Data_Sheet_1_Effects of Obesity on Pulmonary Inflammation and Remodeling in Experimental Moderate Acute Lung Injury.docx

Obese patients are at higher risk of developing acute respiratory distress syndrome (ARDS); however, their survival rates are also higher compared to those of similarly ill non-obese patients. We hypothesized that obesity would not only prevent lung inflammation, but also reduce remodeling in moderate endotoxin-induced acute lung injury (ALI). Obesity was induced by early postnatal overfeeding in Wistar rats in which the litter size was reduced to 3 pups/litter (Obese, n = 18); Control animals (n = 18) were obtained from unculled litters. On postnatal day 150, Control, and Obese animals randomly received E. coli lipopolysaccharide (ALI) or saline (SAL) intratracheally. After 24 h, echocardiography, lung function and morphometry, and biological markers in lung tissue were evaluated. Additionally, mediator expression in neutrophils and macrophages obtained from blood and bronchoalveolar lavage fluid (BALF) was analyzed. Compared to Control-SAL animals, Control-ALI rats showed no changes in echocardiographic parameters, increased lung elastance and resistance, higher monocyte phagocytic capacity, collagen fiber content, myeloperoxidase (MPO) activity, and levels of interleukin (IL-6), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and type III (PCIII), and I (PCI) procollagen in lung tissue, as well as increased expressions of TNF-α and monocyte chemoattractant protein (MCP)-1 in blood and BALF neutrophils. Monocyte (blood) and macrophage (adipose tissue) phagocytic capacities were lower in Obese-ALI compared to Control-ALI animals, and Obese animals exhibited reduced neutrophil migration compared to Control. Obese-ALI animals, compared to Obese-SAL, exhibited increased interventricular septum thickness (p = 0.003) and posterior wall thickness (p = 0.003) and decreased pulmonary acceleration time to pulmonary ejection time ratio (p = 0.005); no changes in lung mechanics, IL-6, TNF-α, TGF-β, PCIII, and PCI in lung tissue; increased IL-10 levels in lung homogenate (p = 0.007); reduced MCP-1 expression in blood neutrophils (p = 0.009); decreased TNF-α expression in blood (p = 0.02) and BALF (p = 0.008) neutrophils; and increased IL-10 expression in monocytes (p = 0.004). In conclusion, after endotoxin challenge, obese rats showed less deterioration of lung function, secondary to anti-inflammatory and anti-fibrotic effects, as well as changes in neutrophil and monocyte/macrophage phenotype in blood and BALF compared to Control rats.

肥胖患者罹患急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）的风险更高，但与病情相当的非肥胖患者相比，其生存率反而更高。本研究提出假设，肥胖不仅可抑制肺部炎症，还能减轻中度内毒素诱导的急性肺损伤（acute lung injury, ALI）的肺组织重构。本研究通过调整Wistar大鼠的每窝产仔数至3只，于出生后早期进行过度喂养以构建肥胖模型（肥胖组，n=18）；对照组（n=18）大鼠则来自未调整产仔数的正常窝仔。在大鼠出生后第150天时，对照组与肥胖组大鼠随机经气管内注入大肠杆菌脂多糖（ALI）或生理盐水（saline, SAL）。造模24小时后，对大鼠开展超声心动图检测、肺功能与形态学分析，并检测肺组织中的生物标志物。此外，本研究还分析了从血液与支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中分离得到的中性粒细胞与巨噬细胞内的介质表达情况。与对照组-生理盐水组（Control-SAL）大鼠相比，对照组-急性肺损伤组（Control-ALI）大鼠的超声心动图参数无明显变化，但肺弹性与气道阻力升高，单核细胞吞噬能力、胶原纤维含量、髓过氧化物酶（myeloperoxidase, MPO）活性，以及肺组织中白细胞介素（interleukin, IL）-6、肿瘤坏死因子（tumor necrosis factor, TNF）-α、转化生长因子（transforming growth factor, TGF）-β、Ⅲ型前胶原（PCIII）与Ⅰ型前胶原（PCI）水平均显著升高；同时血液及支气管肺泡灌洗液中性粒细胞内的TNF-α与单核细胞趋化蛋白（monocyte chemoattractant protein, MCP）-1表达量也有所增加。与对照组-急性肺损伤组大鼠相比，肥胖组-急性肺损伤组（Obese-ALI）大鼠的血液单核细胞与脂肪组织巨噬细胞的吞噬能力更低；且肥胖组大鼠的中性粒细胞迁移能力较对照组更低。与肥胖组-生理盐水组（Obese-SAL）大鼠相比，肥胖组-急性肺损伤组大鼠的室间隔厚度（p=0.003）与后壁厚度（p=0.003）均显著升高，肺动脉加速时间与射血时间的比值显著降低（p=0.005）；肺力学参数、肺组织中IL-6、TNF-α、TGF-β、PCIII及PCI水平无明显变化；肺匀浆中IL-10水平升高（p=0.007）；血液中性粒细胞内MCP-1表达量降低（p=0.009）；血液（p=0.02）及支气管肺泡灌洗液（p=0.008）中性粒细胞内的TNF-α表达量降低；单核细胞内IL-10表达量升高（p=0.004）。综上，与对照组大鼠相比，经内毒素攻击后的肥胖大鼠肺功能恶化程度更轻，这与其抗炎、抗纤维化效应，以及血液与支气管肺泡灌洗液中中性粒细胞、单核细胞/巨噬细胞的表型改变密切相关。