PDF(Pubmed)
Abstract：
BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI.
METHODS: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined.
RESULTS: VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381-661] vs. control: 693 [620-754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6-4.9] vs. control: 4.5 [4.4-4.6], p < 0.05), pneumonia (low VT: 30 [0-58] vs. control: 0 [0-0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1-3] vs. control: 1 [0-1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7-5.0] vs. mod VT + vehicle: 4.8 [4.8-5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04-0.09] vs. mod VT + vehicle: 0.04 [0.03-0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628-2252] vs. mod VT + vehicle: 1885 [1695-2159] pg/mL, p > 0.99) or histopathology.
CONCLUSIONS: \'Double hit\' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI.
METHODS: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined.
RESULTS: VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381-661] vs. control: 693 [620-754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6-4.9] vs. control: 4.5 [4.4-4.6], p < 0.05), pneumonia (low VT: 30 [0-58] vs. control: 0 [0-0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1-3] vs. control: 1 [0-1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7-5.0] vs. mod VT + vehicle: 4.8 [4.8-5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04-0.09] vs. mod VT + vehicle: 0.04 [0.03-0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628-2252] vs. mod VT + vehicle: 1885 [1695-2159] pg/mL, p > 0.99) or histopathology.
CONCLUSIONS: \'Double hit\' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI.
摘要：
背景：急性呼吸窘迫综合征（ARDS）的特征是肺泡水肿，可进展为间隔纤维化。机械通气可以增加肺损伤，被称为呼吸机诱导的肺损伤（VILI）。结缔组织生长因子(CTGF),纤维化的介质，在ARDS患者中增加。阻断CTGF抑制纤维化和可能的血管渗漏。这项研究调查了中和CTGF是否减少VILI中的肺水肿。
方法：LPS给药后，大鼠以低潮气量（6mL/kg;低VT）或中等潮气量（10mL/kg;modVT）机械通气6小时，并用中和CTGF抗体（FG-3154）或安慰剂lgG（载体）治疗。无LPS的对照大鼠以低VT通气6小时。肺湿干重比，FITC标记的葡聚糖通透性，组织病理学,测定了可溶性RAGE。
结果：VILI的特征是PaO2/FiO2比率降低（低VT：540[381-661]与控制：693[620-754]，p<0.05)，增加的湿干重量比（低VT：4.8[4.6-4.9]与控制：4.5[4.4-4.6]，p<0.05)，肺炎（低VT：30[0-58]vs.控制:0[0-0]%,p<0.05）和间质性炎症（低VT：2[1-3]vs.控制:1[0-1],p<0.05)。FG-3154不影响湿干重量比（modVT+FG-3154：4.8[4.7-5.0]与modVT+车辆：4.8[4.8-5.0]，p>0.99)，外渗葡聚糖（modVT+FG-3154：0.06[0.04-0.09]vs.modVT+车辆：0.04[0.03-0.09]µg/mg组织，p>0.99)，sRAGE（modVT+FG-3154：1865[1628-2252]vs.modVT+车辆：1885[1695-2159]pg/mL，p>0.99）或组织病理学。
结论：\'双重打击\'VILI以炎症为特征，氧合受损，肺水肿和组织病理学肺损伤。阻断CTGF不能改善VILI大鼠的氧合，也不能减轻肺水肿。
方法：LPS给药后，大鼠以低潮气量（6mL/kg;低VT）或中等潮气量（10mL/kg;modVT）机械通气6小时，并用中和CTGF抗体（FG-3154）或安慰剂lgG（载体）治疗。无LPS的对照大鼠以低VT通气6小时。肺湿干重比，FITC标记的葡聚糖通透性，组织病理学,测定了可溶性RAGE。
结果：VILI的特征是PaO2/FiO2比率降低（低VT：540[381-661]与控制：693[620-754]，p<0.05)，增加的湿干重量比（低VT：4.8[4.6-4.9]与控制：4.5[4.4-4.6]，p<0.05)，肺炎（低VT：30[0-58]vs.控制:0[0-0]%,p<0.05）和间质性炎症（低VT：2[1-3]vs.控制:1[0-1],p<0.05)。FG-3154不影响湿干重量比（modVT+FG-3154：4.8[4.7-5.0]与modVT+车辆：4.8[4.8-5.0]，p>0.99)，外渗葡聚糖（modVT+FG-3154：0.06[0.04-0.09]vs.modVT+车辆：0.04[0.03-0.09]µg/mg组织，p>0.99)，sRAGE（modVT+FG-3154：1865[1628-2252]vs.modVT+车辆：1885[1695-2159]pg/mL，p>0.99）或组织病理学。
结论：\'双重打击\'VILI以炎症为特征，氧合受损，肺水肿和组织病理学肺损伤。阻断CTGF不能改善VILI大鼠的氧合，也不能减轻肺水肿。
