+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

BRL-44408 maleate, the antagonist of α 2A -adrenoceptor, attenuates endogenous lipopolysacchride-induced acute lung injury through inhibiting the mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway in mice



BRL-44408 maleate, the antagonist of α 2A -adrenoceptor, attenuates endogenous lipopolysacchride-induced acute lung injury through inhibiting the mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway in mice



Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 30(2): 101-106



To explore the effects and mechanism of α2A-adrenergic receptor (α2A-AR) antagonist BRL-44408 maleate on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Sixty male C57BL/6 mice were randomly divided into three groups (n = 20): sham group, LPS group and BRL-44408 maleate pre-treated group (BRL+LPS group). The model of ALI was replicated by intratracheally administrated of LPS (5 mg/kg), and the mice in the sham group were received an equal volume of saline. Mice in the BRL+LPS group were treated with additionally BRL-44408 maleate (5 mg/kg, i.p) at 4 hours before LPS administration. The mice were sacrificed at 6 hours and 24 hours after LPS administration in each group. Among them, 5 mice were used to collect the bronchoalveolar lavage fluid (BALF) and the other 5 mice were sacrificed for lung tissues. The levels of norepinephrine (NE), tumor necrosis factor-α (TNF-α), interleukins (IL-6, IL-10) in BALF were measured by enzyme linked immunosorbent assay (ELISA). The level of protein in BALF was measured by bicinchoninic acid (BCA) method. The histopathological changes and wet/dry (W/D) ratio of lung tissue were observed. The expression of lung phosphorylated mitogen-activated protein kinase kinase (p-MEK) and phosphorylated extracellular regulated protein kinases (p-ERK) were detected by Western Blot. Compared with the sham group, the lung histopathological injury was significantly aggravated, and the histopathological injury score was significantly increased, the lung W/D ratio, and total protein content, NE, TNF-α, IL-6, IL-10 in BALF, and p-MEK and p-ERK expressions were significantly increased in LPS group at 6 hours after model setup [the lung histopathological injury score: 0.70±0.04 vs. 0.14±0.13, W/D ratio: 4.79±0.15 vs. 4.35±0.17, protein content (g/L): 1.51±0.36 vs. 0.46±0.13, NE (ng/L): 85.02±11.28 vs. 47.18±10.30, TNF-α (ng/L): 186.61±21.93 vs. 9.18±2.86, IL-6 (ng/L): 193.45±26.54 vs. 13.58±2.54, IL-10 (ng/L): 113.46±31.23 vs. 25.66±9.41, p-MEK/β-actin: 0.246±0.019 vs. 0.178±0.030, p-ERK/β-actin: 0.257±0.013 vs. 0.175±0.014, all P < 0.05], and increase with time after model setup. Compared with the LPS group, BRL-44408 maleate pretreatment for 6 hours could significantly improve the degree of lung injury and reduce the lung histopathological injury score (0.61±0.05 vs. 0.70±0.04), reduce lung W/D weight ratio (4.51±0.22 vs. 4.79±0.15); the expression of NE, TNF-α, IL-6 in BALF were inhibited [NE (ng/L): 55.77±15.86 vs. 85.02±11.28, TNF-α(ng/L): 54.79±12.68 vs. 186.61±21.93, IL-6 (ng/L): 67.66±20.08 vs. 193.45±26.54], in addition, the up-regulation of p-MEK, p-ERK were significantly inhibited (p-MEK/β-actin: 0.204±0.008 vs. 0.246±0.019, p-ERK/β-actin: 0.186±0.024 vs. 0.257±0.013), with statistically significant differences (all P < 0.05). The protein content and the expression of IL-10 in BALF showed no significant difference. α2A-AR blocker BRL-44408 maleate could alleviate endogenous ALI induced by LPS in mice by inhibiting the MEK/ERK pathway.

(PDF emailed within 1 workday: $29.90)

Accession: 052714936

Download citation: RISBibTeXText

PMID: 29402356


Related references

Glabridin reduces lipopolysaccharide-induced lung injury in rats by inhibiting p38 mitogen activated protein kinase/extracellular regulated protein kinases signaling pathway. Zhonghua Yi Xue Za Zhi 96(48): 3893-3897, 2018

BML-111 attenuates hemorrhagic shock-induced acute lung injury through inhibiting activation of mitogen-activated protein kinase pathway in rats. Journal of Surgical Research 183(2): 710-719, 2013

Mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway is required for bryostatin 1-induced differentiation of the human Acute Lymphoblastic Leukemia cell line Reh. Proceedings of the American Association for Cancer Research Annual Meeting 42: 335, 2001

Suppression of mitochondrial biogenesis through toll-like receptor 4-dependent mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling in endotoxin-induced acute kidney injury. Journal of Pharmacology and Experimental Therapeutics 352(2): 346-357, 2015

Adenosine A2A receptor occupancy stimulates collagen expression by hepatic stellate cells via pathways involving protein kinase A, Src, and extracellular signal-regulated kinases 1/2 signaling cascade or p38 mitogen-activated protein kinase signaling pathway. Molecular Pharmacology 72(6): 1626-1636, 2007

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Journal of Diabetes Investigation 8(4): 434-445, 2016

microRNA-542-5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen-activated protein kinase signaling pathway through the negative regulation of P21-activated kinase 1. Journal of Cellular Biochemistry 120(1): 290-304, 2018

Reversing multidrug resistance in hepatocellular carcinoma cells by inhibiting extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway activity. Oncology Letters 8(5): 2333-2339, 2014

Insulin-induced expression of the activity-regulated cytoskeleton-associated gene (ARC) in human neuroblastoma cells requires p21(ras), mitogen-activated protein kinase/extracellular regulated kinase and src tyrosine kinases but is protein kinase C-independent. Neuroscience Letters 321(3): 153-156, 2002

Induction of mitogen-activated protein kinase phosphatase 1 by the stress-activated protein kinase signaling pathway but not by extracellular signal-regulated kinase in fibroblasts. Journal of Biological Chemistry 271(2): 639-642, 1996

Effects of protein kinase C and motigen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway on mRNA level of inducible nitric oxide synthase in Tca8113 cells. Hua Xi Kou Qiang Yi Xue Za Zhi 36(2): 133-139, 2018

The anti-metastatic agent imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway. Archives of Biochemistry & Biophysics 403(2): 209-218, July 15, 2002

E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration. Journal of Pharmacology and Experimental Therapeutics 335(1): 23-31, 2010

Fluorofenidone attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice via restoring caveolin 1 expression and inhibiting mitogen-activated protein kinase signaling pathway. Shock 38(5): 567-573, 2013

Delphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blocking Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling. Cancer Prevention Research 1(7): 522-531, 2009