Allogeneic human mesenchymal stem cells(University of Miami)

Increasing magnesium intake might reduce the risk of cardiovascular disease (CVD). Whether potential effects on cortisol contribute to these beneficial effects on cardiovascular health remains unclear. We therefore studied effects of long‐term oral magnesium supplementation on glucocorticoid metabolism, specifically on the excretion of urinary cortisol, cortisone and their metabolites, as well as on the ratios reflecting enzymatic activity of 11β‐hydroxysteroid dehydrogenases (11β‐HSDs) and A‐ring reductases.

A post‐hoc analysis of a randomized trial with allocation to a magnesium supplement (350 mg/day) or a placebo for 24‐week.

Forty‐nine overweight men and women, aged between 45 and 70 years.

Cortisol, cortisone and their metabolites (tetrahydrocortisol [THF], allo‐tetrahydrocortisol [allo‐THF] and tetrahydrocortisone [THE]) were measured in 24‐h urine samples. Enzymatic activities of 11β‐HSD overall and of 11β‐HSD type 2 were estimated as the urinary (THF + allo‐THF [THFs])/THE and cortisol/cortisone ratios, respectively. A‐ring reductase activity was assessed by ratios of THF/allo‐THF, allo‐THF/cortisol, THF/cortisol and THE/cortisone.

After 24‐week, urinary cortisol excretion was decreased in the magnesium group as compared with the placebo group (−32 nmol/24‐h, 95% CI: −59; −5 nmol/24‐h, p = .021). Ratios of THFs/THE and cortisol/cortisone were decreased following magnesium supplementation by 0.09 (95% CI: 0.02; 0.17, p = .018) and 0.10 (95% CI: 0.03; 0.17, p = .005), respectively. No effects were observed on A‐ring reductase activity.

We observed a beneficial effect of magnesium supplementation towards a lower 24‐h urinary cortisol excretion together with an increased activity of 11β‐HSD type 2. Our findings may provide another potential mechanism by which increased magnesium intake lowers CVD risk (ClinicalTrials.gov identifier: NCT02235805).

Localization of inflammatory stimuli may direct lung allografts to different phenotypes of chronic dysfunction, such as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). We hypothesized that airway stimulation with lipopolysaccharide (LPS) in rats leads to airway-centered inflammation similar to human BOS.

Rat left lung transplantation was conducted (donor: Brown Norway, recipient: Lewis). Allotransplant recipients received cyclosporine A (CsA) until postoperative day 56 with airway instillation of LPS (Allo-LPS, n = 8), phosphate buffered saline (Allo-PBS, n = 5) from days 35 to 46 (3 times a wk), or no further treatment (n = 4). Some allotransplant recipients received CsA until day 14 and were immunosuppression free after day 15 until day 56. Bronchial and pleural fibrosis were semiquantified; alveolar fibrosis was evaluated with a histological scale.

The Allo-LPS group had significantly increased International Society for Heart and Lung Transplantation rejection grades (grade A, P = 0.005; grade B, P = 0.004), bronchial obstructive proportion (0.34 ± 0.04% [Allo-LPS] versus 0.11 ± 0.04% [Allo-PBS], P = 0.006), and airway resistance (3.05 ± 1.78 cm H2O·s/mL [Allo-LPS] versus 0.83 ± 0.58 cm H2O·s/mL [Allo-PBS], P = 0.007) compared with other groups. Allotransplant recipients that underwent a short course of CsA developed RAS-like fibrosis involving the airways, alveoli, and pleura.

Airway instillation of LPS in allografts under immunosuppression resulted in BOS-like airway-centered inflammation and fibrosis distinct from RAS-like diffuse fibrosis, which was induced by a shortened course of immunosuppression. We propose novel animal models for BOS and RAS after lung transplantation.