Fixed airflow limitation (FAO), prevalent in patients with severe or difficult-to-treat asthma, is mainly caused by airway remodeling. Airway remodeling is initiated by inflammation and involves subsequent pathological changes. Glycyl-l-histidyl-l-lysine (GHK) is a matrikine with anti-inflammatory and antioxidant effects, naturally existing in human tissue. At present, the GHK level in human plasma and whether it is related to airway remodeling of asthma remain unclear. This study was conducted to determine how GHK is involved in airway remodeling in asthma. Our result showed that the plasma GHK levels of patients with asthma were significantly lower than those of age-matched healthy controls. In asthma patients, plasma GHK levels display a moderate correlation with FEF_25–75%, and patients with FAO had significantly lower GHK levels. Ovalbumin-induced mice of asthma model treated with PBS or GHK-Cu (a form of GHK with higher bioavailability) were used to evaluate the effect of exogenous GHK supplement on airway remodeling. GHK-Cu administration alleviated airway remodeling, as reflected by decreased peribronchial collagen deposition and airway mucus secretion, and suppressed epithelial-mesenchymal transition. The therapeutical effect related to decreased TGF-β1 level. Successively, network pharmacology and the validation data of experiments in vivo and vitro demonstrated that GHK-Cu decreased TGF-β1 level by increasing SIRT1 expression and activating SIRT1 deacetylation in airway epithelial cells, thereby alleviating airway remodeling. Collectively, decreased plasma GHK levels were related to FAO in asthma patients. Through the direct binding and activation of SIRT1, exogenous GHK-Cu administration alleviated airway remodeling in asthmatic mice.

固定气流受限（FAO）常见于严重或难以治疗的哮喘患者，主要是由气道重塑引起的。气道重塑由炎症引发并涉及随后的病理变化。Glycyl- l -histidyl - l -lysine (GHK) 是一种苦参碱，具有抗炎和抗氧化作用，天然存在于人体组织中。目前，人血浆中GHK的水平及其是否与哮喘气道重塑有关尚不清楚。本研究旨在确定 GHK 如何参与哮喘气道重塑。我们的结果显示，哮喘患者的血浆 GHK 水平显着低于年龄匹配的健康对照者。在哮喘患者中，血浆 GHK 水平与 FEF 呈中度相关_25-75%，FAO 患者的 GHK 水平显着降低。用 PBS 或 GHK-Cu（一种具有较高生物利用度的 GHK 形式）处理的卵清蛋白诱导的哮喘模型小鼠用于评估外源性 GHK 补充剂对气道重塑的影响。GHK-Cu 给药减轻了气道重塑，表现为支气管周围胶原沉积和气道粘液分泌减少，并抑制了上皮间质转化。治疗效果与TGF-β1水平降低有关。先后开展网络药理学及体内外实验验证数据证明GHK-Cu通过增加SIRT1表达并激活气道上皮细胞中SIRT1去乙酰化来降低TGF-β1水平，从而减轻气道重塑。总的来说，哮喘患者血浆 GHK 水平降低与FAO有关。通过直接结合和激活 SIRT1，外源性 GHK-Cu 给药可减轻哮喘小鼠的气道重塑。