Gonzales Joyce, Patil Rahul S, Kennedy Thomas P, Umapathy Nagavedi S, Lucas Rudolf, Verin Alexander D
Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Biomolecules. 2025 Aug 26;15(9):1232. doi: 10.3390/biom15091232.
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are critical conditions lacking effective pharmacologic therapies. Lipopolysaccharide (LPS), a bacterial endotoxin, is a well-established trigger of ALI. Emerging evidence suggests that heparin derivatives may attenuate lung injury, but their mechanisms remain unclear.
This study evaluated the protective effects of 2-O, 3-O desulfated heparin (ODSH) in a murine model of LPS-induced ALI. Mice received LPS intratracheally with or without ODSH pre-treatment. Lung injury was assessed by bronchoalveolar lavage fluid (BALF) analysis, Evans blue dye albumin EBDA) extravasation, and histopathology.
ODSH treatment significantly reduced BALF protein concentration, inflammatory cell infiltration, and EBDA leakage. ODSH preserved endothelial barrier function in vitro, as evidenced by transendothelial electrical resistance (TER) measurements in human lung microvascular endothelial cell (HLMVEC) monolayers. Histological assessment (H&E staining) and myeloperoxidase (MPO) staining demonstrated reduced lung injury and neutrophil infiltration in the ODSH group. ODSH also downregulated pro-inflammatory mediators (NF-κB, IL-6, p38 MAPK) and upregulated the anti-inflammatory cytokine IL-10.
ODSH mitigates LPS-induced ALI by reducing vascular permeability, neutrophilic inflammation, and pro-inflammatory signaling while enhancing IL-10 expression. These findings suggest ODSH may offer a novel therapeutic approach for treating ALI.
急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征（ARDS）是缺乏有效药物治疗的危急病症。脂多糖（LPS），一种细菌内毒素，是公认的ALI触发因素。新出现的证据表明，肝素衍生物可能减轻肺损伤，但其机制仍不清楚。
本研究评估了2-O，3-O去硫酸化肝素（ODSH）在LPS诱导的ALI小鼠模型中的保护作用。小鼠经气管内给予LPS，预处理组同时给予或不给予ODSH。通过支气管肺泡灌洗液（BALF）分析、伊文思蓝染料白蛋白（EBDA）外渗和组织病理学评估肺损伤。
ODSH治疗显著降低了BALF蛋白浓度、炎症细胞浸润和EBDA渗漏。ODSH在体外保留了内皮屏障功能，人肺微血管内皮细胞（HLMVEC）单层的跨内皮电阻（TER）测量证明了这一点。组织学评估（苏木精-伊红染色）和髓过氧化物酶（MPO）染色显示ODSH组肺损伤和中性粒细胞浸润减少。ODSH还下调了促炎介质（NF-κB、IL-6、p38 MAPK）并上调了抗炎细胞因子IL-10。
ODSH通过降低血管通透性、中性粒细胞炎症和促炎信号传导，同时增强IL-10表达来减轻LPS诱导的ALI。这些发现表明ODSH可能为治疗ALI提供一种新的治疗方法。
