5/100,000 per year and is associated with high mortality [1,2]. The hallmarks of ALI include the disruption of the alveolar-capillary barrier, the extravasation of fluid from the vascular space causing pulmonary edema and the infiltration selleck chemicals Regorafenib of leukocytes into the alveolar space [3,4]. Oxygenation is impaired, and the acute respiratory distress syndrome (ARDS) develops when the oxygenation index deteriorates to a PaO2/FiO2 quotient below 200 [2]. The importance of these inflammatory changes for the pathophysiology of ALI is supported by the finding that experimental lung injury can be substantially reduced through the depletion of neutrophils [5]. During the initial stages of ALI, neutrophils migrate into the alveolar space in response to secreted cytokines.

Furthermore, cytokines increase the activation of alveolar macrophages and aggravate the intra-alveolar inflammation that might become self-propagating within the pulmonary tissue [5,6]. Several investigators have described the importance of this process by identifying a correlation between alveolar cytokine levels and the severity of pulmonary organ injury [7-11]. As a result, pulmonary oxygen exchange is compromised [12,13]. Strategies for the treatment of ALI are aimed at improving pulmonary function through reducing the extent of pulmonary inflammation [14,15].Netrin-1 was initially described in the context of central nervous system (CNS) development, where it influences axonal migration and guides CNS development [16-18]. But netrin-1 is also expressed outside the CNS in the intestine, kidney and lung, where it controls the trafficking of leukocytes from the vascular space [19,20].

During periods of intestinal hypoxia, netrin-1 is induced through hypoxia inducible factor 1-�� and dampens local inflammation of the large intestinal surface [21]. This is in large part dependent on the coexpression of the adenosine 2B receptor (A2BAR), a receptor that is transcriptionally induced during hypoxia and inflammation [22,23]. Similarly to the intestinal organs, the pulmonary surface is composed of a large mucosal lining. This mucosal surface of the lung is characterized by a close proximity of the vascular and the alveolar space building the alveolar-capillary barrier. We were recently able to demonstrate that netrin-1 is expressed in endothelial and epithelial cells within pulmonary tissue and is significantly repressed during inflammatory and mechanical lung injury.

Furthermore, employing animals with endogenous repression of netrin-1, we demonstrated increased pulmonary damage in these animals compared to littermate controls and that a substitution with exogenous netrin-1 resulted in a significant reduction of lung injury [20]. The protective role of netrin-1 in our murine model was also dependent on the A2BAR corroborating Dacomitinib the protective potential of the A2BAR during lung injury [23].