The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury.
BACKGROUND
Acute lung injury (ALI) is an inflammatory disorder of pulmonary or extrapulmonary origin. We have previously demonstrated that netrin-1 dampens murine ALI, and in an attempt to advance this finding into future clinical practice we evaluated whether netrin-1 would reduce alveolar inflammation during porcine ALI.


METHODS
This was a controlled in vivo experimental study in pigs. We induced ALI through lipoploysaccharide (LPS) infusion (50 μg/kg) for 2 hours. Following this, we exposed animals to either vehicle, intravenous netrin-1 (netrin-1 i.v.) or inhaled netrin-1 (netrin-1 inh.). Serum samples and bronchoalveolar lavage (BAL) were obtained to determine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, interleukin-6 and interleukin-8 at baseline and 6 hours following treatment. Myeloperoxidase activity (MPO) and protein levels were determined in the BAL, and tissue samples were obtained for histological evaluation. Finally, animals were scanned with spiral CT.


RESULTS
Following LPS infusion, animals developed acute pulmonary injury. Serum levels of TNF-α and IL-6 were significantly reduced in the netrin-1 i.v. group. BAL demonstrated significantly reduced cytokine levels 6 hours post-netrin-1 treatment (TNF-α: vehicle 633 ± 172 pg/ml, netrin-1 i.v. 84 ± 5 pg/ml, netrin-1 inh. 168 ± 74 pg/ml; both P < 0.05). MPO activity and protein content were significantly reduced in BAL samples from netrin-1-treated animals. Histological sections confirmed reduced inflammatory changes in the netrin-1-treated animals. Computed tomography corroborated reduced pulmonary damage in both netrin-1-treated groups.


CONCLUSIONS
We conclude that treatment with the endogenous anti-inflammatory protein netrin-1 reduces pulmonary inflammation during the initial stages of ALI and should be pursued as a future therapeutic option.
Department of Anesthesiology and Intensive Care Medicine, University Hospital Rostock, Rostock University, Schillingallee 35, Rostock 18057, Germany. christian.mutz@medizin.uni-rostock.de
Christian
C
Mutz
Valbona
V
Mirakaj
Dierk A
DA
Vagts
Phillipp
P
Westermann
Kristina
K
Waibler
Klemens
K
König
Thomas
T
Iber
Gabriele
G
Nöldge-Schomburg
Peter
P
Rosenberger
D055371:Acute Lung Injury / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000502:physiology*; D000075388:Netrin-1; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology*; D013552:Swine; D025521:Tumor Suppressor Proteins / Q000008:administration & dosage / Q000502:physiology*
D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1