The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. Administration of either NG‐monomethyl‐l‐arginine (l‐NMMA) to inhibit endothelium‐derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury. In capsaicin‐pretreated rats, however, l‐NMMA (12.5–100 mg kg−1 i.v.) dose‐dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer d‐NMMA (100 mg kg−1 i.v.) did not induce any detectable mucosal damage. This mucosal injury induced by l‐NMMA was inhibited by concurrent administration of l‐arginine (300 mg kg‐1 i.v.). In indomethacin (5 mg kg−1 i.v.)‐pretreated rats, l‐NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin‐pretreated rats, l‐NMMA induced widespread, severe haemorrhagic necrotic damage. These findings suggest a role for endogenous NO formed from l‐arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.

1The effects of the specific inhibitor of nitric oxide (NO) formation, NG-monomethyl-L-arginine (L-NMMA), on resting systemic arterial blood pressure (BP) and on the actions of both endothelium-dependent and endothelium-independent vasodilators were investigated in the anaesthetized, normotensive rat. 2 Intravenous administration of L-NMMA (12.5-50 mgkg-1; 47-188 pmol kg-1) but not its enantiomer, D-NMMA, induced a dose-related increase in BP, which was reversed by the intravenous administration of L-arginine (150-600 yrmol kg-1), but not D-arginine.3 The vasodepressor responses to intravenous administration of the endothelium-dependent vasodilators, acetylcholine, bradykinin and substance P were significantly inhibited by L-NMMA (94 and 188 pmol kg-' i.v.), but not by D-NMMA. 4 The inhibition by L-NMMA of these vasodepressor responses was reversed by administration of L-arginine, but not D-arginine. 5 Endothelin (ET-1) induced dose-related vasodepressor responses following bolus intravenous administration, which were significantly inhibited by L-NMMA but not by D-NMMA. This inhibition was reversed by administration of L-arginine. 6 The vasodepressor effects of the endothelium-independent vasodilators, glyceryl trinitrate or prostacyclin, were not significantly inhibited by L-NMMA. 7 These findings with L-NMMA suggest that resting blood pressure in the rat is modulated by endogenous NO biosynthesis and that endothelium-dependent vasodilators act through the formation of endogenous NO to exert their actions in vivo.

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The protective or damaging actions on the gastric mucosa, of locally infused nitrovasodilators that donate nitric oxide (NO), have been investigated in the pentobarbitone‐anaesthetized rat. Local intra‐arterial infusion of endothelin‐1 (ET‐1; 5 pmol kg−1 min−1 for 10 min) induced extensive, macroscopically apparent, haemorrhagic injury to the rat gastric mucosa. This damage was dose‐dependently reduced by concurrent local intra‐arterial infusion of glyceryl trinitrate (GTN; 10–40 μg kg−1 min−1) which liberates NO on metabolic transformation, or the nitrosothiol, S‐nitroso‐N‐acetyl‐penicillamine (SNAP, 2.5–10 μg kg−1 min−1) which spontaneously liberates NO. Local infusion of higher doses of SNAP (20 and 40 μg kg−1 min−1, i.a.) did not, however, significantly protect against mucosal injury induced by ET‐1. Furthermore, local infusion alone of these higher doses of SNAP, as well as sodium nitroprusside (10–40 μg kg−1 min−1, i.a.) which also spontaneously liberates NO, induced significant mucosal injury, as assessed macroscopically and confirmed by histology. Local infusion of these higher doses of SNAP and nitroprusside reduced systemic arterial blood pressure (BP), but this was not correlated with the extent of mucosal injury. Furthermore, local infusion of GTN (10–40 μg kg−1 min−1, i.a.) alone, which also reduced BP, failed to induce gastric mucosal damage. These findings suggest that exogenous NO can protect the rat gastric mucosa from damage induced by the vasoconstrictor peptide ET‐1, which may reflect local microcirculatory interactions. However, the unregulated release of high levels of NO within the microvasculature induces mucosal injury.

Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunosuppressive properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Recent data have identified that GM-CSF-expressing CD4 T cells and Th17 cells have critical roles in the pathogenesis of arthritis and other inflammatory diseases. Although many studies have demonstrated that MSCs can either prevent or suppress inflammation, no studies have addressed their modulation on GM-CSF-expressing CD4 T cells and on the plasticity of Th17 cells. To address this, a single dose of human expanded adiposederived mesenchymal stem cells (eASCs) was administered to mice with established collageninduced arthritis. A beneficial effect was observed soon after the infusion of the eASCs as shown by a significant decrease in the severity of arthritis. This was accompanied by reduced number of pathogenic GM-CSF 1 CD4 1 T cells in the spleen and peripheral blood and by an increase in the number of different subsets of regulatory T cells like FOXP3 1 CD4 1 T cells and IL10 1 IL17 2 CD4 1 T cells in the draining lymph nodes (LNs). Interestingly, increased numbers of Th17 cells coexpressing IL10 were also found in draining LNs. These results demonstrate that eASCs ameliorated arthritis after the onset of the disease by reducing the total number of pathogenic GM-CSF 1 CD4 1 T and by increasing the number of different subsets of regulatory T cells in draining LNs, including Th17 cells expressing IL10. All these cellular responses, ultimately, lead to the reestablishment of the regulatory/inflammatory balance in the draining LNs. STEM CELLS 2015;33:3493-3503 SIGNIFICANCE STATEMENTWe identify, for the first time, a novel mechanism by which adipose-derived mesenchymal stem cells modulate ongoing immune responses by promoting an early adaptive T cell signature characterized by decreased levels of pathogenic GM-CSF-secreting CD41, superscript T cells, increased levels of regulatory T cells and plasticity of effector Th17 cells towards an IL10-driven anti-inflammatory response thus shifting the inflammatory/regulatory balance from GM-CSF inflammatory predominance to IL10 regulatory predominance. Altogether, these data will offer much needed further insight into the mechanisms of action of mesenchymal stem cells for their translation to the clinic.