The neuronal guidance protein netrin-1 reduces alveolar inflammation in a model of porcine acute lung injury

IntroductionAcute lung injury (ALI) is an inflammatory disorder of pulmonary or extra-pulmonary 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 (50microg/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) was obtained to determine levels of tumor necrosis factor-alpha (TNF-alpha), Interleukin (IL)-1beta, 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-alpha 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-alpha: vehicle 633+/-172pg/ml, netrin-1 i.v. 84+/-5pg/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 therapeutical option.