Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis
Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis
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DOI：
10.1067/msy.2003.84
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发表时间：
2003-02-01
期刊：
影响因子：
3.8
通讯作者：
Gaber, AO
中科院分区：
文献类型：
--
作者：
Callicutt, CS;Sabek, O;Gaber, AO
背景。重症急性胰腺炎肺损伤是由浸润性白细胞介导的。我们的实验室先前已经证明，急性胰腺炎急性肺损伤导致血管粘附分子-1 （VCAM-1）细胞表面受体在肺血管内皮和中性粒细胞隔离上的表达上调。本研究的目的是确定阻断VCAM-1在急性胰腺炎中的表达是否会改变急性肺损伤。用添加胆碱缺乏的乙硫氨酸（CDE）的饲料诱导年轻雌性小鼠急性胰腺炎。饮食开始后，一组（治疗急性胰腺炎[n = 18]）在48、96和120小时用2.35 mg/kg阻断剂量的单克隆抗vcam -1受体抗体（Ab）治疗。第二组（急性胰腺炎治疗对照组[n = 5]）在同一时间点用相似剂量的VCAM-1（非结合抗体）同型对照组进行治疗。第三组（急性胰腺炎未治疗组[n = 12]）给予CDE饮食，第四组（对照组[n = 11]）给予标准食物，不给予Ab治疗。所有动物在144小时内被杀死。采用双放射标记单克隆抗体法定量检测肺组织中VCAM-1细胞表面表达。采用转移酶介导的三磷酸脱氧尿苷缺口末端标记法检测细胞凋亡。采用骨髓过氧化物酶（AVO）法和CD18染色法检测肺白细胞隔离。与对照组相比，急性胰腺炎动物肺VCAM-1细胞表面表达显著增加（P < 0.001），急性胰腺炎治疗动物肺VCAM-1细胞表面表达降至接近对照组水平。在组织学检查中，治疗后的急性胰腺炎动物的肺损伤和细胞凋亡明显少于未治疗的急性胰腺炎动物。与未治疗的胰腺炎动物（P < 0.0001）或急性胰腺炎治疗对照组（P < 0.03）相比，治疗后胰腺炎动物白细胞隔离和AVO活性显著降低。阻断肺血管内皮上的vcam - 1可减少白细胞粘附和向肺内募集，从而减轻严重急性胰腺炎患者的肺损伤。临床上，VCAM-1拮抗剂可能是严重急性胰腺炎远端器官损伤治疗的重要辅助手段。
Background. Lung injury in severe acute pancreatitis is mediated by infiltrating leukocytes. Our laboratory has previously demonstrated that acute lung injury in acute pancreatitis results in an up-regulation of vascular adhesion molecule-1 (VCAM-1) cell surface receptor expression on pulmonary vascular endothelium and neutrophil sequestration. The objective of this study was to determine whether blocking expression of VCAM-1 in acute pancreatitis would modify acute pulmonary injury.Methods. Young female mice were fed a,choline-deficient ethionine (CDE) supplemented diet to induce acute pancreatitis. After initiation of the diet, one group (acute pancreatitis treated [n = 18]) was treated with blocking doses (2.35 mg/kg) of monoclonal anti-VCAM-1 receptor antibody (Ab) at 48, 96, and 120 hours. A second group (acute pancreatitis treated control [n = 5]) was treated with a similar dose of an isotypic control for VCAM-1 (nonbinding Ab) at the same time points. A third group (acute pancreatitis untreated [n = 12]) received a CDE diet, and a fourth group (control [n = 11]) received standard food with no Ab treatment. All animals were killed at 144 hours. The dual radiolabeled monoclonal Ab method was used to quantitate VCAM-1 cell surface expression in lung tissue. Lung injury was assessed histologically, and apoptosis was detected by transferase-mediated deoxyuridine triphosphate nick end labeling assay. Pulmonary leukocyte sequestration was determined by myeloperoxidase (AVO) assay and CD18 staining.Results. Pulmonary VCAM-1 cell surface expression was significantly increased in animals with acute pancreatitis when compared to controls (P < .001) and was reduced to near control levels in acute Pancreatitis treated animals. On histologic examination, treated animals with acute pancreatitis exhibited significantly less lung injury and apoptosis than did untreated animals with acute pancreatitis. Leukocyte sequestration and AVO activity were significantly reduced in the treated animals with pancreatitis compared to untreated animals with pancreatitis (P < .0001) or acute pancreatitis treated controls (P < .03).Conclusions. Blocking VCAM-l on pulmonary vascular endothelium decreases leukocyte adherence and recruitment into the lung, hence reducing lung injury in severe acute pancreatitis. Clinically, VCAM-1 antagonism may be an important adjunct to evolving therapy for distant organ injury in severe acute pancreatitis.