Department of Cardiovascular Research, Shinshu University School of Medicine, Japan; Department of Anesthesiology, Shinshu University School of Medicine, Japan.
Department of Cardiovascular Research, Shinshu University School of Medicine, Japan.
Peptides. 2024 Jan;171:171118. doi: 10.1016/j.peptides.2023.171118. Epub 2023 Nov 25.
Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2 mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3 mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.
急性呼吸窘迫综合征（ARDS）是一种危及生命的肺部疾病，其特征为广泛的炎症和肺水肿。肾上腺髓质素（AM）是一种具有多种功能的生物活性肽，有望应用于治疗 ARDS。其功能主要通过两种受体活性修饰蛋白（RAMP）调节，即 RAMP2 和 RAMP3，它们与 AM 受体降钙素受体样受体（CLR）结合。然而，RAMP2 和 RAMP3 在 ARDS 中的作用仍不清楚。我们通过气管内给予脂多糖（LPS）建立了 ARDS 小鼠模型，并分析了 RAMP2 和 RAMP3 的病理生理意义。随着 LPS 给药，RAMP2 的表达下降，而 RAMP3 的表达在低剂量时增加，在高剂量时下降。在 LPS 给药后，药物诱导的血管内皮细胞特异性 RAMP2 敲除小鼠（DI-E-RAMP2）表现出生存率降低、肺重量增加，肺组织中凋亡细胞增多。DI-E-RAMP2 小鼠表现出 Epac1（调节血管内皮细胞屏障功能）表达降低，而 RAMP3 则代偿性上调。相比之下，在 LPS 给药后，RAMP3 小鼠的生存率、肺重量或肺病理学没有明显变化，尽管在炎症后期它们的 iNOS、TNF-α 和 NLRP3 表达明显下调。基于转录组分析，RAMP2 对 AM 的循环调节作用贡献更大，而 RAMP3 对其炎症调节作用贡献更大。这些发现表明，虽然 RAMP2 和 RAMP3 都参与了 ARDS 的发病机制，但它们的功能明显不同。进一步阐明 RAMP2 和 RAMP3 的病理生理意义和功能差异，对于 AM 在 ARDS 中的未来治疗应用至关重要。
