Abstract | BACKGROUND: The epithelial sodium channel (ENaC) is the driving force for pulmonary edema absorption in acute lung injury (ALI). Netrin-1 is a newly found anti-inflammatory factor that works by activating the adenosine 2B receptor (A2BAR). Meanwhile, activated A2BAR has the potential to enhance ENaC-dependent alveolar fluid clearance (AFC). However, whether netrin-1 can increase ENaC-mediated AFC by activating A2BAR remains unclear. OBJECTIVES: To investigate the effect of netrin-1 on AFC in ALI and clarify the pathway via which netrin-1 regulates the expression of ENaC in vivo and in vitro. METHODS: An ALI model was established by intratracheal instillation of lipopolysaccharide (LPS; 5 mg/kg) in C57BL/J mice, followed by netrin-1 with or without pretreatment with PSB1115, via the caudal vein. Twenty-four hours later, the lungs were isolated for determination of the bronchoalveolar lavage fluid, the lung wet/dry weight (W/D) ratio, AFC, the expressions of α-, β-, and γ-ENaC, and cyclic adenosine monophosphate (cAMP) levels. LPS-stimulated MLE-12 cells were incubated with netrin-1 with or without preincubation with PSB1115. Twenty-four hours later, the expressions of α-, β-, and γ-ENaC were detected. RESULTS: In vivo, netrin-1 expression was significantly decreased during ALI. Substituted netrin-1 significantly dampened the lung injury, decreased the W/D ratio, and enhanced AFC, the expressions of α-, β-, and γ-ENaC, and cAMP levels in ALI, which were abolished by specific A2BAR inhibitor PSB1115. In vitro, netrin-1 increased the expressions of α-, β-, and γ-ENaC, which were prevented by PSB1115. CONCLUSION:
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Authors | Jing He, Yan Zhao, Wang Deng, Dao-xin Wang |
Journal | Respiration; international review of thoracic diseases
(Respiration)
Vol. 87
Issue 5
Pg. 394-407
( 2014)
ISSN: 1423-0356 [Electronic] Switzerland |
PMID | 24663055
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 1-propyl-8-(4-sulfophenyl)xanthine
- Adenosine A2 Receptor Antagonists
- Epithelial Sodium Channels
- Lipopolysaccharides
- Nerve Growth Factors
- Ntn1 protein, mouse
- Receptor, Adenosine A2B
- Scnn1a protein, mouse
- Scnn1b protein, mouse
- Scnn1g protein, mouse
- Tumor Suppressor Proteins
- Xanthines
- Netrin-1
- Cyclic AMP
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Topics |
- Acute Lung Injury
(chemically induced, metabolism)
- Adenosine A2 Receptor Antagonists
- Animals
- Cyclic AMP
(metabolism)
- Disease Models, Animal
- Epithelial Sodium Channels
(drug effects, metabolism)
- Lipopolysaccharides
(toxicity)
- Lung
(drug effects, metabolism)
- Mice
- Mice, Inbred C57BL
- Nerve Growth Factors
(metabolism, pharmacology)
- Netrin-1
- Pulmonary Edema
(chemically induced, metabolism)
- Receptor, Adenosine A2B
(drug effects, metabolism)
- Respiratory Tract Absorption
(drug effects)
- Tumor Suppressor Proteins
(metabolism, pharmacology)
- Xanthines
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