Abdelhady Rasha, Cavalu Simona, Saber Sameh, Elmowafy Rasha, Morsy Nesreen Elsayed, Ibrahim Samar, Abdeldaiem Mahmoud Said Ibrahim, Samy Mervat, Abd-Eldayem Marwa A, Shata Ahmed, Elgharabawy Rehab Mohamed
Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum 63514, Egypt.
Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania.
Biomed Pharmacother. 2023 May;161:114553. doi: 10.1016/j.biopha.2023.114553. Epub 2023 Mar 17.
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. There is currently no definitive cure for IPF. The present study establishes a platform for the development of a novel therapeutic approach for the treatment of PF using the atypical antidepressant, mirtazapine. In the endotracheal bleomycin rat model, mirtazapine interfered with the activation of NLRP3 inflammasome via downregulating the NLRP3 on the gene and protein expression levels. Accordingly, the downstream mediators IL-1β and IL-18 were repressed. Such observation is potentially a direct result of the reported improvement in oxidative stress. Additionally, mirtazapine corrected the bleomycin-induced disparities in the levels of the fibrogenic mediators TGF-β, PDGF-BB, and TIMP-1, in consequence, the lung content of hydroxyproline and the expression of α-SMA were reduced. Besides, mirtazapine curbed the ICAM-1 and the chemotactic cytokines MCP-1 and CXCL4. This protective property of mirtazapine resulted in improving the BALF total and differential cell counts, diminishing LDH activity, and reducing the BALF total protein. Moreover, the inflammation and fibrosis scores were accordingly lower. To conclude, we reveal for the first time the efficacy of mirtazapine as a potential treatment for PF. The combination of social isolation, sleep problems, breathing difficulties, and fear of death can lead to psychological distress and depression in patients with IPF. Hence, mirtazapine is a promising treatment option that may improve the prognosis for IPF patients due to its antifibrotic effects, as well as its ability to alleviate depressive episodes.
特发性肺纤维化（IPF）是一种进行性且不可逆的肺部疾病，预后较差。目前尚无治愈IPF的确切方法。本研究建立了一个平台，用于开发一种使用非典型抗抑郁药米氮平治疗肺纤维化（PF）的新型治疗方法。在气管内注射博来霉素的大鼠模型中，米氮平通过下调基因和蛋白质表达水平的NLRP3来干扰NLRP3炎性小体的激活。因此，下游介质白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）受到抑制。这种观察结果可能是所报道的氧化应激改善的直接结果。此外，米氮平纠正了博来霉素诱导的促纤维化介质转化生长因子-β（TGF-β）、血小板衍生生长因子-BB（PDGF-BB）和金属蛋白酶组织抑制因子-1（TIMP-1）水平的差异，结果，肺组织中羟脯氨酸含量和α-平滑肌肌动蛋白（α-SMA）的表达降低。此外，米氮平抑制了细胞间黏附分子-1（ICAM-1）以及趋化细胞因子单核细胞趋化蛋白-1（MCP-1）和CXC趋化因子配体4（CXCL4）。米氮平的这种保护特性导致支气管肺泡灌洗液（BALF）中总细胞数和分类细胞数增加，乳酸脱氢酶（LDH）活性降低，BALF总蛋白减少。此外，炎症和纤维化评分相应降低。总之，我们首次揭示了米氮平作为PF潜在治疗方法的疗效。社交隔离、睡眠问题、呼吸困难和对死亡的恐惧相结合，可导致IPF患者出现心理困扰和抑郁。因此，米氮平是一种有前景的治疗选择，由于其抗纤维化作用以及缓解抑郁发作的能力，可能会改善IPF患者的预后。
