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

Mutz, Christian; Mirakaj, Valbona; Vagts, Dierk A.; Westermann, Phillipp; Waibler, Kristina; König, Klemens; Iber, Thomas; Nöldge-Schomburg, Gabriele; Rosenberger, Peter

doi:10.1186/cc9301

Cited by 29 publications

(20 citation statements)

References 40 publications

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“…Originally, netrin-1 was demonstrated to attenuate LPS-induced sepsis through inhibition of leucocyte migration 6. Studies in kidney ischaemia–reperfusion injury,7 10 hypoxia-induced inflammation,2 acute lung injury8 43 and peritonitis9 support this observation by demonstrating a tissue-protective role for netrin-1 through suppression of inflammation. Presently, a number of downstream receptor signalling pathways have been implicated in netrin-1-mediated tissue protection observed in these studies.…”

Section: Discussionmentioning

confidence: 98%

Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

Aherne

Collins

Masterson

et al. 2011

Gut

113

154

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BackgroundInflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease.DesignDSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1+/− mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function.ResultsConsistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin-1-mediated protection during DSS-colitis.ConclusionsThe present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking.

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Section: Discussionmentioning

confidence: 98%

Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

Aherne

Collins

Masterson

et al. 2011

Gut

113

154

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“…Since adenosine is an important regulator of airway surface liquid volume (25) and serves a protective role during hypoxia and inflammation (24), this nucleoside could play an essential role in the progression of the disease. Concerning another HIF-1 target gene potentially involved in CF pathology, the antiinflammatory protein netrin-1 seems to be a good candidate as netrin-1 has been shown to reduce pulmonary inflammation during the initial stages of acute lung injury (26) and HIF-1α-dependent induction of netrin-1 attenuates hypoxia-elicited inflammation at mucosal surfaces (27).…”

Section: Discussionmentioning

confidence: 99%

Impaired expression of hypoxia-inducible factor-1α in cystic fibrosis airway epithelial cells – A role for HIF-1 in the pathophysiology of CF?

Legendre

Mooij

Adams

et al. 2011

Journal of Cystic Fibrosis

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The continuous infection-inflammation cycle plays a crucial role in the progression of cystic fibrosis (CF) disease. This noxious loop can be aggravated by a reduced partial pressure of oxygen in the blood, hypoxemia, present in CF patients. These interconnected factors, hypoxia, inflammation and infection, by stabilizing the hypoxia-inducible factor-1α (HIF-1α) protein subunit, are able to activate the transcription factor HIF-1. To date, data investigating the potential role of HIF-1 in CF are scarce. Our results demonstrated that HIF-1α protein expression was altered in CF-affected compared to CFTR-corrected airway epithelial cells in unsimulated and simulated hypoxic conditions. In contrast, when CF-affected cells were infected with Pseudomonas aeruginosa, HIF-1α was more stabilized compared to CFTR-corrected cells. As HIF-1 is linked with an efficient immune response and pulmonary complications in cystic fibrosis, this difference in HIF-1α protein levels could have an impact in the CF pathology and the persistence of P. aeruginosa infection.

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“…Again other studies demonstrated that during intestinal inflammation – such as occurs in the setting of inflammatory bowel disease – netrin-1 signaling dampens intestinal inflammation via signaling events involving extracellular adenosine receptors [3,10]. Consistent with these findings, again other studies revealed that netrin-1 signaling through the Adora2b adenosine receptor is protective during inflammatory peritonitis [11] or acute lung injury [12,13]. …”

Section: Introductionmentioning

confidence: 54%

Protective role for netrin-1 during diabetic nephropathy

et al. 2013

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Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney-protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1+/− mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue-protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease.

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

Cited by 29 publications

References 40 publications

Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis

Impaired expression of hypoxia-inducible factor-1α in cystic fibrosis airway epithelial cells – A role for HIF-1 in the pathophysiology of CF?

Protective role for netrin-1 during diabetic nephropathy

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