The online version of this article (doi:10.1186/cc9301) contains supplementary material, which is available to authorized users.
Christian Mutz, Valbona Mirakaj contributed equally to this work.
The authors declare that they have no competing interests.
The hypothesis was developed by PR and VM; animal experiments were performed by CM, PW, and KW; and in vitro analysis was performed by KK and VM. The manuscript was written and edited by DAV, TI, GNS and PR.
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.
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.
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.
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.
Authors’ original file for figure 113054_2010_8793_MOESM1_ESM.jpeg
Authors’ original file for figure 213054_2010_8793_MOESM2_ESM.jpeg
Authors’ original file for figure 313054_2010_8793_MOESM3_ESM.jpeg
Authors’ original file for figure 413054_2010_8793_MOESM4_ESM.jpeg
Authors’ original file for figure 513054_2010_8793_MOESM5_ESM.jpeg
Authors’ original file for figure 613054_2010_8793_MOESM6_ESM.bmp
Authors’ original file for figure 713054_2010_8793_MOESM7_ESM.bmp
Abraham E, Carmody A, Shenkar R, Arcaroli J: Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2000, 279: L1137-L1145. PubMed
Brower RG, Morris A, MacIntyre N, Matthay MA, Hayden D, Thompson T, Clemmer T, Lanken PN, Schoenfeld D: Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. Crit Care Med 2003, 31: 2592-2597. 10.1097/01.CCM.0000057909.18362.F6 CrossRefPubMed
Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K: Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995, 107: 1062-1073. 10.1378/chest.107.4.1062 CrossRefPubMed
Vagts DA, Iber T, Puccini M, Szabo B, Haberstroh J, Villinger F, Geiger K, Noldge-Schomburg GF: The effects of thoracic epidural anesthesia on hepatic perfusion and oxygenation in healthy pigs during general anesthesia and surgical stress. Anesth Analg 2003, 97: 1824-1832. 10.1213/01.ANE.0000087062.94268.C5 CrossRefPubMed
Henes J, Schmit MA, Morote-Garcia JC, Mirakaj V, Kohler D, Glover L, Eldh T, Walter U, Karhausen J, Colgan SP, Rosenberger P: Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury. FASEB J 2009, 23: 4244-4255. 10.1096/fj.09-138693 PubMedCentralCrossRefPubMed
Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE: Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 1986, 133: 218-225. PubMed
Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998, 338: 347-354. 10.1056/NEJM199802053380602 CrossRefPubMed
Grasso S, Stripoli T, Sacchi M, Trerotoli P, Staffieri F, Franchini D, De Monte V, Valentini V, Pugliese P, Crovace A, Driessen B, Fiore T: Inhomogeneity of lung parenchyma during the open lung strategy: a computed tomography scan study. Am J Respir Crit Care Med 2009, 180: 415-423. 10.1164/rccm.200901-0156OC CrossRefPubMed
- The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury
Dierk A Vagts
- BioMed Central
Neu im Fachgebiet AINS
Meistgelesene Bücher aus dem Fachgebiet AINS
e.Med Kampagnen-Visual, Mail Icon II