Hydrogen Treatment Protects Mice Against Chronic Pancreatitis by Restoring Regulatory T Cells Loss

Abstract

Background/Aims: Chronic pancreatitis is an inflammatory disease of the pancreas characterized by progressive tissue destruction and fibrogenesis. The development of chronic pancreatitis is associated with immune cell dysregulation. Currently, the specific and effective treatment of chronic pancreatitis remains absent. Methods: By using an L-arginine induced chronic pancreatitis mouse model, we tested the therapeutic potential of hydrogen, a strong hydroxyl radicals scavenger, in the chronic pancreatitis model. Tissue inflammation, damage and fibrosis were analyzed on HE, TUNEL, MPO, and sirius staining. Pancreas levels of MDA content, SOD activity, TNF-α , IL-10 cytokine expression and serum amylase and lipase activity were determined by ELISA and absorbance assay. Apoptosis, T cells subtype proportion and intracellular level of reactive oxygen species (ROS) were analyzed by flow cytometry. Tregs adoptive transfer and CD25 neutralization were used to validate the role of Tregs in chronic pancreatitis. Results: We found that hydrogen treatment significantly improved multiple symptoms of chronic pancreatitis. The number of Tregs was reduced in chronic pancreatitis mice, while hydrogen treatment restored the Treg loss by L-arginine administrations. Depletion of Tregs abolished the protective effect of hydrogen treatment in chronic pancreatitis. In vitro study showed that hydrogen blocked ROS generation in Tregs and promoted Tregs survival. Conclusion: Hydrogen treatment showed reliable benefits in controlling the severity of chronic pancreatitis. Our study supported that hydrogen could be used as a novel treatment in chronic pancreatitis patient in the future.

Hydrogen: A Novel Option in Human Disease Treatment

“…H 2 can also regulate inflammation by regulating the physiological pathway of T cells. For example, hydrogen treatment can inhibit the overactivation of the immune system by restoring the loss of regulatory T cells (Tregs) [ 15 ] and alleviates inflammation by preventing activation-regulated chemokine-mediated T-cell chemotaxis. The regulation effects of H 2 on programmed cell death, oxidative stress, and mitochondrial function are closely related to the inflammatory response.…”

“…Recent studies have found that H 2 can relieve the dysregulated Th1/Th2 balance and can influence the number of T-regulatory cells (Tregs). H 2 was first reported to restore Treg loss in a rat model of chronic pancreatitis [ 15 ] and was later proven to increase CD4+CD25+Foxp3+Treg cells and significantly reduce nasal mucosa damage in animals with allergic rhinitis, which may be secondary to the restoration of Th1/Th2 balance [ 37 ]. Upregulation of Tregs has been reported in cerebral I/R models [ 28 ].…”

Alcohol and Smoking Mediated Modulations in Adaptive Immunity in Pancreatitis

“…In the L-arginine based CP model, Chen et al tested the therapeutic potential of hydrogen treatment as a potent scavenger of hydroxyl radicals. There was an overall improvement in CP pathology upon hydrogen treatment, as L-arginine-induced pancreatitis leads to ROS-mediated T-lymphocyte apoptosis, especially T-regs, and restoration of depleted T-regs by hydrogen treatment decreased disease severity and promoted their survival [39]. Apart from the pancreatitis-associated antigens and IL-10-producing FoxP3 + T-regs, CP patients have an increased number of antigen-specific CCR7 + CD45RA − central memory T-cells as compared to the healthy and CP-resected controls [40].…”

“…Using natural products, such as apigenin, rhein and tocotrienol-rich fraction (TRF) from palm oil, for targeting PSCs shows promise in reversing fibrosis in CP [100][101][102]. Some reports demonstrate that recovering T-reg loss and restoring IL-10 levels during CP suppress CD8 + T-cell over-activation and hence reduces the severity of CP [39,86]. Apart from targeting, the major area of focus in pancreatitis research at present is finding a robust, reliable and promising diagnostic marker for determining the severity of AP and MOF driven by AP.…”

Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside

“…However, the effective target and the precise molecular mechanisms of H 2 are not clear. Recent studies have indicated that H 2 can regulate both innate and adaptive immune responses, such as inhibiting lipopolysaccharide/interferon γ-induced NO via blocking ASK-1 and its downstream signaling molecules, p38 and JNK, as well as IκBα in macrophages [70], restoring the L-arginine-induced CD25 + Foxp3 + regulatory T cells loss in mice [71]. However, the functions of H 2 in regulating cardiovascular immune responses still need further investigation.…”