Immunosuppression therapy is ineffective at preventing chronic rejection of lung allografts (bronchiolitis obliterans syndrome [BOS]) and proinflammatory cytokines by steroid-resistant lymphocytes. The class III NAD-sirtuin 1 (SIRT1) is an important negative regulator of inflammation; however, SIRT1 activity following lung transplant has not been studied. We hypothesized that SIRT1 expression is decreased in proinflammatory lymphocytes following lung transplant and that treatment with SIRT1 activators (resveratrol, curcumin) and agents that prevent NAD depletion (theophylline) upregulate SIRT1 and reduce proinflammatory cytokine expression in these cells.
Intracellular proinflammatory cytokines and SIRT1 were measured in blood T, natural killer T-like cell (NKT-like), and natural killer (NK) cells from patients with BOS (n = 10), stable lung transplant patients (n = 11), and healthy aged-matched controls (n = 10). Blood was cultured in the presence of ±25 µM resveratrol, ±1 µM curcumin, ±5 mg/L theophylline, ±1µM prednisolone and cytokines, and SIRT1 assessed using flow cytometry.
There was a loss of SIRT1 in T, NK-like, and NK cells in BOS patients compared with stable patients and controls (%CD8+ SIRT1+ T cells: 17 ± 10; 37 ± 10; 30 ± 10) (mean ± SEM BOS, stable, control, respectively) (P < 0.05 for all). Loss of SIRT1 was associated with increased T, NKT-like, and NK cells expressing interferon (IFN)γ and tumor necrosis factor (TNF)α. SIRT1 expression by T cells significantly associated with FEV1 (R = 0.655, P = 0.006) and with time posttransplant (R = −0.552, P = 0.041). All treatments upregulated SIRT1 and inhibited IFNγ and TNFα production by T, NK, and NKT-like cells additively.
BOS is associated with decreased SIRT1 in peripheral blood proinflammatory T, NK, and NKT-like lymphocytes following lung transplant. Treatment options that increase SIRT1 may improve graft survival.
1 Department of Thoracic Medicine, Lung Research, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia.
2 Department of Medicine, University of Adelaide, Adelaide, South Australia.
3 Department of Thoracic Medicine, Royal Adelaide Hospital, South Australian Lung Transplant Service, Adelaide, South Australia.
Received 6 March 2019. Revision received 13 May 2019.
Accepted 15 May 2019.
The authors declare no conflicts of interest.
The research study was funded by the Royal Adelaide Hospital Respiratory Clinical Trials Unit.
Correspondence: Greg Hodge, PhD, Chronic Inflammatory Lung Disease Research Laboratory, Thoracic Medicine, Royal Adelaide Hospital, Adelaide, S Australia 5000. (firstname.lastname@example.org).