Up-Regulation of TNFα mRNA in the Rat Spleen Following Induction of Acute Pancreatitis

doi:10.1006/jsre.1995.1224

Journal of Surgical Research

Volume 59, Issue 6, December 1995, Pages 687-693

https://doi.org/10.1006/jsre.1995.1224 Get rights and content

Abstract

Tumor necrosis factor-alpha (TNFα) is postulated to be a mediator of the systemic complications associated with acute pancreatitis. Neutralization of TNFα with monoclonal antibody ameliorates the morbidity and mortality associated with acute pancreatitis in a rat model. Although high levels of TNFα are measurable in peripheral blood in acute pancreatitis, specific sites of TNFα production in this disease have not been described. In this study we show that induction of pancreatitis causes up-regulation of TNFα messenger RNA (mRNA) at a distant organ site, the spleen. Hemisplenectomies were performed in male Sprague-Dawley rats prior to induction of pancreatitis by pancreatic duct infusion of artificial bile. Completion hemisplenectomies were then performed at 30 min, 1 hr, and 2 hr after pancreatitis induction. Quantitation of TNFα mRNA in the hemispleens before and after pancreatitis using a semiquantitative reverse transcriptase-polymerase chain reaction method revealed an 80-fold increase in amount of TNFα mRNA by 2 hr after induction of pancreatitis. By contrast, control rats receiving a sham operation showed no significant increase in TNFα mRNA expression after infusion of the pancreatic duct with saline. The increase in TNFα mRNA production was associated with increased serum TNFα product levels and was independent of endotoxin. We conclude that severe acute pancreatitis in the rat model is associated with significant up-regulation of TNFα mRNA in splenic mononuclear cells. These data provide evidence that the local events of acute pancreatitis can induce up-regulation of TNFα mRNA at a distant site and suggest a possible mechanism of pathogenesis of the systemic manifestations of this disease.

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Cited by (32)

A New Role for the Spleen: Aggravation of the Systemic Inflammatory Response in Rats with Severe Acute Pancreatitis
2019, American Journal of Pathology
Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). We investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histologic, immunohistochemical, and immunologic analyses. After SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the splenic marginal zone. Rats with splenectomy developed acute pancreatitis more slowly than rats without splenectomy. In addition, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and IL-6 and exhibited less acinar cell death, leukocyte infiltration, and interstitial edema than those of rats without splenectomy. Compared with splenectomy alone, cotreatment with splenectomy and the administration of splenic cells originating from a rat with SAP 12 hours after induction increased systemic inflammation in SAP rats. Splenic factors exacerbated SAP-associated liver and lung injury and accentuated intestinal mucosal barrier dysfunction. Splenectomy altered the serum cytokine profile in rats with SAP. In a rat model of SAP, the spleen exacerbated the systematic inflammatory responses and injury to multiple organs, indicating a new role for the spleen in SAP.
Hypothermia slows sequential and parallel steps initiated during caerulein pancreatitis
2014, Pancreatology
Citation Excerpt :
Despite several pharmacologic trials conducted to improve outcomes in AP patients using serine protease inhibitors [9–18], there is no conclusive data from such studies showing benefit. Similarly, while cytokines like TNF-α are increased in AP [19–23] there have been conflicting case reports of the effect of anti-TNF therapy on the course of AP [24–26]. Hypothermia has been shown to prevent inflammatory mediator generation and cell death in various systems.
Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs.
Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37 °C, 34 °C, 31 °C, 29 °C and 25 °C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37 °C, 23 °C and 4 °C.
There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29 °C, and in cell injury at 34 °C, compared to those at 37 °C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23 °C were respectively, 53%, 64% and 26% of that at 37 °C. Acinar cooling to 31 °C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37 °C.
Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury.
The Inflammatory Cascade in Acute Pancreatitis: Relevance to Clinical Disease
2007, Surgical Clinics of North America
Citation Excerpt :
The number of agents used in experimental animals to modify, ameliorate, or abort AP is too large to enumerate. The authors' laboratory embarked on a series of experiments to modify the disease using TNF α blockers [79,93–95]. These observations were reproduced by others [64,96], although TNF was not found routinely in plasma samples of patients who had AP [97].
Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis
2003, Surgery
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. (Surgery 2003;133:186-96.)
Cytokines and acute pancreatitis
1999, Bailliere's Best Practice in Clinical Gastroenterology
Cytokines have been shown to play a pivotal role in multiple organ dysfunction, a major cause of death in severe acute pancreatitis. Moreover, the two-hit hypothesis of the cytokine-induced systemic inflammatory response syndrome explains the variable individual response to severe acute pancreatitis and the impact of secondary events such as sepsis or therapeutic intervention. Many experimental anti-cytokine therapies have been administered following induction of experimental pancreatitis, and have proved to be therapeutic. Patients with severe pancreatitis present early because of pain. Clearly then a window for therapeutic intervention is available between onset of symptoms and peak pro-inflammatory cytokine expression. It is this fundamental observation that convinces many in the field that the treatment of AP will be one of the first clinical successes for novel drugs or therapy that seek to modulate the inflammatory response.
Overexpression of the PC3/TIS21/BTG2 mRNA is part of the stress response induced by acute pancreatitis in rats
1998, Biochemical and Biophysical Research Communications
We have previously shown that the acute phase reaction of the pancreas is a powerful emergency mechanism which protects the organism against further pancreatic aggression. In an attempt to understand the mechanisms involved in this protective effect we tried to characterize at the molecular level the phenotypic changes of the pancreatic cell during acute stress. Using a systematic approach, we identified the PC3/TIS21/BTG2 mRNA as strongly overexpressed in pancreas during the acute phase of pancreatitis. PC3/TIS21/BTG2 mRNA is also overexpressed in liver and kidney during acute pancreatitis but not in the other tissues analyzed. In addition, PC3/TIS21/BTG2 mRNA is overexpressed in kidney after a 30-min ischemia. Since acute pancreatitis and kidney ischemia-reperfusion-induced injury were associated with apoptosis, and PC3/TIS21/BTG2 has an antiapoptotic activity, we speculate that this protein may play a role in the control of apoptosis progression in these tissues.

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Regular ArticleUp-Regulation of TNFα mRNA in the Rat Spleen Following Induction of Acute Pancreatitis

Abstract

Regular Article
Up-Regulation of TNFα mRNA in the Rat Spleen Following Induction of Acute Pancreatitis