Section of Pharmacology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale Gaetano Pieraccini, 6, 50139, Florence, Italy.
Section of Pharmacology, Department of Medicine and Surgery, University of Perugia, Piazzale Severi, 1 06132 S. Andrea Delle Fratte, Perugia, Italy.
Inflamm Res. 2023 Nov;72(10-11):2037-2052. doi: 10.1007/s00011-023-01802-3. Epub 2023 Oct 10.
This study investigates the interactions between histaminergic system and glucocorticoid-induced leucin zipper (GILZ) in the inflammatory process and glucocorticoid modulation in lung fibrosis.
Wild-type (WT) and GILZ Knock-Out (KO) mice were treated with bleomycin (0.05 IU) or saline, delivered by intra-tracheal injection. After surgery, mice received a continuous infusion of JNJ7777120 (JNJ, 2 mg/kg b.wt.) or vehicle for 21 days. Lung function was studied by measuring airway resistance to air insufflation through the analysis of pressure at airway opening (PAO). Lung samples were collected to evaluate the expression of histamine HR, Anx-A1, and p65-NF-kB, the activity of myeloperoxidase (MPO), and the production of pro-inflammatory cytokines.
Airway fibrosis and remodeling were assessed by measuring TGF-β production and α-SMA deposition. JNJ reduces PAO in WT but not in GILZ KO mice (from 22 ± 1 mm to 15 ± 0.5 and from 24 ± 1.5 to 19 ± 0.5 respectively), MPO activity (from 204 ± 3.13 pmol/mg to 73.88 ± 2.63 in WT and from 221 ± 4.46 pmol/mg to 107 ± 5.54 in GILZ KO), the inflammatory response, TGF-β production, and α-SMA deposition in comparison to WT and GILZ KO vehicle groups.
In conclusion, the role of HR and GILZ in relation to glucocorticoids could pave the way for innovative therapies to counteract pulmonary fibrosis.
本研究旨在探讨组氨酸能系统与糖皮质激素诱导亮氨酸拉链（GILZ）在炎症过程和肺纤维化中糖皮质激素调节中的相互作用。
采用博来霉素（0.05 IU）或生理盐水通过气管内注射处理野生型（WT）和 GILZ 敲除（KO）小鼠。手术后，小鼠接受 JNJ7777120（JNJ，2 mg/kg b.wt.）或载体连续输注 21 天。通过测量气道开口处压力（PAO）分析空气吹入时气道阻力来研究肺功能。收集肺组织样本以评估组氨酸 HR、Anx-A1 和 p65-NF-kB 的表达、髓过氧化物酶（MPO）活性和促炎细胞因子的产生。
通过测量 TGF-β 产生和 α-SMA 沉积来评估气道纤维化和重塑。JNJ 降低 WT 但不降低 GILZ KO 小鼠的 PAO（从 22±1 mm 降至 15±0.5 和从 24±1.5 降至 19±0.5）、MPO 活性（从 204±3.13 pmol/mg 降至 WT 的 73.88±2.63 和 GILZ KO 的 107±5.54）、炎症反应、TGF-β 产生和 α-SMA 沉积与 WT 和 GILZ KO 载体组相比。
总之，HR 和 GILZ 与糖皮质激素的关系可能为对抗肺纤维化的创新疗法铺平道路。
