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Netrin-1 promotes epithelial sodium channel-mediated alveolar fluid clearance via activation of the adenosine 2B receptor in lipopolysaccharide-induced acute lung injury.

AbstractBACKGROUND:
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:
These results indicate that netrin-1 dampens pulmonary inflammation and increases ENaC-mediated AFC to alleviate pulmonary edema in LPS-induced ALI by enhancing cAMP levels through the activation of A2BAR.
AuthorsJing He, Yan Zhao, Wang Deng, Dao-xin Wang
JournalRespiration; international review of thoracic diseases (Respiration) Vol. 87 Issue 5 Pg. 394-407 ( 2014) ISSN: 1423-0356 [Electronic] Switzerland
PMID24663055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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