Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis

The pathogenesis of acute pancreatitis is incompletely defined, but the outcome is determined in part by an acute inflammatory process. Pancreatitis-associated inflammation appears to play a role in the local retroperitoneal injury as well as in the associated dysfunction of remote organs such as the lung. Tumor necrosis factor (TNF) appears to be a proximal mediator of the inflammatory response. In this study, anti-TNF antibody was administered to rats with caerulein-induced pancreatitis to determine if the observed increases in pancreatic and pulmonary microvascular permeability were related to plasma TNF activity. In contrast to the expected findings, blockade of TNF activity was found to increase the amount of edema formation in both the pulmonary and pancreatic microvascular beds. The mechanism is not known; however, blockade of TNF-induced down regulation of phagocytic cell activity, ablation of TNF-dependent feedback inhibition of other cytokines, failure of induction of endogenous antioxidant systems, or inactivation of the TNF control of microvascular tone are all possible explanations. This is potentially an important observation as clinical strategies are now being developed to modify the inflammatory response in ways presumed advantageous to an injured host.     

Early microcirculatory derangement in mild and severe pancreatitis models in mice

An in vivo microscopic technique was used to clarify the increase in microvascular permeability and enhanced leukocyte–endothelium interaction of pancreatic microcirculation in experimental pancreatitis of differing severity. Using bovine albumin fluorescein isothiocyanate (FITC) and carboxyfluorescein diacetate succinimidyl ester (CFDASE) as tracers, the change in permeability and the behavior of leukocytes in the acinar microcirculation were quantified during the initial 1, 2, 6, and 12 h after the induction of caerulein pancreatitis in mice. Cold stress was added to produce the severe model. It was revealed that the early microcirculatory changes in the pancreas of caerulein pancreatitis included the increased permeability of endothelial lining and an accumulation of extravasated fluid in the perilobular space, which were more severe if cold stress was added. A decrease in flow velocity was also noted 2 h after the onset of severe pancreatitis. Leukocyte adherence to the endothelial cells was not observed during the first 12 h in either model of severity. In contrast, observation of the hepatic microcirculation revealed a significant number of adherent leukocytes 2 h after the induction of severe pancreatitis. These results suggest that during the early course of acute pancreatitis, leukocyte adherence in the pancreatic microcirculation is a secondary event following the increase in pancreatic vascular permeability. Received: February 21, 2000 / Accepted: March 6, 2001     

Neutral endopeptidase determines the severity of pancreatitis-associated lung injury

BACKGROUND: Neutral endopeptidase (NEP) is a cell-surface metalloprotease that degrades proinflammatory peptides such as substance P, neurokinin A, and bradykinin. Inhibition of NEP exacerbates both experimental pancreatitis and the associated lung injury. It is unclear if worsened lung injury is the indirect result of more severe pancreatitis or if it is a direct effect of NEP inhibition in the lung. MATERIALS AND METHODS: We used a model of pancreatitis-associated lung injury (PALI) to test the hypothesis that antagonism or genetic deletion of NEP augments PALI inflammation and pulmonary damage irregardless of the degree of pancreatitic inflammation. RESULTS: In NEP(+/+) mice, intraperitoneal injection of porcine pancreatic elastase (elastase, 0.085 U/g at t = 0 h and t = 1 h) caused a 7-fold increase in lung myeloperoxidase (MPO) activity and marked pulmonary edema, neutrophil infiltration, and hemorrhage at 4 h as compared to control animals. The pattern of lung injury induced by elastase mimicked that observed among a separate group of animals with PALI induced by cerulein but was not associated with pancreatitis. Both NEP(-/-) mice and NEP(+/+) mice pretreated with the NEP antagonist phosphoramidon (10 mg/kg s.c.) had significant elevations of lung MPO and worsened lung histology compared to NEP(+/+) mice given elastase alone. Antagonism of either the vanilloid receptor transient receptor vanilloid 1 or the substance P receptor NK1-R had no effect on elastase-mediated lung injury in NEP-deficient mice. CONCLUSIONS: NEP is an inhibitor of pancreatic elastase-induced lung injury, presumably via degradation of proinflammatory mediators.     

Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis

OBJECTIVE: To determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury. SUMMARY BACKGROUND DATA: Lung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury. METHODS: Young female mice were fed a choline-deficient/ethionine-supplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor alpha levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay. RESULTS: All mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestration, and a decreased microvascular permeability by more than twofold. CONCLUSIONS: These results demonstrate for the first time that treatment targeting the cell surface expression of ICAM-1 after the induction of AP ameliorates pulmonary injury, even in the face of severe pancreatic disease.     

Hypertonic saline attenuates end-organ damage in an experimental model of acute pancreatitis

BACKGROUND: Hypertonic saline (HTS) has been noted previously to reduce neutrophil activation. The aim of this study was to elucidate the effect of hypertonic resuscitation on the development of end-organ damage in an animal model of pancreatitis. METHODS: Pancreatitis was induced in Sprague-Dawley rats by intraperitoneal injection of 20 per cent L-arginine. Animals were randomized into four groups (each n = 8): controls; pancreatitis without intervention; pancreatitis plus intravenous resuscitation with normal saline (0.9 per cent sodium chloride 2 ml/kg) at 24 and 48 h; or HTS (7.5 per cent sodium chloride 2 ml/kg) at these time points. Pulmonary endothelial leakage was assessed by measurement of lung wet : dry ratios, bronchoalveolar lavage protein and myeloperoxidase activity. RESULTS: Animals that received HTS showed less pancreatic damage than those resuscitated with normal saline (1.0 versus 3.0; P = 0.04). Lung injury scores were also significantly diminished in the HTS group (1.0 versus 3.5; P = 0.03). Pulmonary neutrophil sequestration (myeloperoxidase activity 1.80 units/g) and increased endothelial permeability (bronchoalveolar lavage protein content 1287 microgram/ml) were evident in animals resuscitated with normal saline compared with HTS (1.22 units/g and 277 microgram/ml respectively; P < 0.02). CONCLUSION: HTS resuscitation results in a significant attenuation of end-organ injury following a systemic inflammatory response to severe pancreatitis.     

皮下注射蛙皮缩胆囊肽诱发急性胰腺炎的早期胰腺微循环损伤特征

目的探索急性胰腺炎（ＡＰ）实验动物模型的早期胰腺局部微循环损伤特征及其规律。方法用异硫氰酸荧光素（ＦＩＴＣ）标记红细胞（ＦＩＴＣＲＢＣ）活体微循环技术、微血管树脂和墨汁灌注光镜和扫描电镜技术,对蛙皮缩胆囊肽（ｃａｅｒｕｌｅｉｎ）诱发ＡＰ早期胰腺局部微循环改变进行动态观察。结果实验组血淀粉酶均增高;光镜及扫描电镜显示胰腺小叶内动脉括约肌早期出现损伤,细胞胞浆内大量空泡形成,表现为持续痉挛,所属微动脉支配区域毛细血管床构形紊乱;ＦＩＴＣＲＢＣ显示胰腺微循环的流速减慢、流量减少（Ｐ＜００１）;机能毛细血管密度减少、出现灌注不稳定和不规则间歇性灌流（Ｐ＜００５）。结论ＡＰ早期胰腺微循环紊乱的始动环节是胰腺小叶内动脉括约肌损伤及其痉挛,是导致胰腺缺血、微循环障碍的早期关键因素。     

Pancreatic microcirculation in acute pancreatitis

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. Received for publication on Jan. 29, 1997; accepted on April 24, 1997     

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.     

Recombinant soluble P-selectin glycoprotein ligand 1 moderates local and remote injuries following experimental lower-torso ischaemia.

BACKGROUND: A central role for the polymorphonuclear leucocyte (PMN) in skeletal muscle ischaemia-reperfusion has been demonstrated by the observation that PMN depletion reduced local and remote pulmonary vascular permeability. This study investigated the role of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist, in moderating injury. METHODS: Mice underwent 2 h of hindlimb ischaemia and 3 h of reperfusion. Muscle and lung vascular permeability index (PI) was assessed by extravasation of (125)I-radiolabelled albumin. Lung myelo peroxidase (MPO) activity was also measured. RESULTS: In mice treated with rPSGL-Ig 1 mg/kg before reperfusion (n = 12) muscle PI was reduced by 40 per cent, whereas it was moderated by 20 per cent in animals treated 30 min after reperfusion (n = 15). Lung PI in mice treated with rPSGL-Ig before (n = 12) and 30 min after (n = 15) reperfusion was reduced by over 99 and 98 per cent respectively. Lung MPO activity in mice treated with rPSGL-Ig before (n = 10) and 30 min after (n = 12) reperfusion was reduced by 68 and 58 per cent respectively. Treatment with rPSGL-Ig 1 h after reperfusion, or with m20ek.Fc 1 mg/kg (n = 9; negative control for rPSGL-Ig which is inactive for selectin binding) before reperfusion failed significantly to moderate local or remote organ injury. CONCLUSION: Selectin blockade moderated local skeletal muscle and remote lung injury following hindlimb ischaemia--reperfusion. Significantly, delayed antiselectin therapy also decreased injury.     

Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis

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 (MPO) 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 MPO 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-1 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.     

Endotoxin potentiates lung injury in cerulein-induced pancreatitis

BACKGROUND: In this study we examine the effect of endotoxin (lipopolysaccharide) on lung injury in the setting of acute pancreatitis (AP). METHODS: Twelve hourly injections of cerulein (50 microg/kg/h) were used to induce pancreatitis in mice. Intraperitoneal lipopolysaccharide (LPS [6 mg/kg]) was administered 24 hours after the initial cerulein injection. Twenty-four hours after LPS injection, myeloperoxidase (MPO) activity, nuclear factor (NF)-kappaB activation, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and chemokines MIP-2 and KC levels were measured in pancreas, liver, and lung tissues. Four groups of mice were studied: cerulein-LPS, cerulein-saline, saline-LPS, and saline-saline treated mice. RESULTS: Elevated serum lipase confirmed pancreatitis in cerulein treated mice. Lung MPO activity was significantly increased in the cerulein-LPS group. NF-kappaB was activated in the liver but not in pancreas and lung tissue. Chemokines MIP-2 and KC were elevated in pancreatic tissue only. CONCLUSIONS: These findings suggest that gram-negative infections may be an important predisposition for the development of adult respiratory distress syndrome in the setting of AP and that hepatic NF-kappaB may mediate multisystem injury.     

Free radical inhibition and serial chemiluminescence in evolving experimental pancreatitis.

Oxygen free radical activity and inhibition were examined in experimental pancreatitis. Twenty-five rats were randomized to five groups: controls received intravenous saline, to simulate pancreatitis one group received intravenous caerulein (5 micrograms kg-1 h-1), and three groups received sodium taurocholate via the pancreatic duct (0.2 ml, 5 per cent), either alone, following allopurinol or immediately before superoxide dismutase. Chemiluminescence (a phenomenon based on the emission of light during chemical reactions and which is dependent on oxygen free radical activity) was used as an index of oxygen free radical activity and was measured in tissue samples at 5-min intervals following induction of pancreatitis. The control mean(s.e.m.) serum amylase level 1 h after induction of pancreatitis was 635(13) units. It was significantly elevated in caerulein-induced pancreatitis, 1833(118) units (P less than 0.05) and exceeded 3000 units in all taurocholate-infused animals. Mean(s.e.m.) chemiluminescence ranged from 44 (8) mV 100 mg-1 at time zero to 404(113) mV 100 mg-1 at 1 h in controls. In caerulein-induced pancreatitis mean(s.e.m.) chemiluminescence peaked at 20 min (1399(239) mV 100 mg-1, P less than 0.02) and in taurocholate-induced pancreatitis at 15 min (2316(95) mV 100 mg-1, P less than 0.004). Superoxide dismutase significantly reduced chemiluminescence and hyperamylasaemia in taurocholate groups. Increasing oxygen free radical activity paralleled evolving pancreatitis. Superoxide dismutase may have a therapeutic role in pancreatitis.     

Selective inducible nitric oxide synthase (iNOS) inhibition attenuates remote acute lung injury in a model of ruptured abdominal aortic aneurysm

OBJECTIVE: Abdominal aortic aneurysm rupture is associated with a systemic inflammatory response syndrome and acute lung injury. Using a selective inducible nitric oxide synthase (iNOS) inhibitor, N(6)-(iminoethyl)-lysine (L-NIL), we explored the role of iNOS in the early pro-inflammatory signaling and acute lung injury in experimental abdominal aortic aneurysm rupture. MATERIALS AND METHODS: Anesthetized rats were randomized to sham control or shock and clamp (s + c) groups, which underwent one hour of hemorrhagic shock, followed by 45 minutes of supramesenteric aortic clamping, and then two hours resuscitated reperfusion. Animals in s + c were randomized to receive intravenous L-NIL at 50 microg/kg/h or saline at the start of reperfusion. Pulmonary permeability to (125)I-labeled albumin, myeloperoxidase (MPO) activity, cytokine levels, and semi-quantitative RT-PCR for mRNA were indicators of microvascular permeability, leuco-sequestration, and pro-inflammatory signaling, respectively. RESULTS: Lung permeability index were significantly increased in s + c compared to sham (4.43 +/- 0.96 versus 1.30 +/- 0.17, P < 0.01), and attenuated by L-NIL treatment (2.14 +/- 0.70, P < 0.05). Lung tissue MPO activity was significantly increased in s + c compared to sham (2.80 +/- 0.32 versus 1.03 +/- 0.29, P < 0.002), and attenuated by L-NIL treatment (1.50 +/- 0.20, P < 0.007). Lung tissue iNOS activity was significantly increased in s + c compared to sham animals (P < 0.05), and attenuated by L-NIL treatment (P < 0.05). Lung tissue iNOS mRNA was upregulated 8-fold in s + c compared to sham (P < 0.05). Data represents mean +/- standard error mean, comparisons with ANOVA. CONCLUSIONS: These data suggest that in our model of ruptured abdominal aortic aneurysm iNOS plays a crucial role in reperfusion lung injury. Selective inhibition of iNOS during early reperfusion prevents neutrophil mediated acute lung injury.     

The impact of intestinal ischaemia-reperfusion on caerulein-induced oedematous experimental pancreatitis

BACKGROUND: Intestinal ischaemia is a feature of severe acute pancreatitis. It is not known whether intestinal ischaemia and reperfusion contributes to the progression from mild to severe pancreatitis. AIM: The aim of this study was to examine the impact of intestinal ischaemia-reperfusion on caerulein-induced oedematous experimental pancreatitis. METHOD: Male Wistar rats (n = 48) were randomised to 6 experimental groups: controls (CO), saline infusion (S), saline infusion and intestinal ischaemia-reperfusion (SIR), caerulein infusion (C), caerulein and sham operation (CS), and caerulein infusion with intestinal ischaemia reperfusion (CIR). Caerulein was infused over 6 h to induce mild oedematous pancreatitis. Clamping the superior mesenteric artery for 10 min induced mild intestinal ischaemia. The reperfusion time was 24 h. The primary end point was histology of the pancreas at 24 h. RESULTS: There was no significant difference in histologic severity of pancreatitis at 24 h (Kruskal-Wallis, p = 0.37). CONCLUSION: The severity of acute oedematous pancreatitis was not increased by 10 min of intestinal ischaemia followed by 24 h of reperfusion.     

Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis

BACKGROUND: Pulmonary complications from pancreatitis involve parenchymal destruction via proteolytic enzymes. Matrix metalloproteinases (MMPs) may play an important role in pulmonary injury following acute severe pancreatitis. We hypothesized that local and distant organ injury would be decreased by the presence of an MMP inhibitor (Batimistat; BB-94) following severe acute pancreatitis (AP). METHODS: Eighteen male rats were randomized into two groups: BB-94 (AP + 40 mg/kg/24 h BB-94 ip x three doses) or control (AP + 20 ml/kg/24 h normal saline ip x three doses). Necrotizing AP was induced by retrograde infusion of 5% sodium taurocholate (1.5 ml/kg) into the pancreatic duct. Twenty additional animals were randomized into BB-94 and control groups for the survival study. Serum was evaluated for amylase and MMP activity. Pancreatic sections were graded for edema, necrosis, neutrophil infiltrate, and hemorrhage. Myloperoxidase (MPO) activity was used to determine PMN infiltration in the lung. Evan's Blue dye extravasation was used to quantify vascular permeability. RESULTS: Animals in the BB-94 group had decreased amylase levels (1086.0 +/- 61.7 U/L vs 2232.7 +/- 309.9 U/L; P < 0.05), decreased cellular infiltrate (1.4 +/- 0.2 vs 2.3 +/- 0.2; P < 0.02), and decreased necrosis (4.1 +/- 0.3 vs 6.1 +/- 0.4; P < 0.005) compared to the control group. Lung tissue following pancreatitis in the BB-94 group demonstrated decreased MPO activity (41.5 +/- 2.4 units vs 57.3 +/- 2.9 units; P < 0.05) and decreased vascular permeability (18.3 +/- 2.8 mg/100 g vs 30.1 +/- 4.6 mg/100 g; P < 0.05). Animals treated with BB-94 had 100% survival compared to 50% survival in control at 72 h. CONCLUSIONS: Pancreatitis results in increased local and distant MMP activity. Pulmonary and pancreatic injury following AP can be abrogated by treatment with an MMP inhibitor (Batimistat; BB-94) which may result in decreased morbidity and mortality.     

降钙素基因相关肽对急性胰腺炎胰腺微循环的影响

目的 研究降钙素基因相关肽（CGRP）对急性胰腺炎（AP）胰腺微循环及血管通透性的作用。方法 测定各组SD大鼠胰腺血流、微血管通透性，并对胰腺病理切片进行评分、对比。结果 （1）AP时胰腺血流发生显著改变；在AP模型建立前及过程中皮下注射CGRP，胰腺血流量、血液流速显著增加，胰腺病变程度减轻；在AP模型建立后注射CGRP，上述指标无改善。（2）AP时皮下注射CGRP，可使胰腺微循环血管通透性显著降低。结论 在AP模型建立前或同时皮下注射CGRP可以增加胰腺的血流量、血液流速，降低微血管通透性，减轻胰腺组织的损伤程度。     

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。