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     

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     

急性胰腺炎早期胰腺微循环的改变

目的 探讨急性胰腺炎时胰腺微循环的变化。方法 采用文献回顾的方法．对有关急性胰腺炎时胰腺微循环变化进行综述。结果 在急性胰腺炎早期．胰腺微循环发生了一系列变化。主要表现为微血管收缩，血流速度减慢．血管壁通透性升高，白细胞在毛细血管后小静脉壁上黏附，胰腺灌注量减少等。结论 急性胰腺炎早期胰腺微循环紊乱在胰腺炎的发生、发展中起重要作用。     

Disturbances of the microcirculation in acute pancreatitis

BACKGROUND: Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Pancreatitis affects both the systemic and pancreatic vasculature. This review focuses on the underlying processes involved in the changes of microvascular anatomy following acute pancreatitis. METHODS: A Medline/PubMed search (January 1966 to December 2005) with manual cross-referencing was conducted. All relevant articles investigating the pancreatic microcirculatory anatomy and the effect of pancreatitis on the microcirculation were included. RESULTS: The pancreas is susceptible to ischaemic insult, which can exacerbate acute pancreatitis. There is also increasing evidence of pancreatic and systemic microvascular disturbances in the pathogenesis of pancreatitis, including vasoconstriction, shunting, inadequate perfusion, and increased blood viscosity and coagulation. These processes may be caused or exacerbated by ischaemia-reperfusion injury and the development of oxygen-derived free radicals. CONCLUSION: Acute pancreatitis impairs the pancreatic and systemic microcirculation, which is a key pathological process in the development of severe necrotizing disease.     

Therapy for microcirculatory disorders in severe acute pancreatitis: Effectiveness of platelet-activating factor receptor blockade vs. endothelin receptor blockade

Many of the complications of severe acute pancreatitis are the result of the amplifying effects of microcirculatory disruption. The factors causing microcirculatory disorders in acute pancreatitis involve vasoactive mediators such as platelet-activating factor (PAF) and endothelin-1 (ET) activated during the inflammatory response to pancreatic injury. To further evaluate the potential therapeutic role of specific receptor antagonists (RA) to these mediators, the present study compares the effect of PAF and ET receptor blockade on microcirculation and organ function in a well-established rodent model of severe acute pancreatitis. Six hours after acute pancreatitis induction, rats were randomized to therapy with ET-RA (50 mg/kg LU-135252), PAF-RA (82 μg/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparototnized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment both ET-RA and PAF-RA significantly improved capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. The beneficial effects of receptor antagonist treatment on microcirculation were associated with decreased fluid loss into the third space, improved renal and respiratory function, and survival. Although both receptor antagonists likewise improved capillary blood flow, ET-RA was significantly more effective in counteracting leukocyte rolling and capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of PAF and ET receptor blockade on microcirculation inside and outside the pancreas, organ function, and survival when given at the early stage of severe pancreatitis. Because ET-RA was more effective in stabilizing capillary permeability and avoiding subsequent fluid loss into the third space, we propose that ET-RA should be tested in a clinical trial (either in comparison or in addition to PAF-RA). Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

Intra-abdominal sepsis attenuates local inflammation-mediated increases in microvascular permeability at remote sites in mice in vivo

BACKGROUND: Given that leukocyte delivery to remote sites is diminished in states of systemic inflammation, such as sepsis, and activated leukocytes may be responsible for endothelial injury leading to vascular leakage, we hypothesized that intra-abdominal sepsis would diminish microvascular leakage at remote sites by altering leukocyte-endothelial interactions. METHODS: Using a murine intravital microscopy model, we examined leukocyte-endothelial interactions and vascular leakage at a peripheral site in the presence of local and/or systemic inflammation. Forty mice were randomized to 1 of 4 study groups: local infection (orchitis), systemic infection (intra-abdominal sepsis by cecal ligation and puncture), local and systemic infection, and control. Postcapillary venules of the cremaster muscle were examined by bright light and fluorescence intravital microscopy. Microvascular leakage was determined after intravenous administration of fluorescent albumin. RESULTS: Systemic infection attenuated the increases in both leukocyte adherence and local infection-induced microvascular permeability. Neutrophil cell-surface expression of L-selectin, as determined by flow cytometry, diminished with both local and systemic infection, whereas expression of CD11b increased with systemic, but not local, infection. CONCLUSIONS: These data suggest that systemic (intra-abdominal) sepsis diminishes local inflammation-mediated vascular leakage by attenuating leukocyte adherence.     

Technetium-99m-labeled white blood cells: a new method to define the local and systemic role of leukocytes in acute experimental pancreatitis.

OBJECTIVE: We developed a new method to quantitate leukocyte accumulation in tissues and used it to examine the time course and severity of acute experimental pancreatitis. BACKGROUND: Leukocyte activation and infiltration are believed to be critical steps in the progression from mild to severe pancreatitis and responsible for many of its systemic complications. METHODS: Pancreatitis of graded severity was induced in Sprague-Dawley rats with a combination of caerulein and controlled intraductal infusion. Technetium-99m (99mTc)-labeled leukocytes were quantified in pancreas, lung, liver, spleen, and kidney and compared with myeloperoxidase activity. The severity of pancreatitis was ascertained by wet/dry weight ratio, plasma amylase, and trypsinogen activation peptide in the pancreas. The time course of leukocyte accumulation was determined over 24 hours. RESULTS: Pancreatic leukocyte infiltration correlated well with tissue myeloperoxidase concentrations. In mild pancreatitis, leukocytes accumulated only in the pancreas. Moderate and severe pancreatitis were characterized by much greater leukocyte infiltration in the pancreas than in mild disease (p < 0.01), and increased 99mTc radioactivity was detectable in the lung as early as 3 hours. 99mTc radioactivity correlated directly with the three levels of pancreatitis. CONCLUSIONS: Mild pancreatitis is characterized by low-level leukocyte activation and accumulation in the pancreas without recruitment of other organs; marked leukocyte accumulation was found in the pancreas and in the lung in more severe grades of pancreatitis. These findings provide a basis for the pathophysiologic production of cytokines and oxygen free radicals, which potentiate organ injury in severe pancreatitis. This study validates a new tool to study local and systemic effects of leukocytes in pancreatitis as well as new therapeutic hypotheses.     

Microcirculatory derangements in acute pancreatitis

During the past decade, a considerable number of experimental studies have confirmed the hypothesis that microcirculatory derangements play a pivotal role in the pathogenesis of acute pancreatitis, including the process of conversion from edematous to necrotizing injury. Predominant microcirculatory disorders are nutritive capillary perfusion failure, with the consequence of prolonged focal hypoxia or anoxia, and inflammation-associated microvascular leukocyte recruitment, CD11b- and intercellular adhesion molecule (ICAM)-1-mediated leukocyte-endothelial cell interaction and loss of endothelial integrity, which may result in both edema formation and necrosis. A variety of proinflammatory mediators, such as oxygen radicals, leukotrienes, platelet-activating factor, and interleukins, but also bradykinin and endothelins, seem to be involved in triggering the manifestations of these microcirculatory disorders. In contrast, the anti-inflammatory interleukin-10, as well as nitric oxide, are thought to be capable of protecting from these pancreatitis-associated microvascular injuries. This knowledge may be encouraging for the development of novel therapeutic strategies, aiming at the attenuation of microcirculatory disorders, and, thus, preventing tissue injury in acute pancreatitis. Received: July 4, 2000 / Accepted: December 28, 2000     

Treatment of acute pancreatitis with beta-adrenergic agonist drugs

An increase in microvascular permeability may be important in the pathogenesis of acute pancreatitis. beta-adrenergic receptor agonist drugs are known to inhibit the increase in microvascular permeability induced by histamine and related vasoactive substances. These inflammatory mediators have been shown to be released during the course of experimental and human pancreatitis. We investigated the effect of isoproterenol and terbutaline sulfate on the development of acute edematous (AEP) and acute hemorrhagic (AHP) pancreatitis in a feline model of biliary pancreatitis. When given at the time of pancreatic insult, isoproterenol prevented the development of both AEP and AHP. Both isoproterenol and terbutaline sulfate reduced the severity of pancreatic inflammation, even when given up to 12 hours after the onset of AEP. Although neither drug was effective in treating established AHP, our findings suggest that, if given early in the course of the disease, they may be useful in preventing the progression of AEP to AHP.     

Pancreatic ischaemia in experimental acute pancreatitis: mechanism, significance and therapy

Much clinical and experimental evidence suggests that pancreatic ischaemia in the early phase of acute pancreatitis is important in the development of pancreatic necrosis. While depletion of intravascular volume has often been assumed to be the main circulatory defect, an additional disturbance of pancreatic microcirculation has been demonstrated experimentally. Possible contributory mechanisms include chemical-induced vasoconstriction, direct injury of vessel wall, intravascular coagulation and increased endothelial permeability resulting in pancreatic oedema, haemoconcentration and impaired venous drainage. Pancreatic ischaemia as a consequence of these local effects seems to be responsible for the transition of mild pancreatitis to parenchymal necrosis. In experimental models the beneficial effect of various drugs and of sympathetic blockade has been ascribed to an improvement in pancreatic perfusion. Although effective volume therapy is generally accepted as the mainstay of conservative treatment in acute pancreatitis, the efficacy of different fluid preparations is still controversial, and simple fluid resuscitation has not been shown to prevent the development of parenchymal necrosis. The specific impairment of pancreatic microcirculation cannot be prevented merely by replenishment of intravascular volume with crystalloids, albumin or plasma despite normalization of macrohaemodynamics. In contrast, partial replacement of blood by dextran preparations has been shown to increase pancreatic perfusion by improving blood fluidity. Isovolaemic haemodilution in conjunction with conventional fluid therapy may provide a new and effective means of protecting the pancreas from secondary injury due to the early ischaemic phase of acute pancreatitis.     

Role of integrins and intracellular adhesion molecule-1 in lung injury after intestinal ischemia-reperfusion

BACKGROUND: We tested the hypothesis that lung injury after intestinal ischemia-reperfusion (IR) requires the activation of CD11/CD18 glycoprotein complex and its ligand, intracellular adhesion molecule-1 (ICAM-1), on pulmonary endothelial surface. METHODS: Rats were assigned to one of six groups including sham operation, intestinal IR (60/120 min) and IR plus treatment with one of the following monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1. Pulmonary microvascular permeability, neutrophil accumulation, and expression of adhesion molecules were evaluated. RESULTS: Intestinal IR resulted in lung injury characterized by a marked increase in microvascular permeability, neutrophil accumulation and upregulated expression of leukocyte integrins and ICAM-1. The increase in pulmonary microvascular permability and neutrophil accumulation elicited by intestinal reperfusion was effectively prevented by administration of blocking antibodies against ICAM-1, CD11, and CD18. CONCLUSIONS: These results indicate that adhesion molecules contribute to the lung injury after intestinal IR. Immunoneutralization of certain of these adhesion molecules may prevent intestinal IR-induced lung injury.     

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。     

Effect of salvianolic acid B on TNF-a induced cerebral microcirculatory changes ina micro-invasive mouse model

Purpose: To investigate the effects of salvianolic acid B (SAB) on tumor necrosis factor a (TNF-a) induced alterations of cerebral microcirculation with a bone-abrading model. Methods: The influences of craniotomy model and bone-abrading model on cerebral microcirculation were compared. The bone-abrading method was used to detect the effects of intracerebroventricular application of 40 mg/kg$bw TNF-a on cerebral venular leakage of fluorescein isothiocyanate (FITC)- albulmin and the rolling and adhesion of leukocytes on venules with fluorescence tracer rhodamine 6G. The therapeutical effects of SAB on TNF-a induced microcirculatory alteration were observed, with continuous intravenous injection of 5 mg/kg$h SAB starting at 20 min before or 20 min after TNF-a administration, respectively. The expressions of CD11b/CD18 and CD62L in leukocytes were measured with flow cytometry. Immunohistochemical staining was also used to detect E-selectin and ICAM-1 expression in endothelial cells. Results: Compared with craniotomy method, the bone-abrading method preserved a higher erythrocyte velocity in cerebral venules and more opening capillaries. TNF-a intervention only caused responses of vascular hyperpermeability and leukocyte rolling on venular walls, without leukocyte adhesion and other hemodynamic changes. Pre- or post-SAB treatment attenuated those responses and suppressed the enhanced expressions of CD11b/CD18 and CD62L in leukocytes and E-selectin and ICAM-1 in endothelial cells induced by TNF-a. Conclusions: The pre- and post-applications of SAB during TNF-a stimulation could suppress adhesive molecular expression and subsequently attenuate the increase of cerebral vascular permeability and leukocyte rolling.     

Therapeutic effect of isovolemic hemodilution with dextran 60 on the impairment of pancreatic microcirculation in acute biliary pancreatitis.

Dextran of different molecular weight (Dx 40, Dx 60/70) has often been evaluated as adjunct treatment of experimental acute pancreatitis. A beneficial effect has been documented by a decrease in its lethality. However, the mechanism of action is poorly understood. A specific effect on the pancreatic microcirculation generally has not been documented and differentiation from unspecific improvement of pancreatic blood flow due to volume expansion has been difficult. This investigation was designed to quantify the effect of dextran on the impairment of pancreatic microcirculation during acute biliary pancreatitis by means of intravital microscopy. Dextran 60 (Dx 60, molecular weight 60,000) was chosen in light of the increase in vascular permeability in the early stage of pancreatitis as demonstrated previously in the same model. Isovolemic hemodilution, i.e., exchange of whole blood for Dx 60 was used as a mode of administration to achieve instantaneous onset of therapy without changes in intravascular volume. In the control group a progressive reduction of pancreatic capillary perfusion commenced 30 minutes after induction of acute pancreatitis, resulting in cessation of nutritive tissue perfusion after 3 hours. In the animals subjected to hemodilution, stabilization of the pancreatic microcirculation was accomplished throughout the observation period of 6 hours. Because volume-related effects could be excluded by the protocol and by monitoring central venous pressure and hematocrit, a specific effect of hemodilution with DX 60 on the pancreatic microcirculation is indicated by our results.     

Mast cell degranulation inhibits IL-2-induced microvascular protein leakage.

The therapeutic efficacy of interleukin-2 (IL-2) in the treatment of cancer has been limited by a "vascular leak syndrome" and related toxicities. To better understand the pathophysiology of the "vascular leak syndrome," we tested a hypothesis that mast cell degranulation mediated the acute increase in microvascular protein leakage seen immediately following IL-2 administration. After the cremaster muscle was prepared for intravital microscopy, anesthetized Sprague-Dawley rats were injected with fluorescein isothiocyanate-labeled albumin for fluorescent microscopy. Animals were treated by the intravenous injection of IL-2 (1 x 10(6) U/kg) (n = 6), the control IL-2-vehicle (n = 5), or IL-2 (1 x 10(6) U/kg) after mast cell degranulation with compound 48/80 (n = 6). Relative interstitial fluorescent intensity was quantitated by a computerized image analysis system as an index of microvascular protein leakage. IL-2 acutely induced protein leakage from the microcirculation. Mast cell degranulation with 48/80 prior to IL-2 treatment prevented protein leakage, but did not alter IL-2-induced leukocyte-endothelial adherence. These data suggest that mast cell-mediated events may be responsible for the acute increase in microvascular permeability seen with IL-2 administration and that leukocyte-endothelial adherence alone is not solely responsible.     

Effects of timing of diatrizoate (water-soluble contrast medium) administration on pancreatic microcirculatory derangement in cerulein pancreatitis in rats

OBJECTIVE: We investigated whether the timing of administration of contrast medium after onset of acute pancreatitis is critical in determining the magnitude of microcirculatory derangement. METHODS: An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuous infusion of cerulein (15 mg/kg per hour). The mean arterial pressure was monitored continuously by means of a femoral artery catheter. Diatrizoate (Hypaque-76), a water-soluble contrast medium, was delivered through a femoral vein catheter at doses corresponding to those given to humans, either 1, 2, or 3 hours after pancreatitis induction. In vivo microscopy and laser-Doppler flowmetry were used to investigate microcirculatory derangement. The water contents of the pancreas and lung, the malondialdehyde levels of the pancreas, and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hours after infusion of cerulein). RESULTS: Early administration of contrast medium (1 hour after pancreatitis induction) resulted in significantly greater changes in microcirculation and mean arterial pressure than did late administration (2 or 3 hours after pancreatitis induction). Rats given contrast medium 1 hour after induction also had highest pancreas and lung water contents, the highest pancreas malondialdehyde levels, and the highest serum trypsinogen activation peptide levels. CONCLUSION: These results show that a water soluble contrast medium that is often used for computed tomographic imaging of the pancreas can adversely affect the pancreatic microcirculatory parameters, such as tissue perfusion and leukocyte sticking, and hemodynamics in a cerulein-induced model of acute pancreatitis. Early administration seems to cause more severe derangement of the pancreatic microcirculation.     

In Vivo Imaging of Human Pancreatic Microcirculation and Pancreatic Tissue Injury in Clinical Pancreas Transplantation

Pancreatitis remains to be a major complication following clinical pancreas transplantation. We performed orthogonal polarized spectral (OPS) imaging for direct in vivo visualization and quantification of human pancreatic microcirculation in six healthy donors for living donor liver transplantation and 13 patients undergoing simultaneous pancreas-kidney transplantation. We further determined the impact of microvascular dysfunction during early reperfusion on pancreatic graft injury. Exocrine and endocrine pancreatic impairment was determined by analysis of serum lipase, amylase and C-peptide levels. Compared to normal pancreas in liver donors (homogeneous acinar perfusion) functional capillary density (FCD) and capillary red blood flow velocity of reperfused grafts were significantly decreased. Elevated CRP concentrations on day 2 post-transplant and serum lipase and amylase levels determined on days 4-5 significantly correlated with microvascular dysfunction during the first 30 min of graft reperfusion. Post-transplant serum C-peptide also correlated significantly with pancreatic capillary perfusion. OPS imaging allows to intra-operatively assess physiologic pancreatic microcirculation and to determine microcirculatory impairment during early graft reperfusion. This impairment correlated with the manifestation of post-transplant dysfunction of both exocrine and endocrine pancreatic tissue. OPS imaging may be used clinically to determine the efficacy of interventions, aiming at attenuating microcirculatory impairment during the acute post-transplant reperfusion phase.     

Etiology and pathogenesis of acute pancreatitis]

The pathogenesis of acute pancreatitis is based on the following principles: 1. Biliary. In biliary pancreatitis there is a causal relationship between the induction of acute pancreatitis and the migration of gallstones. The basic pathomechanism seems to be a combination of an increase in permeability and pressure in the ductal system. 2. Intraacinar. Caerulein-pancreatitis is a well established experimental model which reflects the intracellular/interstitial type of activation. Basolateral secretion of pancreatic enzymes into the interstitial space represents the initial event. Intracellular activation of trypsin by the fusion of zymogen-granules and lysosomes has been advocated as an alternative mechanism. 3. Alcohol. The acute alcohol pancreatitis comprises a combined pathogenesis. Obstruction and reflux as well as the cytotoxic effect of alcohol seem to be the main principles. 4. Disturbance of pancreatic microcirculation. Ischemia of the pancreas seems to play a key role in the transition from pancreatic edema to necrosis. Improvement of capillary perfusion by isovolemic hemodilution with dextran 60 has been shown to be an efficient therapeutic tool.     

微循环障碍在急性出血坏死性胰腺炎病程中的作用及丹参的治疗效果

用3%牛磺胆酸钠经胆胰管逆行注射,制成大鼠急性出血坏死性胰腺炎(AHNP)模型,并用丹参进行实验性治疗。结果:模型制作后6小时,对照组胰腺即出现严重的出血坏死及微血管破坏,血清胰酶活性显著升高(P<0.01),12小时后血清胰酶活性呈进行性降低,胰腺微血管及组织学病变则进行性加重;而丹参治疗组24小时时胰腺微血管损害及组织学病变显著改善(P<0.01)。作者认为微循环障碍是加重AHNP后期胰腺病变的重要因素,丹参能改善胰腺的微循环,对AHNP有一定治疗作用。     

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.