Netrin-1 dampens pulmonary inflammation during acute lung injury.
BACKGROUND
Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.


OBJECTIVE
To test the role of pulmonary netrin-1 during ALI.


METHODS
Pulmonary netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1(+/-), and A2BAR(-/-) animals. Exogenous netrin-1 was used to evaluate its impact on pulmonary inflammation.


RESULTS
Wild-type animals demonstrated repression of pulmonary netrin-1 after LPS inhalation. In vitro studies confirmed the repression of netrin-1. Studies in the putative netrin-1 promoter identified a nuclear factor-kappaB-dependent mechanism to be involved in this repression. Ntn1(+/-) animals demonstrated increased inflammatory changes after LPS inhalation compared with Ntn1(+/+) animals. Reconstitution with netrin-1 dampened the infiltration of neutrophils and cytokine production in the alveolar space. This effect was dependent on the adenosine 2b receptor. The importance of netrin-1 for the control of pulmonary inflammation could be corroborated in a model of ventilator-induced lung injury.


CONCLUSIONS
Pulmonary netrin-1 levels are repressed during ALI. This results in pronounced pulmonary damage, an increased infiltration of neutrophils, and increased pulmonary inflammation. Exogenous netrin-1 significantly dampens the extent of ALI through the adenosine 2B receptor.
Mirakaj
Valbona
V
Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University, Tübingen, Germany.
Thix
Cyril A
CA
Laucher
Stefanie
S
Mielke
Carina
C
Morote-Garcia
Julio C
JC
Schmit
Marthe A
MA
Henes
Janek
J
Unertl
Klaus E
KE
Köhler
David
D
Rosenberger
Peter
P
D055371:Acute Lung Injury / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000276:immunology* / Q000378:metabolism; D000075388:Netrin-1; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000276:immunology* / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000276:immunology / Q000378:metabolism
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1