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Hellman KM, Yu PY, Oladosu FA, Segel C, Han A, Prasad PV, Jilling T, Tu FF. The Effects of Platelet-Activating Factor on Uterine Contractility, Perfusion, Hypoxia, and Pain in Mice. Reprod Sci 2017. [PMID: 28631554 DOI: 10.1177/1933719117715122] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It is widely hypothesized that menstrual pain is triggered by prostaglandin synthesis that evokes high-pressure uterine contractions and ischemia. However, the effects of molecules implicated in menstrual pain on uterine contractility, perfusion, and oxygenation in vivo have been rarely demonstrated. Studies in women that do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) have reported elevated levels of platelet-activating factor (PAF). To establish in vivo evidence of PAF's capability to impair uterine homeostasis and to elicit visceral pain, we examined the effects of the PAF receptor agonist (carbamyl PAF [CPAF]) in comparison to other molecules hypothesized to play a role in uterine pain in mice. Uterine pressure was increased by oxytocin, prostaglandin F2α (PGF2α), and CPAF. Even in the absence of inflammatory molecules, uterine contractions reduced uterine oxygenation by 38%. CPAF reduced uterine perfusion by 40% ± 8% and elicited further oxygen desaturation approaching hypoxia (9.4 ± 3.4 mm Hg Pao2). Intraperitoneal injections of CPAF and PGF2α evoked visceral pain and pelvic hyperalgesia in awake wild-type mice. However, pain was not observed in identically injected PAF-receptor knockout mice. Thus, our model provides a demonstration that a molecule implicated in NSAID-resistant dysmenorrhea has a detrimental effect on uterine homeostasis and is capable of causing visceral pain. Our results support the general hypothesis that menstrual cramps are caused by uterine contractions, impaired perfusion, and reduced oxygenation. Since this study was limited to mice, confirmation of these results in humans would be valuable for development of novel therapeutics targeted at inflammatory precursors, contractility, perfusion, and tissue oxygenation.
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Affiliation(s)
- Kevin M Hellman
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
- 2 Deptartment of Obstetrics and Gynecology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Peter Y Yu
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
| | - Folabomi A Oladosu
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
- 2 Deptartment of Obstetrics and Gynecology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Chaya Segel
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
| | - Alice Han
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
| | - Pottumarthi V Prasad
- 3 Department of Radiology, NorthShore University HealthSystem, Evanston, IL, USA
| | - Tamas Jilling
- 4 Department of Pediatrics, NorthShore University HealthSystem, Evanston, IL, USA
| | - Frank F Tu
- 1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA
- 2 Deptartment of Obstetrics and Gynecology, University of Chicago Pritzker School of Medicine, Chicago, IL, USA
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Akinosoglou K, Gogos C. Immune-modulating therapy in acute pancreatitis: Fact or fiction. World J Gastroenterol 2014; 20:15200-15215. [PMID: 25386069 PMCID: PMC4223254 DOI: 10.3748/wjg.v20.i41.15200] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/21/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future.
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Wan MH, Huang W, Latawiec D, Jiang K, Booth DM, Elliott V, Mukherjee R, Xia Q. Review of experimental animal models of biliary acute pancreatitis and recent advances in basic research. HPB (Oxford) 2012; 14:73-81. [PMID: 22221567 PMCID: PMC3277048 DOI: 10.1111/j.1477-2574.2011.00408.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Acute pancreatitis (AP) is a formidable disease, which, in severe forms, causes significant mortality. Biliary AP, or gallstone obstruction-associated AP, accounts for 30-50% of all clinical cases of AP. In biliary AP, pancreatic acinar cell (PAC) death (the initiating event in the disease) is believed to occur as acinar cells make contact with bile salts when bile refluxes into the pancreatic duct. Recent advances have unveiled an important receptor responsible for the major function of bile acids on acinar cells, namely, the cell surface G-protein-coupled bile acid receptor-1 (Gpbar1), located in the apical pole of the PAC. High concentrations of bile acids induce cytosolic Ca(2+) overload and inhibit mitochondrial adenosine triphosphate (ATP) production, resulting in cell injury to both PACs and pancreatic ductal epithelial cells. Various bile salts are employed to induce experimental AP, most commonly sodium taurocholate. Recent characterization of taurolithocholic acid 3-sulphate on PACs has led researchers to focus on this bile salt because of its potency in causing acinar cell injury at relatively low, sub-detergent concentrations, which strongly implicates action via the receptor Gpbar1. Improved surgical techniques have enabled the infusion of bile salts into the pancreatic duct to induce experimental biliary AP in mice, which allows the use of these transgenic animals as powerful tools. This review summarizes recent findings using transgenic mice in experimental biliary AP.
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Affiliation(s)
- Mei H Wan
- Pancreatic Diseases Research Group, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan UniversityChengdu, China
| | - Wei Huang
- Pancreatic Diseases Research Group, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan UniversityChengdu, China,Liverpool National Institute of Health Research (NIHR) Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of LiverpoolLiverpool, UK
| | - Diane Latawiec
- Liverpool National Institute of Health Research (NIHR) Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of LiverpoolLiverpool, UK
| | - Kun Jiang
- Pancreatic Diseases Research Group, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan UniversityChengdu, China
| | - David M Booth
- Liverpool National Institute of Health Research (NIHR) Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of LiverpoolLiverpool, UK
| | - Victoria Elliott
- Liverpool National Institute of Health Research (NIHR) Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of LiverpoolLiverpool, UK
| | - Rajarshi Mukherjee
- Liverpool National Institute of Health Research (NIHR) Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, University of LiverpoolLiverpool, UK
| | - Qing Xia
- Pancreatic Diseases Research Group, Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan UniversityChengdu, China
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Uhlmann D, Lauer H, Serr F, Witzigmann H. Pathophysiological role of platelets and platelet system in acute pancreatitis. Microvasc Res 2008; 76:114-123. [PMID: 18586042 DOI: 10.1016/j.mvr.2008.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2008] [Revised: 04/23/2008] [Accepted: 05/29/2008] [Indexed: 02/07/2023]
Abstract
The most successful approach for restoring normal long-term glucose homeostasis in type I diabetes mellitus is whole-organ pancreas transplantation. Graft pancreatitis is observed in up to 20% of patients and may lead to loss of the transplanted organ. Several pathophysiological events have been implicated in this form of pancreatitis. The most important cause of early graft pancreatitis is ischemia/reperfusion (I/R)-related disturbance of microvascular perfusion with subsequent hypoxic tissue damage. Recently, considerable evidence accumulated that, among a variety of other pathophysiological events, the activation of platelets can contribute to I/R injury in the course of acute pancreatitis experimentally and clinically. This review summarizes the events affecting platelet function and, therefore, pancreatic microcirculation leading to acute pancreatitis. Therapeutic approaches and own results are presented.
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Affiliation(s)
- Dirk Uhlmann
- 2nd Department of Surgery, University of Leipzig, Germany.
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Abstract
The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against Post Endoscopic retrograde cholangiopancreatography Pancreatitis (PEP). The protease inhibitor Gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-α) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.
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De Campos T, Deree J, Coimbra R. From acute pancreatitis to end-organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt) 2007; 8:107-20. [PMID: 17381402 DOI: 10.1089/sur.2006.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Multi-organ dysfunction, and in particular lung injury, is often responsible for the unfavorable outcome of patients with severe acute pancreatitis. Understanding of the mechanisms by which local inflammation in the pancreas leads to end-organ injury is crucial for the development of new therapeutic strategies. METHODS A MEDLINE search was performed with the terms "acute pancreatitis," "lung injury," "inflammatory response," "SIRS," and "multi-organ dysfunction." Pertinent articles were selected for analysis. RESULTS Modulation of the inflammatory response using a combination of immunomodulatory agents may decrease the incidence of severe pancreatitis-related acute lung injury and acute respiratory distress syndrome. CONCLUSION Clinical trials are of utmost importance to establish the validity of such strategies.
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Affiliation(s)
- Tercio De Campos
- Division of Trauma, University of California-San Diego, 200 W. Arbor Drive, San Diego, CA 92103, USA
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Abstract
Acute pancreatitis generates a complex cascade of immunological events that affect the pathogenesis and the progression of this disease. Several inflammatory mediators seem to play a critical role in the pathogenesis of pancreatitis and the subsequent inflammatory response. In turn, these mediators can influence hemostasis. Coagulation abnormalities occur in acute pancreatitis and are related to its severity. The contribution of blood platelets in the disturbed hemostasis in acute pancreatitis, although extensively studied, remains obscure. This article reviews the local and systemic implications of hemostatic abnormalities during acute pancreatitis. Furthermore, we discuss the prognostic value and the potential therapeutic implications of platelet activation and other hemostatic variables.
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Affiliation(s)
- Anna Kakafika
- Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College School of Medicine, London, UK
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Abstract
Acute pancreatitis has an incidence of approximately 40 cases per year per 100,000 adults. Although usually self-limiting, 10% to 20% of afflicted patients will progress to severe pancreatitis. The mortality rate among patients with severe pancreatitis may approach 30% when they progress to multisystem organ failure. The development of acute pancreatitis illustrates the requirement for understanding the basic mechanisms of disease progression to drive the exploration of therapeutic options. The pathogenesis of acute pancreatitis involves the interplay of local and systemic immune responses that are often difficult to characterize, particularly when results from animal models are used as a foundation for human trials. Experimental studies suggest that the prognosis for acute pancreatitis depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic, anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. The critical players of this interaction include the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, IL-8, and platelet activating factor (PAF). The anti-inflammatory cytokines IL-10, as well as TNF-soluble receptors and IL-1 receptor antagonist, have also been shown to be intimately involved in the inflammatory response to acute pancreatitis. Other compounds implicated in disease pathogenesis in experimental models include complement, bradykinin, nitric oxide, reactive oxygen intermediates, substance P, and higher polyamines. Several of these mediators have been documented to be present at increased concentrations in the plasma of patients with severe, acute pancreatitis. Preclinical work has shown that some of these mediators are markers for disease activity, whereas other inflammatory components may actually drive the disease process as important mediators. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. Although the manipulations of specific mediators in animal models may be promising, they may not transition well to the human clinical setting. However, continued reliance on experimental animal models of acute pancreatitis may be necessary to determine the underlying causes of disease. Full understanding of these basic mechanisms involves determining not only which mediators are present, but also closely documenting the kinetics of their appearance. Measurement of the inflammatory response may also serve to identify diagnostic markers for the presence of acute pancreatitis and provide insight into prognosis. Understanding the models, documenting the markers, and deciphering the mediators have the potential to improve treatment of acute pancreatitis.
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Affiliation(s)
- Jill Granger
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA
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Haraldsen P, Wang XD, Sun ZW, Lasson Å, Börjesson A, Wallén R, Andersson R. Pancreatitis-associated pulmonary injury: Effects of lexipafant, a platelet-activating factor antagonist. JOURNAL OF ORGAN DYSFUNCTION 2006; 2:53-64. [DOI: 10.1080/17471060500424021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
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Hać S, Dobosz M, Kaczor JJ, Rzepko R, Aleksandrowicz-Wrona E, Wajda Z, Sledziński Z, Krajewski J. Neutrophil engagement and septic challenge in acute experimental pancreatitis in rats. World J Gastroenterol 2005; 11:6459-65. [PMID: 16425416 PMCID: PMC4355786 DOI: 10.3748/wjg.v11.i41.6459] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of neutrophil adhesion molecule blockade with monoclonal antibody (MoAb CD11b) and E. coli lipopolysaccharide (LPS) administration on experimental acute pancreatitis (AP).
METHODS: AP was induced by four ip injections of cerulein (Cn) at 1-h intervals. MoAb CD 11b and LPS were administered at the beginning of the experiment.
RESULTS: The neutrophil count and chemiluminescence were diminished at the beginning of AP. The oxidative stress parameters were found within the pancreatic gland. MoAb CD 11b used for AP resulted in a significant reduction of pancreatic infiltration and pancreatitis oxidative stress parameters. Serum interleukin-6 (IL-6) was not detected in AP animals, whereas high serum IL-6 concentration was noted only in animals receiving LPS.
CONCLUSION: Neutrophils are involved in pancreatic damage in the early stage of AP. Neutrophil infiltration reduction protects the pancreatic gland from destruction during AP. LPS does not change the early course of Cn pancreatitis in rats.
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Affiliation(s)
- Stanisław Hać
- Department of General Endocrine and Transplant Surgery, Medical University of Gdańsk, Poland.
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Denham W, Norman J. Potential new therapies for the treatment of acute pancreatitis. Expert Opin Investig Drugs 2005; 8:973-82. [PMID: 15992099 DOI: 10.1517/13543784.8.7.973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The treatment of acute pancreatitis has remained virtually unchanged for the past 50 years, in large part due to a poor understanding of the initial intracellular events. Furthermore, there is a lack of knowledge regarding the mediator(s) responsible for the progression of the disease from local pancreatic inflammation to a systemic inflammatory disease, as well as the mediator(s) responsible for distant organ dysfunction and failure. With recent advances in the pathophysiology of pancreatitis, in particular the role of the inflammatory mediators interleukin-1 beta, tumour necrosis factor alpha and platelet-activating factor, the potential for new effective therapies has been realised. At present, a number of inflammatory mediator antagonists are being tested in humans, with the hope that we may soon develop a specific treatment for a disease, which thus far, has none.
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Affiliation(s)
- W Denham
- Department of Surgery, MDC 16, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA.
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Hać S, Dobosz M, Kaczor J, Rzepko R. Influence of molecule CD 11b blockade on the course of acute ceruleine pancreatitis in rats. Exp Mol Pathol 2004; 77:57-65. [PMID: 15215051 DOI: 10.1016/j.yexmp.2003.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2003] [Indexed: 02/07/2023]
Abstract
Polymorphonuclear cells (PMN) activation is an essential step in acute pancreatitis (AP). We investigated the activation status of PMN, oxidative stress and pancreatic damage in early stage of experimental ceruleine pancreatitis in rats. The PMN action was modulated by monoclonal antibody CD 11b administration. The circulating WBC and polymorphonuclear cells count was reduced after AP induction. Chemiluminescence of whole blood PMN was remarkably reduced in AP group and increased after MoAb CD 11b administration. The CD 11b blockade significantly reduced the WBC infiltration and malondialdehyde (MDA) concentration within pancreatic gland. These data suggest that activated PMN are an important factor in early AP pathogenesis. Neutrophil aggregation within pancreatic gland modulated by monoclonal antibody CD11b contribute to the extent of injury during the early stage of ceruleine experimental pancreatitis in rats.
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Affiliation(s)
- Stanisław Hać
- Department of General Gastroenterological and Endocrine Surgery, Medical University of Gdañsk, Gdansk, Poland.
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Zhao H, Chen JW, Zhou YK, Zhou XF, Li PY. Influence of platelet activating factor on expression of adhesion molecules in experimental pancreatitis. World J Gastroenterol 2003; 9:338-41. [PMID: 12532462 PMCID: PMC4611342 DOI: 10.3748/wjg.v9.i2.338] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether Platelet activating factor (PAF) has a regulation role in the expression of adhesion molecules and accumulation of neutrophils in a murine model of acute pancreatitis.
METHODS: One hundred twenty-eight Kunming mice were divided into four groups. Group 1 received 0.1 mL saline s.c. every hour for three hours (sham). Group 2 received cerulein (50 μg/kg dose s.c.) every hour for three hours. Group 3 received AP and additional challenge of PAF (50 mg/kg in absolute ethanol) (AP/PAF). Group 4 received AP, plus therapeutic treatment with GAB (25 mg dose i.p.) immediately after the first challenge of cerulein (AP/GAB). Animals were sacrificed at 12 h after the first challenge of saline or cerulein. Adhesion molecules of pancreas were semi-quantified by SP methods. Standard assays were performed for serum amylase and myeloperoxidase activity (MPO) of pancreas. Histology of pancreas was scored in a blind manner. Water content of pancreas was also measured at the same time.
RESULTS: Control pancreata showed negligible adhesion molecule expression and neutrophil accumulation. There were evident adhesion molecules expression and neutrophil accumulation in AP and AP/PAF compared with sham (P < 0.05). AP/GAB had a lower level of adhesion molecules, neutrophils, and water content versus AP and AP/PAF (P < 0.05). Histology showed a trend toward improvement in AP/GAB, but did not reach statistical significance.
CONCLUSION: PAF can induce the expression of adhesion molecules that mediate neutrophil accumulation. The PAF antagonist reduces the expression of adhesion molecules and the severity of inflammation when given immediately after the induction of mild AP in mice. These results suggest that PAF antagonism may be useful in the treatment of mild pancreatitis after its clinical onset.
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Affiliation(s)
- Hua Zhao
- Department of General Surgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei Province, China.
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Wereszczynska-Siemiatkowska U, Dlugosz JW, Siemiatkowski A, Chyczewski L, Gabryelewicz A. Lysosomal activity of pulmonary alveolar macrophages in acute experimental pancreatitis in rats with reference to positive PAF-antagonist (BN 52021) effect. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2000; 52:119-25. [PMID: 10965985 DOI: 10.1016/s0940-2993(00)80095-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The activation of pulmonary alveolar macrophages (PAM's), might play an important role in severe complications of acute pancreatitis. The aim of our study was to assess the labilization of macrophage lysosomal membranes and release of lysosomal cathepsin B (CB) and N-acetyl-beta-D-hexosaminidase (NAH) into bronchoalveolar lavage fluid (BALF) during taurocholate acute pancreatitis (AP) in rats treated with PAF-antagonist--BN 52021. Total activity of CB increased by 374% after 6 h and by 237% after 12 h of AP in lysosomal enriched fraction of PAM's. Fractional free activity of CB increased to 40% after 6 h and to 38% after 12 h of AP. Free activity of CB was increased 5 fold in the supernatant of macrophage homogenate, and 10 fold in the supernatant of BALF after 6 h of AP. The values of NAH activity roughly paralleled that of CB. Treatment with BN 52021 (5 mg x kg(-1) every 6 h i.v.) partially normalized the measured parameters. Our results indicate that the PAF-antagonist BN 52021 reduced the increase of total and free activity of lysosomal hydrolases of PAM's and partly prevented the labilization of their lysosomal membranes. Therefore, an important mechanism of BN 52021 beneficial effect in pulmonary complications of acute pancreatitis could be dependent on the stabilization of PAM's lysosomes.
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Denham W, Norman J. The potential role of therapeutic cytokine manipulation in acute pancreatitis. Surg Clin North Am 1999; 79:767-81. [PMID: 10470326 DOI: 10.1016/s0039-6109(05)70042-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The central, detrimental role of the inflammatory cytokines IL-1 and TNF and the biologically active phospholipid PAF in the pathogenesis of AP has been established over the past 8 years. A number of antagonists to these mediators have been used successfully in the laboratory setting and are currently being examined in prospective randomized trials. The effectiveness of any antagonist depends not only on its ability to block the effects of the inflammatory mediators but also on its administration early enough in the course of the pancreatitis before pancreatic necrosis or organ dysfunction.
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Affiliation(s)
- W Denham
- Department of Surgery, University of South Florida College of Medicine, Tampa, USA
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Liu Q, Djuricin G, Rossi H, Bewsey K, Nathan C, Gattuso P, Weinstein RA, Prinz RA. The Effect of Lexipafant on Bacterial Translocation in Acute Necrotizing Pancreatitis in Rats. Am Surg 1999. [DOI: 10.1177/000313489906500703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Bacterial translocation (BT) from the gastrointestinal tract to mesenteric lymph nodes (MLNs) and other extra intestinal organs is an important source of infection in acute pancreatitis (AP). Lexipafant (BB-882) is a potent platelet-activating factor receptor antagonist that has an anti-inflammatory effect. To examine whether BB-882 could affect BT in acute necrotizing pancreatitis, 48 male Sprague Dawley rats (250–350 g) were studied. AP was induced in Group I and Group II by pressure injection of 3% taurocholate and trypsin into the common biliopancreatic duct (1 mL/kg of body weight). Group I rats received BB-882 (10 mg/kg, ip qd) and Group II rats received a similar volume of normal saline as a placebo postoperatively for 2 days. Group III and Group IV received BB-882 and placebo, respectively, after an exploratory laparotomy. At 48 hours postoperatively, blood was drawn for culture, serum amylase, and tumor necrosis factor (TNF)-α determinations. Specimens from MLNs, spleen, liver, pancreas, and cecum were harvested for culture of Gram-positive, Gram-negative, and anaerobic bacteria. Quantitative cecal cultures of Gram-positive, Gram-negative, and anaerobic bacteria were obtained. A point scoring system for five histological features that include interstitial edema, inflammatory cellular infiltration, fat necrosis, parenchymal necrosis, and hemorrhage was used to evaluate the severity of pancreatitis. There was no difference in serum amylase levels (2415 ± 127 IU/L versus 2476 ± 170 IU/L), serum TNF-α levels (7820 ± 1396 pg/mL versus 7318 ± 681 pg/mL), and the mean pancreatic histology score (5.9 ± 1.2 versus 6.5 ± 1.1) between Group I and Group II, respectively (P gt 0.05). Seven of 12 Group I rats had BT to MLNs, compared with 11 of 12 rats in Group II (P > 0.05). Five of 12 Group I rats had BT to distant sites such as pancreas, spleen, liver, and/or blood, compared with 11 of 12 rats in Group II (P < 0.05). BB-882 treatment decreases bacterial spread to distant sites, but does not reduce serum amylase levels and serum TNF-α levels or ameliorate pancreatic damage in rats with AP.
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Affiliation(s)
- Qiang Liu
- Departments of General Surgery, Chicago, Illinois
| | | | | | - Kelly Bewsey
- Departments of General Surgery, Chicago, Illinois
| | - Catherine Nathan
- Section of Infectious Disease, Cook County Hospital, Chicago, Illinois
| | - Paolo Gattuso
- Departments of Pathology, Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois
| | - Robert A. Weinstein
- Departments of Internal Medicine, Chicago, Illinois
- Section of Infectious Disease, Cook County Hospital, Chicago, Illinois
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Kingsnorth AN. Platelet-activating factor. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1996; 219:28-31. [PMID: 8865468 DOI: 10.3109/00365529609104996] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Platelet-activating factor (PAF) is a proinflammatory lipid. It has been strongly implicated in the regulation of pancreatic exocrine secretion and in the local and systemic events which occur in acute pancreatitis. PAF antagonists, when given as pretreatment, ameliorate the severity of experimental acute pancreatitis by reducing serum amylase, oxidative injury, morphological changes, polymorph infiltration, pulmonary damage, and exudative levels of PAF in blood and peritoneal fluid. The novel, potent PAF antagonist, lexipafant, can ameliorate microvascular-induced acute pancreatitis after induction of the disease. It also reduces lung injury by preventing increased pulmonary capillary permeability. In a double-blind, randomized, Phase II, clinical study of lexipafant in human acute pancreatitis, a clinical benefit was found, as indicated by a significant reduction in an organ failure score measured during 72 h of infusion. In addition, organ failure recovered in seven of 12 severe acute pancreatitis patients treated with lexipafant, but recovered in only two of 11 patients given placebo. New organ failure developed in a further two patients on placebo. The results of these studies indicate that lexipafant is a potential therapy for the treatment of human acute pancreatitis. A multicentre, Phase III, UK study in patients with severe acute pancreatitis is currently underway.
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Affiliation(s)
- A N Kingsnorth
- Dept. of Surgery, Derriford Hospital, University of Plymouth, England, UK
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Kingsnorth AN, Galloway SW, Formela LJ. Randomized, double-blind phase II trial of Lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br J Surg 1995; 82:1414-20. [PMID: 7489182 DOI: 10.1002/bjs.1800821039] [Citation(s) in RCA: 156] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The aims of the study were to determine whether the platelet-activating factor antagonist Lexipafant could alter the clinical course and suppress the inflammatory response of human acute pancreatitis. In a double-blind, placebo-controlled study 83 patients were randomized to receive Lexipafant 60 mg intravenously for 3 days, or placebo. Clinical progression was assessed by daily Acute Physiology And Chronic Health Evaluation (APACHE) II score and organ failure score (OFS). The magnitude of the inflammatory response on days 1-5 was assessed by serial measurement of interleukin (IL) 8, IL-6, E-selectin, polymorphonuclear elastase-alpha1-antitrypsin (PMNE-alpha 1-AT), and C-reactive protein (CRP). At entry, patients receiving Lexipafant (n = 42) or placebo (n = 41) were matched for age and sex, aetiology, APACHE II score and OFS. The disease was classified as severe in 29 patients (APACHE II score eight or more). There was a significant reduction in the incidence of organ failure (P = 0.041) and in total OFS (P = 0.048) at the end of medication (72 h). During this time seven of 12 patients with severe acute pancreatitis who had Lexipafant recovered from an organ failure; only two of 11 with severe acute pancreatitis who had placebo recovered from an organ failure and two others developed new organ failure. Lexipafant treatment significantly reduced serum IL-8 (P = 0.038), and IL-6 declined on day 1. Plasma PMNE-alpha 1-AT complexes peaked on day 1; the gradual fall to baseline over 5 days observed in controls did not occur in patients given Lexipafant. No effect was observed on serum CRP. This study provides a rationale for further clinical trials with the potent PAF antagonist Lexipafant in human acute pancreatitis.
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Liu X, Nakano I, Yamaguchi H, Ito T, Goto M, Koyanagi S, Kinjoh M, Nawata H. Protective effect of nitric oxide on development of acute pancreatitis in rats. Dig Dis Sci 1995; 40:2162-9. [PMID: 7587783 DOI: 10.1007/bf02209000] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Nitric oxide (NO) has been implicated to regulate pancreatic circulation, promote capillary integrity, and inhibit leukocyte adhesion. We investigated the role of NO in the development of pancreatitis. Nitro-L-arginine, an inhibitor of NO synthase, in total dose of 35 mg/kg body wt was infused in the rats with edematous pancreatitis induced by two intraperitoneal injections of cerulein (20 micrograms/kg). L-Arginine (125 or 250 mg/kg), a NO donor was intravenously administered twice in the rats with hemorrhagic pancreatitis induced by water-immersion stress plus two intraperitoneal injections of cerulein (40 micrograms/kg). The degree of pancreas edema, serum amylase levels, and histologic alterations were investigated. Nitro-L-arginine exacerbated cerulein-induced pancreatitis and caused a decrease in pancreatic blood flow. L-Arginine ameliorated the severity of hemorrhagic pancreatitis dose dependently and improved the pancreatic blood flow. These findings suggest that NO could confer protection against the development of hemorrhagic pancreatitis, probably through improvement of the pancreatic microcirculation.
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Affiliation(s)
- X Liu
- Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka City, Japan
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Summers JB, Albert DH. Platelet activating factor antagonists. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 1995; 32:67-168. [PMID: 7748804 DOI: 10.1016/s1054-3589(08)61012-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- J B Summers
- Abbott Laboratories, Abbott Park, Illinois 60064, USA
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