Diabetes mellitus has been shown to impair respiratory function. The diaphragm is an important skeletal muscle involved in respiration. Hydrogen sulfide (H₂S) is one of the three endogenous gas messengers in mammals, which exhibits anti-fibrotic activity in some types of diabetes-related complications. However, whether and how H₂S exerts its anti-fibrotic activity on the diabetic diaphragmatic muscle remains unclear. In this study, we explored the anti-fibrotic activity of exogenous H₂S on the diaphragm using a streptozotocin (STZ)-induced diabetic rat model. The results showed that diaphragmatic biomechanical parameters were decreased, whereas the levels of inflammatory cytokines, collagen, and nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-related protein expression were increased in diabetic diaphragms. This implies that diabetes causes fibrosis of the diaphragm muscle through activation of NLRP3 inflammasome. After supplementation with exogenous H₂S, the diaphragmatic biomechanical and pathological alterations were ameliorated and activation of NLRP3 inflammasome was inhibited, followed by a decline in diaphragm muscle inflammation and fibrosis. These results demonstrate for the first time that exogenous H₂S effectively attenuates STZ-induced diabetic diaphragm muscle fibrosis, and that the underlying mechanism may be associated with suppression of the NLRP3 inflammasome-mediated inflammatory reaction.

Impact statement

Diabetes mellitus is a group of chronic metabolic disorders, which causes serious damage to a variety of organs, such as the retina, heart, and skeletal muscle. The diaphragm is an important skeletal muscle involved in respiration in mammals. Fibrosis of the diaphragm muscle affects its contractility, which in turn impairs respiratory function. Accumulating evidence suggests that exogenous hydrogen sulfide (H₂S) exhibits anti-fibrotic activity in diabetes mellitus, but whether and how H₂S exerts this anti-fibrotic effect in the diabetic diaphragm remains unclear. The current work for the first time reveals that exogenous H₂S attenuates hyperglycemia-induced fibrosis of the diaphragm muscle and strengthens diaphragmatic biomechanical properties in diabetes mellitus, and the mechanism may involve the alleviation of collagen deposition by suppression of the nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-mediated inflammatory reaction. Therefore, H₂S supplementation could be used as an efficient targeted therapy against the NLRP3 inflammasome in the diabetic diaphragm.

中文翻译：

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外源性硫化氢对链脲佐菌素诱导的糖尿病大鼠膈肌纤维化的保护作用。

糖尿病已被证明会损害呼吸功能。横膈膜是参与呼吸的重要骨骼肌。硫化氢 (H ₂ S) 是哺乳动物的三种内源性气体信使之一，在某些类型的糖尿病相关并发症中表现出抗纤维化活性。然而，H ₂ S是否以及如何对糖尿病膈肌发挥其抗纤维化活性仍不清楚。在这项研究中，我们探索了外源性 H ₂的抗纤维化活性使用链脲佐菌素 (STZ) 诱导的糖尿病大鼠模型在横膈膜上出现 S。结果表明，糖尿病膈肌的膈肌生物力学参数降低，而炎症细胞因子、胶原蛋白和核苷酸结合寡聚化结构域样受体蛋白 (NLRP) 3 炎性体相关蛋白的表达水平增加。这意味着糖尿病通过激活 NLRP3 炎性体导致膈肌纤维化。补充外源性H ₂ S后，膈肌生物力学和病理学改变得到改善，NLRP3炎性体的激活受到抑制，随后膈肌炎症和纤维化减少。这些结果首次证明外源 H ₂S 可有效减轻 STZ 诱导的糖尿病膈肌纤维化，其潜在机制可能与抑制 NLRP3 炎症小体介导的炎症反应有关。

影响陈述

糖尿病是一组慢性代谢紊乱，对视网膜、心脏、骨骼肌等多种器官造成严重损害。横膈膜是参与哺乳动物呼吸的重要骨骼肌。膈肌纤维化影响其收缩性，进而损害呼吸功能。越来越多的证据表明，外源性硫化氢 (H ₂ S) 在糖尿病中表现出抗纤维化活性，但 H ₂ S是否以及如何在糖尿病膈肌中发挥这种抗纤维化作用仍不清楚。目前的工作首次揭示了外源 H ₂S 减轻高血糖引起的膈肌纤维化并增强糖尿病的膈肌生物力学特性，其机制可能涉及通过抑制核苷酸结合寡聚化结构域样受体蛋白 (NLRP) 3 炎症小体介导的炎症来减轻胶原沉积反应。因此，H ₂ S 补充剂可用作针对糖尿病膈肌中 NLRP3 炎性体的有效靶向治疗。