MMP-9及其抑制剂对实验性重症急性胰腺炎继发肺损伤的影响

目的　探讨基质金属蛋白酶 9(MMP 9)对实验性重症急性胰腺炎继发肺损伤的影响及其抑制剂 (BB 94)对重症急性胰腺炎 (SAP)继发肺损伤的预防作用。方法　SD大鼠随机分为 3组 :假手术组 (对照组 ,n =10 ) ,SAP组 (n =14 ) ,MMP抑制剂干预的SAP组 (干预组 ,n =15 )。SAP动物成模后 2 4h取材 ,检测各组肺湿重系数 ,血清淀粉酶量 ,白细胞数 ,支气管肺泡灌洗液细胞数、蛋白量 ,肺损伤评分 ,肺组织MMP 9表达等指标。结果　SAP组上述各项指标均显著高于的对照组和干预组 ,差异均有显著意义 (P <0 .0 1)。SAP组肺组织内MMP 9阳性呈高表达 ,其中强阳性为 6例 ,而对照组中仅有弱阳性表达 2例 ,干预组为弱阳性 5例 ;对照组和MMP组均显著弱于SAP组 (P <0 .0 1)。结论　在SAP发病中因炎性细胞受炎症因子的激活而大量释放MMP 9,这与SAP时肺的损害有密切关系。应用MMP抑制剂可减轻SAP的病理生理过程。     

Platelet activating factor antagonism reduces the systemic inflammatory response in a murine model of acute pancreatitis

BACKGROUND: The platelet activating factor (PAF) antagonist, Lexipafant, has been used in experimental models and clinical trials to treat severe acute pancreatitis (AP). The purpose of this study was to determine whether Lexipafant reduces the local and systemic components of AP in a murine model of mild, edematous AP. MATERIALS AND METHODS: Forty-eight female Swiss-Webster mice were divided into four groups. Group 1 received 50 microl of saline ip every hour for 6 h (sham). Group 2 received saline treatment, plus Lexipafant (25 mg/kg dose ip, every 3 h starting 1 h after the first saline injection) (sham/Lex). Group 3 received cerulein (50 microg/kg dose ip, every hour for 6 h) (AP). Group 4 received AP, plus therapeutic treatment with Lexipafant (AP/Lex). Animals were sacrificed 3 h after the last injection. Serum cytokine levels were determined by ELISA. Standard assays were performed for serum amylase activity and lung myeloperoxidase activity (MPO). Histology was scored by two blinded investigators. RESULTS: Serum cytokines (TNFalpha, IL-1beta), lung MPO, and serum amylase activity were reduced by PAF antagonism. Histology showed a trend toward improvement with Lexipafant, but did not reach statistical significance. CONCLUSION: The PAF antagonism reduces the severity of systemic inflammation when given after the induction of mild AP in mice. These results suggest that Lexipafant may be useful in the treatment of mild pancreatitis after its clinical onset.     

Cardiotrophin-1 attenuates endotoxin-induced acute lung injury.

Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokine family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Recent evidence suggests that, like other members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 microgram/kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (myeloperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechanisms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylcholine) and endothelium-independent (response to sodium nitroprusside) relaxation following alpha-adrenergic (phenylephrine)-stimulated preconstriction. CT-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0.2 units MPO/g wet lung (gwl) vs 6. 3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Similarly, CT-1 prevented ETX-induced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and -independent pulmonary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin-induced acute lung injury.     

Endothelial adhesivity, pulmonary hemodynamics and nitric oxide synthesis in ischemia-reperfusion.

OBJECTIVE: Alterations in nitric oxide synthesis, endothelial adhesivity and pulmonary hemodynamics are investigated in an animal model of lung ischemia-reperfusion. METHODS: Two sets of rats, each containing seven animals, were either subjected to unilateral pulmonary ischemia and reperfusion (Study Group) or underwent the same surgical procedure without ischemia (Control Group). Pulmonary artery pressure (PAP), pulmonary blood flow (PBF) trend, NOS-2, intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) and cGMP expression of the reperfused lung tissue and, final paO(2) were compared between the two groups. RESULTS: ICAM-1 expression was increased (369+/-114 vs. 115+/-65; P=0.02), NOS-2 expression and tissue cGMP levels were decreased (377+/-44 vs. 452+/-54; P=0.03 and 7.8+/-3.5 vs. 9.4+/-2.3 pmol/ml; P=0.03, respectively) and MPO activity was increased (2.7+/-0.9-3.5+/-0.8; P=0.03) in the reperfused lungs. Pulmonary artery pressure was 15+/-7 mmHg in the Control Group vs. 22+/-16 mmHg in the Study Group (P=0.04) at the 30th min of reperfusion. Pulmonary blood flow was greater in the Study Group at the beginning of reperfusion (9.5+/-4.1 vs. 7.1+/-3.1 ml/min at the 30th min) but considerably reduced thereafter (3.2+/-1. 4 vs. 6.2+/-2.1 at the 60th minute and 2.9+/-1.6 vs. 5.8+/-1.9 at the 120th min). At the end of the experiment, paO(2) was 95+/-30 in the Control Group vs. 71+/-32 in the Study Group (P=0.03). CONCLUSIONS: These data establish that nitric oxide synthesis was suppressed after reperfusion. Pulmonary blood flow was first increased and then reduced. A parallel increase in MPO and ICAM-1 indicated proinflammatory reaction. Decreased tissue cGMP level was consistent with the suppressed NOS-2 production. Organ function was negatively influenced as represented by the decreased oxygenation, probably due to no-reflow phenomenon.     

Renal matrix metalloproteinase activity is unaffected by experimental ischemia-reperfusion injury and matrix metalloproteinase inhibition does not alter outcome of renal function

BACKGROUND: Ischemia-reperfusion injury can lead to organ damage, such as delayed graft function in kidney transplantation. Reactive oxygen species that play a key role in this disorder may directly activate latent matrix metalloproteinases (MMP). In the kidney, little is known about the role of MMP in ischemia-reperfusion. Therefore, the aim of our study was to analyze activity/expression of MMP and to assess their functional role by the use of the MMP inhibitor BB-94 (Batimastat). METHODS: Renal ischemia was induced by left renal pedicle occlusion for 60 min, preceded by right nephrectomy. Thirty-two female Sprague-Dawley rats were analyzed: sham-operated rats (n = 8), treated sham-operated rats (n = 4), ischemic rats (n = 12), and treated ischemic rats (n = 8). Batimastat therapy (30 mg/kg body weight/day) was initiated 2 days prior to induction of ischemia. Animals were sacrificed 12 h (n = 8) and 24 h (n = 24) after ischemia for analyses of MMP activity/expression and of plasma creatinine levels. RESULTS: We found no evidence for an alteration in the activity or expression of MMP as a result of renal ischemia-reperfusion. Importantly, plasma creatinine levels significantly increased to a mean of 374 +/- 61 micromol/l in ischemic rats after 24 h, almost identical to the BB-94-treated ischemic rats (384 +/- 36 micromol/l). The creatinine levels in sham-operated rats remained within normal limits. CONCLUSION: MMP play no role during the early phase of experimental renal ischemia-reperfusion injury.     

Assessment of posttraumatic polymorphonuclear leukocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastine treatment.

Polymorphonuclear leukocytes (PMN) are implicated in the pathogenesis of traumatic brain injury. We tested the following hypotheses: (1) leukocyte accumulation is present in brain tissue 24 h posttrauma, (2) leukocyte accumulation represents PMN, and (3) prior systemic PMN depletion attenuates brain tissue PMN accumulation. Trauma was induced in exposed right parietal cortex by weightdrop in anesthetized Wistar rats (n = 24). Of the traumatized rats, 12 were PMN-depleted with vinblastine sulfate i.v. Controls were 12 normal rats and 5 sham-operated rats (craniotomy). Sections of traumatized and contralateral hemispheres were analyzed for myeloperoxidase (MPO) activity. Brain MPO activity was increased fivefold at 24 h posttrauma, but only in the traumatized hemisphere (0.448 +/- 0.133 U/g vs 0.090 +/- 0.022 U/g in trauma vs normal, respectively, p < 0.05, mean +/- SEM). PMN depletion attenuated this increase in MPO activity and decreased circulating PMN counts (0.07 +/- 0.032 x 10(9)/L vs 0.894 +/- 0.294 x 10(9)/L PMN-depleted-trauma vs trauma rats, respectively, p < 0.05). Leukocyte accumulation in the brain posttrauma was confirmed by MPO assay. Inhibition of MPO activity in the PMN-depleted group and the specificity of vinblastine treatment for depletion of circulating PMN suggest that leukocyte accumulation in the brain at 24 h posttrauma is largely due to PMN.     

Activation of nociceptive neurons in T9 and T10 in cerulein pancreatitis

Mechanisms of pain transduction in acute pancreatitis are poorly understood. Increased Fos expression in the spinal cord is a marker of activation of nociceptive neurons. We hypothesized that cerulein pancreatitis leads to increased Fos expression at T9 and T10, which receive sensory input from the pancreas. Rats were injected with cerulein (100 microg/kg, s.c.) or saline carrier (NS). Endpoints at 4, 6, and 10 h were serum amylase, myeloperoxidase activity (MPO), and spinal cord Fos expression (number of immunoreactive nuclei/section dorsal gray matter). Fos-like immunoreactivity (FLI) at T9-T10 was compared to internal controls (T6, T12). An average of 20 spinal cord histologic sections were evaluated per rat. Some animals were injected with the mu-opioid receptor agonist, buprenorphine (90 microg/kg, s.c.), 3 h after cerulein, and their endpoints were measured at 6 h. Analysis of variance and t tests were used for statistical analysis. Results are means +/- SEM. As expected, cerulein induced edematous pancreatitis, with a 4-fold increase in serum amylase at 6 h [cer (n = 8): 14,000 +/- 1,300 U/ml versus NS (n = 10): 3,700 +/- 300, P < 0.005)] and a 2-fold increase in MPO activity (0.25 +/- 0.05) activity units/dry wt versus 0.13 +/- 0.02, P < 0.05). Cerulein induced nearly a 2-fold increase in FLI at T9 and T10 [n = 10 (cer) and n = 13 (NS): T9, 14 +/- 1.5 versus 7.8 +/- 0.88; T10, 15 +/- 1.7 versus 8.3 +/- 0.70; P < 0.05]. Peak effects of cerulein on FLI occurred at 6 h and were greatest at T9/T10 with relative sparing of T6/T12. T6/T12 expression was similar in experimental and control groups. Buprenorphine significantly reduced both serum amylase and FLI and T9/T10. Cerulein-induced acute pancreatitis in rat increases visceral nociceptive signaling at spinal cord levels T9 and T10, with a peak at 6 h. Blockade of this effect by the mu-opioid receptor agonist buprenorphine could occur either by direct activation of central opioid receptors and/or an anti-inflammatory mechanism. FLI is a useful tool for studying the pathophysiology of pain in experimental acute pancreatitis.     

Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer

Blockade of vascular endothelial growth factor (VEGF) and inhibition of matrix metalloproteinases (MMP) are promising therapies for cancer. This study assessed the effects of a neutralizing anti-VEGF antibody (A4.6.1) and an MMP inhibitor (BB-94) on pancreatic cancer (PaCa) in vivo. Five million cells of two human PaCa cell lines (AsPC-1 and HPAF-2) were injected subcutaneously into nude mice; 1 mm³ fragments of the resulting tumors were implanted into the pancreas of other mice. Animals were randomized into a control group and three treatment groups: A4.6.1 (100 Μg intraperitoneally twice weekly); BB-94 (50 mg/kg every other day); and combination (A4.6.1 plus BB-94). Treatment was started after 3 days and continued for 14 weeks. Tumor volume, local and distant spread (score), and ascites were determined at autopsy. Microvessel density as a parameter of neoangiogenesis was analyzed in CD31-stained tumor sections. Both monotherapies reduced tumor volume (HPAF-2: −89% by A4.6.1 and −75% by BB-94; AsPC-1: −48% by A4.6.1 and −72% by BB-94), spread (HPAF-2: -−76% by A4.6.1 and -58% by BB-94; AsPC-1: −32% by A4.6.1 and −54% by BB-94), and microvessel density (HPAF-2: −75% by A4.6.1 and −30% by BB-94; AsPC-1: −59% by A4.6.1 and −30% by BB-94), resulting in a tendency toward increased survival (HPAF-2: 8 of 8 animals by A4.6.1 or BB-94 vs. 4 of 8; AsPC-1: 3 of 8 by A4.6.1, 4 of 8 by BB-94 vs. 1 of 8). Combination therapy yielded additional effects in the HPAF-2 group with regard to tumor volume (−95%) and development of ascites (0 of 8 vs. 2 of 8 by A4.6.1 or BB-94 vs. 5 of 8 control mice). Both VEGF blockade and MMP inhibition reduce primary tumor size, metastasis, and angiogenesis, thereby increasing survival in experimental pancreatic cancer. Combination treatment results in additive effects in moderately differentiated HPAF-2 tumors. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation). Supported by the R.S. Hirshberg Foundation and the Deutsche Forschungsgemeinschaft (grant HO 1843-1).     

一氧化氮胰腺保护作用与巯基物质和氧自由基的关系

目的　探讨内源性一氧化氮 (NO)对大鼠急性坏死性胰腺炎的作用及其与巯基物质和脂质过氧化之间的关系。　方法　以 5 %牛磺胆酸钠溶液胰胆管注射 (1ml/kg)制成大鼠急性坏死性胰腺炎模型 ,以工具药L 硝基精氨酸 (L NNA)为内源性NO的阻断剂 ,观察内源性NO对胰腺损伤程度、血清淀粉酶浓度、胰腺组织内巯基物质含量和脂质过氧化终产物丙二醛 (MDA)含量的影响。　结果　牛磺胆酸钠胰胆管注射可造成胰腺组织明显的水肿和坏死 ,部分 (2 / 7)发生胰腺实质内出血 ;血清淀粉酶浓度显著升高 ,胰腺组织巯基物质含量降低 ,MDA含量增加 [(1 2 5± 0 2 8)nmol/mg蛋白质vs.(0 5± 0 0 3)nmol/mg蛋白质 ,P <0 0 5 ]。以L NNA(12 5mg/kg)阻断内源性NO ,可明显加重胰腺组织坏死 ,胰腺实质内出血率增加 (10 / 12 ,83 3 % ) ,并血清淀粉酶浓度进一步升高 ,胰腺组织MDA含量进一步增加 [(3 0± 0 40 )nmol/mg蛋白质vs.(1 2 5± 0 2 8)nmol/mg蛋白质 ,P <0 0 5 ]。但对胰腺组织内巯基物质的含量没有影响。　结论　内源性NO具有胰腺保护作用 ,其保护机制可能与抗氧自由基有关。巯基物质可能不参与NO的胰腺保护机制。     

Amylase:creatinine clearance ratios, serum amylase, and lipase after operations with cardiopulmonary bypass

Forty-two adults who underwent cardiac operations were studied prospectively for evidence of clinical or subclinical pancreatitis. Clinically detectable pancreatitis was not seen. Serum amylase and lipase levels did not change significantly following operation. The amylase:creatinine clearance ratio (ACCR) immediately following operation was abnormally elevated in 31% of the samples obtained, and the mean ACCR increased from 2.08 +/- 1.85% before operation to 6.2% +/- 6.77% (P less than 0.05). An abnormally elevated ACCR was most often associated with a low urine creatinine concentration. The mean urine creatinine level decreased significantly from 78 +/- 53 mg/dl before operation to 38 +/- 49 mg/dl immediately following operation (P less than 0.02), and 73% of the samples obtained at that time had an abnormally low urine creatinine level (P less than 0.01). The abnormalities observed in ACCR and urine creatinine could not be related to any of several variables presumed to reflect the degree of perioperative physiologic stress, nor could they be related to postoperative hemodynamic performance. It was concluded that ACCR rises following cardiac operation because of perioperative changes in renal function, and not as a reflection of subclinical pancreatic injury.     

Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control

OBJECTIVE: To investigate the effect of a matrix metalloproteinase (MMP) inhibitor, BB-94, on the viability, invasion, and metastases of pancreatic cancer. SUMMARY BACKGROUND DATA: Inhibitors of MMPs, enzymes that degrade extracellular matrix, have been tested as single chemotherapeutic agents for pancreatic cancer. METHODS: Capan1 and AsPC1 cell lines were studied. BB-94 cytotoxicity was evaluated by cell proliferation assays. Production of MMP2 and MMP9 in conditioned media was demonstrated by gelatin zymography. The in vitro effect of BB-94 on cell invasion was assayed using invasion chambers. Hepatic metastases from pancreatic cancer were induced by intrasplenic injections of Capan1 or AsPC1 cells in nude mice. The in vivo effect of BB-94 on liver metastases was evaluated by comparing animals receiving BB-94 treatment with controls receiving vehicle alone. Variables measured included death rate and tumor burden (liver-to-body weight ratio). RESULTS: BB-94 was not cytotoxic between 3 and 3,000 ng/mL. Zymography demonstrated production of MMP2 and MMP9 by both cell lines, with complete inhibition of these enzymes by BB-94 at 48 ng/mL. Invasion chamber assays showed that BB-94 (48-400 ng/mL) impeded cell invasion in vitro compared with untreated controls. In vivo, BB-94 prevented death or reduced the death rate from hepatic metastases in animals injected with Capan1 or AsPC1 cells. BB-94 treatment resulted in significant reductions in hepatic tumor burden compared with untreated controls. CONCLUSIONS: Inhibition of MMP reduces both growth of pancreatic cancer metastases and the death rate. These actions do not reflect cytotoxicity but rather result from impaired cancer cell attachment, migration, and organ invasion. MMP inhibitors may provide an additive effect to cytotoxic agents in multidimensional treatment regimens for pancreatic cancer.     

Substance P is a determinant of lethality in diet-induced hemorrhagic pancreatitis in mice

BACKGROUND: The neuropeptide substance P (SP) induces plasma extravasation and neutrophil infiltration by activating the neurokinin 1-receptor (NK1-R). SP-induced neurogenic inflammation is terminated by the cell surface enzyme neutral endopeptidase (NEP), which degrades SP. We determined whether genetic deletion of the NK1-R reduces mortality and, conversely, whether genetic deletion of NEP increases mortality in a lethal model of hemorrhagic pancreatitis. METHODS: Necrotizing pancreatitis was induced by feeding mice a diet deficient in choline and supplemented with ethionine. We determined the length of survival, the severity of pancreatitis (by measuring the neutrophil enzyme myeloperoxidase [MPO] and by histologic evaluation), and the severity of pancreatitis-associated lung injury (lung MPO and histology) in NK1-R (+/+)/(-/-) and NEP (+/+)/(-/-) mice. RESULTS: Genetic deletion of the NK1-R significantly improved survival (100% vs 8% at 120 hours, P <.001) and reduced pancreatic MPO and acinar cell necrosis. Conversely, genetic deletion of NEP significantly worsened survival (0% vs 90% at 120 hours, P <.001) and exacerbated pancreatic MPO and pancreatitis-associated lung injury. CONCLUSIONS: Substance P is an important determinant of lethality in this model of necrotizing pancreatitis. Defects in NEP expression could lead to uncontrolled inflammation.     

Matrix metalloproteinase inhibition improves survival in an orthotopic model of human pancreatic cancer

Matrix metalloproteinases (MMPs) have been implicated in the growth and invasiveness of primary and metastatic tumors. Hypothesizing that MMP inhibition would slow cancer growth, the MMP inhibitor BB-94 (batimistat) was evaluated in an orthotopic animal model of human pancreatic carcinoma. Ten million human pancreatic cancer cells were surgically implanted into the pancreata of 30 athymic nu/nu mice. Intraperitoneal administration of 30 mg/kg BB-94 or vehicle control began 7 days after tumor implantation (13 mice with confirmed implantations in each group) and continued daily for 21 days, and then three times weekly until death or sacrifice at day 70. Representative tumors harvested from mice in each group were analyzed for presence and activity of MMP-2 and MMP-9. Animal weights were significantly higher in the BB-94-treated group at sacrifice (mean 58.4 ±7.9 g vs. 39.8 ±6.2 g; P<0.05, Student’s t test). The likelihood of survival to 70 days was significantly higher in the treated group (4 of 13 vs. 0 of 13, P <0.05, Z-test for end points) than in the control group as was overall survival (P = 0.03, Wilcoxon test). Nine mice in the control group developed metastases to the liver, peritoneum, abdominal wall, or local lymph nodes, whereas only two mice in the BB-94 group had evidence of metastatic disease (P <0.02, Fisher’s exact test), in both instances confined to the abdominal wall. Tumors from treated mice manifested lower MMP activity than those from control animals. These reports support the use of MMP inhibitors alone or as an adjunct in the treatment of pancreatic cancer. Presented in part at the Thirty-Seventh Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, Calif., May 19–22, 1996.     

1-磷酸鞘氨醇对大鼠急性坏死性胰腺炎肺损伤保护作用

目的探讨1-磷酸鞘氨醇（S1P）对大鼠急性坏死性胰腺炎肺损伤（ANP—U模型组）的保护作用及机制。方法36只Wistar大鼠随机分为假手术组、模型组、s1P处理组（S1P组）。3组动物于术后6h留取标本作如下实验：（1）测定血清淀粉酶和血脂肪酶。（2）测定左肺组织髓过氧化物酶（MPO）。（3）行左肺组织病理学检查。（4）取左肺进行肺泡灌洗测定蛋白含量；细胞沉淀涂片行白细胞和中性粒细胞计数。（5）行胰腺组织病理学检查。结果S1P组在造模后6h，肺组织MPO水平、肺泡灌洗液蛋白含量、肺泡灌洗液白细胞及中性粒细胞计数均显著低于模型组（均为P〈0．01）；肺组织病理组织学改变显著减轻。与模型组比，S1P组血清淀粉酶、脂肪酶及胰腺病理无明显改变。结论S1P对大鼠ANP—IL有明显的保护作用；其有可能作为临床治疗的有效手段。     

粘附分子基因表达在大鼠急性坏死性胰腺炎肺损伤中的作用

目的　研究急性坏死性胰腺炎 (ANP)大鼠肺组织细胞间粘附分子 1(ICAM 1)mRNA的表达情况及其与肺损伤的关系。方法　将 33只Wistar大鼠随机分为正常对照组和胰腺炎不同时间点 (1、4、12和 2 4h)各组 ,用逆行胰胆管注射方法制备ANP模型。采用逆转录聚合酶链反应法检测ANP大鼠肺组织中ICAM 1mRNA表达 ,同时观察肺组织髓过氧化物酶 (MPO)及病理改变。结果造模ANP 1h后大鼠肺组织中ICAM 1mRNA(0 82± 0 0 3)比正常对照组 (0 41± 0 0 4)的表达水平高 (P <0 0 5 ) ,并持续升高至 12h及 2 4h(分别为 1 17± 0 0 5及 1 11± 0 0 4) ,同时伴有肺组织病理损害 ,其严重程度与ICAM 1mRNA表达、MPO及肺MPO与ICAM 1mRNA表达均呈正相关 ,相关系数分别为0 85、0 85及 0 96 (P <0 0 5 )。结论　ANP大鼠早期肺组织中ICAM 1mRNA呈过度表达 ,肺损伤严重程度与ICAM 1mRNA表达的高低有关。肺组织中ICAM 1过度表达及中性粒细胞浸润是ANP肺损害发生的原因之一。     

静脉输注维生素E对急性胰腺炎时肺脏脂质过氧化损害的保护作用

目的观察维生素E（VE）对急性胰腺炎（AP）时肺组织脂质过氧化的保护作用。方法采用3％牛磺胆酸钠按O1mg／kg体重注入胰管内制成AP动物模型后,经肠系膜静脉按100mg／kg体重注入VE乳剂或相同体积的生理盐水,术后6小时和24小时活杀动物检测血清淀粉酶、脂肪酸及磷脂酶A_2（PLA_2）活性;肺脏组织丙二醛（MDA）含量、超氧化物歧化酶（SOD）活性及三磷酸腺着（ATP）含量。结果VE组动物肺脏组织炎性病理改变较AP组明显减轻;血清淀粉酶、脂肪酶及PLA_2活性均较AP组显著降低（P＜0．05）。肺脏组织MDA含量较AP组巳著降低（P＜0．05）,SOD活性及ATP含量较AP组显著升高（P＜0.05）。结论氧自由基所引发的脂质过氧化作用是急性胰腺炎时肺脏损害发病过程中的重要因素之一,应用较大剂量VE可减轻肺脏组织损害。     

Pulmonary microcirculation in mild and severe experimental pancreatitis

BACKGROUND: Research aimed at elucidating the pathogenesis of pancreatitis-associated lung injury and evaluating novel strategies for preventing respiratory complications in acute pancreatitis (AP) has not yet involved intravital microscopic (IVM) studies of pulmonary microcirculation in animals with severe disease. OBJECTIVE: To characterize and compare pulmonary microcirculation in severe/necrotizing (NP) and mild/edematous pancreatitis (EP) in the rat. METHODS: EP was induced by intravenous cerulein infusion (n = 10) and NP by a standardized intraductal infusion of glycodeoxycholic acid followed by intravenous cerulein (n = 10). After 24 h a left-sided thoracotomy was performed for IVM examination of pulmonary capillary blood flow, permeability, leukocyte sticking and the thickness of alveolar septi. Further measurements included monitoring of arterial blood gases and histological evaluation of lung injury. RESULTS: In animals with NP, histology revealed severe pulmonary edema together with clustering of polymorphonuclear leukocytes in pulmonary microvessels and alveoli. IVM showed a greater number (n) of leukocytes sticking on the endothelium of pulmonary capillaries (9.4 +/- 0.7 vs. 1.8 +/- 0.2 in healthy control animals) and increased capillary permeability (260 +/- 14 vs. 136 +/- 6% relative fluorescein intensity) while capillary blood flow was decreased (0.41 +/- 0.05 vs. 0.57 +/- 0.03 mm/s). In comparison, changes in EP were significantly less pronounced (flow 0.5 +/- 0.04 mm/s, permeability 156 +/- 4%, leukocyte sticking n = 4.6 +/- 0.7). CONCLUSIONS: These findings suggest that deterioration of pulmonary microcirculation in AP correlates with disease severity and that a model featuring NP may therefore be more suitable to further study pancreatitis-associated pulmonary injury.     

Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction

BACKGROUND: Activated mast cells can produce and release a number of inflammatory mediators involved in the pathophysiology of acute conditions. The aim of the present study was to evaluate the role of activated tissue mast cells in the pathogenesis of multiple organ dysfunction syndrome following acute pancreatitis (AP). METHODS: AP was induced by the intraductal infusion of 5 per cent sodium taurodeoxycholate in the rat. Some 30 min before induction of AP, a mast cell stabilizer (sodium cromoglycate (SCG)) or antihistamines (pyrilamine, cyproheptadine, meclizine and amitriptyline) were administered intra peritoneally. Plasma exudation of radiolabelled albumin, histamine, myeloperoxidase (MPO), monocyte chemoattractant protein (MCP) 1 and adhesion molecules (platelet endothelial cell adhesion molecule (PECAM) 1 and L-selectin) were measured. RESULTS: The mast cell stabilizer significantly reduced plasma exudation in the pancreas, colon and lungs (P < 0.05), decreased the release of histamine at 1 h (P < 0.05), and reduced MPO activity and MCP-1 levels in the colon and lungs (P < 0.05) but not in the pancreas. Expression of PECAM-1 and L-selectin on total circulating leucocytes in rats with AP and SCG pretreatment did not differ from that in sham controls, while levels in animals that had AP and saline pretreatment were half of those seen following sham operation. CONCLUSION: Activation of mast cells after induction of AP is involved in the development of endothelial barrier dysfunction in both the pancreas and extrapancreatic organs/tissues, particularly in the lungs and colon. This may, at least partly, contribute to the sequential development of multiple organ dysfunction and organ/tissue-specific endothelial barrier dysfunction.