubMed (original) (raw)

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice

Yun-Feng Ni et al. Respir Res. 2010.

Abstract

Background: Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.

Objective: To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.

Methods: ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-kappaB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.

Results: Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-alpha, IL-1beta and NO. Furthermore, the expression of NF-kappaB p65 in nucleus was markedly suppressed by butyrate pretreatment.

Conclusions: Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-kappaB activation.

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Figures

Figure 1

Figure 1

Effect of butyrate on MPO activity and NO concentrations in lung tissues of mice with ALI. A. The MPO activity in lung tissues at each time point after LPS administration and the effect of butyrate pretreatment. B. The concentrations of NO in lung tissues at each time point after LPS administration and the effect of butyrate pretreatment. Data are expressed as mean ± SEM, *P < 0.05 vs. control and butyrate group; #P < 0.05 vs. LPS group.

Figure 2

Figure 2

Effect of butyrate on the concentrations of TNF-α and IL-1β in BALF of mice with ALI. A. The concentrations of TNF-α in BALF at each time point after LPS administration and the effect of butyrate pretreatment. B. The concentrations of IL-1β in BALF at each time point after LPS administration and the effect of butyrate pretreatment. Data are expressed as mean ± SEM, *P < 0.05 vs. control and butyrate group; #P < 0.05 vs. LPS group.

Figure 3

Figure 3

Effect of butyrate on the lung edema of mice with ALI. At each time point after LPS administration, pretreatment of butyrate decreased lung wet/dry ratios markedly. Data are expressed as mean ± SEM, *P < 0.05 vs. control and butyrate group; #P < 0.05 vs. LPS group.

Figure 4

Figure 4

Effect of butyrate on the pulmonary histopathological changes of mice with ALI. Lung sections stained with hematoxylin-eosin from 24 hours after LPS administration revealed pulmonary histopathological changes (original magnification ×200). A. control group: normal structure. B. butyrate group: same as control group. C. LPS group: alveolar wall thickness, hemorrhage, alveolus collapse and obvious inflammatory cells infiltration. D. LPS + butyrate group: minor histopathological changes compared with LPS group.

Figure 5

Figure 5

Effect of butyrate on the nuclear expression of NF-κB in lung tissues of mice with ALI. A., B. and C. Representative Western blots showed the nuclear expression of NF-κB p65 in lung tissues in different groups. D. Mean ± SEM NF-κB p65 optical densitometry from different groups. Pretreatment of butyrate significantly repressed the expression of NF-κB p65 in nucleus at 1, 3 and 6 hours after LPS administration. Data are expressed as mean ± SEM, *P < 0.05 vs. control and butyrate group; #P < 0.05 vs. LPS group.

Figure 6

Figure 6

Effect of butyrate on the cytoplasmic expression of NF-κB in lung tissues of mice with ALI. A., B. and C. Representative Western blots showed the cytoplasmic expression of NF-κB p65 in lung tissues in different groups. D. Mean ± SEM NF-κB p65 optical densitometry from different groups. The expression of NF-κB p65 in cytoplasm was significantly reduced by LPS administration and these changes were inhibited by butyrate pretreatment. Data are expressed as mean ± SEM, *P < 0.05 vs. control and butyrate group; #P < 0.05 vs. LPS group.

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