Arginase 1: An Unexpected Mediator of Pulmonary Capillary Barrier Dysfunction in Models of Acute Lung Injury

Abstract

The integrity of epithelial and endothelial barriers in the lower airspaces of the lungs has to be tightly regulated, in order to prevent leakage and to assure efficient gas exchange between the alveoli and capillaries. Both G− and G+ bacterial toxins, such as lipopolysaccharide and pneumolysin, respectively, can be released in high concentrations within the pulmonary compartments upon antibiotic treatment of patients suffering from acute respiratory distress syndrome (ARDS) or severe pneumonia. These toxins are able to impair endothelial barrier function, either directly, or indirectly, by induction of pro-inflammatory mediators and neutrophil sequestration. Toxin-induced endothelial hyperpermeability can involve myosin light chain phosphorylation and/or microtubule rearrangement. Endothelial nitric oxide synthase (eNOS) was proposed to be a guardian of basal barrier function, since eNOS knock-out mice display an impaired expression of inter-endothelial junction proteins and as such an increased vascular permeability, as compared to wild type mice. The enzyme arginase, the activity of which can be regulated by the redox status of the cell, exists in two isoforms – arginase 1 (cytosolic) and arginase 2 (mitochondrial) – both of which can be expressed in lung microvascular endothelial cells. Upon activation, arginase competes with eNOS for the substrate l-arginine, as such impairing eNOS-dependent NO generation and promoting reactive oxygen species generation by the enzyme. This mini-review will discuss recent findings regarding the interaction between bacterial toxins and arginase during acute lung injury and will as such address the role of arginase in bacterial toxin-induced pulmonary endothelial barrier dysfunction.

Impaired up-Expression of pro-Oxidation Genes by Oligoribonucleotides at Influenza А Virus Infection in vivo

“…Next, we estimated an ability of the ORNs to affect the level of LPO products in mice lungs at the influenza virus infection and detected that the ORNs injection for prevention and treatment can decrease the level of LPO products by 20 and 15 % respectively in influenza infected mice, indicating that these ORNs probable decrease of the protein level of nos2 and xdh at the influenza virus infection. Activation of arginase in the airway epithelial cells leads to a reduction in iNOS mRNA and protein expression, as such reducing NO generation [21]. In our study, we found that influenza virus upregulated the mRNA expression arg2 (p < 0.05) and that the ORNs decrease overexpression of this gene at the influenza virus infection.…”

OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase

“…29 To determine the contribution of individual Arg isoforms to total arginase activity in HAEC, we individually silenced Arg1 and Arg2 using adenovirally mediated shRNA transduction. Arg2 silencing inhibited total arginase activity to <25% of control levels, whereas Arg1 knockdown had little effect on total HAEC arginase activity (Online Figure IA).…”

The effects of the M2a macrophage-induced axonal regeneration of neurons by arginase 1

“…Arg1 promotes cytoskeletal formation. Polyamines in the nervous system increase tubulin expression, promote cell scaffolding formation in neurons, and induce axonal extension [22][23][24]. Arg1 can block the inhibition of axonal regeneration by myelin-related inhibitors.…”