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3.
J Surg Res ; 97(2): 109-16, 2001 May 15.
Article in English | MEDLINE | ID: mdl-11341785

ABSTRACT

BACKGROUND: Approximately 200,000 incisional hernias are repaired annually in the United States. The high incidence (11-20%) and recurrence rate (24-54%) for incisional hernias have not changed appreciably in 75 years. Mechanical advances in suture material, incision orientation, and closure technique have failed to eliminate this common surgical complication. A biological approach to acute wound failure may offer a new strategy. METHODS: A rodent incisional hernia model was used. Seventy rats underwent 5-cm midline celiotomies and were closed with fine, fast-absorbing sutures to induce intentional acute wound failure. Group 1 received no other treatment. The midline fascia in groups 2 and 3 was injected immediately prior to incision with 100 microl of vehicle alone or vehicle containing 1 microg of transforming growth factor beta(2) (TGF-beta(2)). Necropsy was performed on Postoperative Day 28 and the wounds were examined for herniation. RESULTS: Incisional hernias developed in 88% (35/40) and 79% (11/14) of untreated incisions and those treated with vehicle alone. No hernias formed in the TGF-beta(2)-treated incisions (0/16, P < 0.05). Standard histology and immunohistochemistry demonstrated enhanced macrophage, lymphocyte, and fibroblast chemotaxis and increased collagen I and III production in TGF-beta(2) treated incisions. CONCLUSIONS: Treatment of abdominal wall fascial incisions with TGF-beta(2) prevented the development of incisional hernias in this rat model. TGF-beta(2) stimulated fascial macrophage and fibroblast chemotaxis as well as acute wound collagen production. A biological approach such as this may reduce the incidence of incisional hernia formation in humans.


Subject(s)
Hernia, Ventral/prevention & control , Postoperative Complications/prevention & control , Transforming Growth Factor beta/pharmacology , Abdominal Muscles/surgery , Animals , Disease Models, Animal , Hernia, Ventral/drug therapy , Hernia, Ventral/epidemiology , Incidence , Postoperative Complications/drug therapy , Postoperative Complications/epidemiology , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta2 , Wound Healing/drug effects
4.
Surgery ; 129(2): 203-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11174713

ABSTRACT

BACKGROUND: Optimal healing of the fascial layer is a necessary component of complete abdominal wall repair. The majority of acute wound healing studies have focused on the dermis. We designed a model of abdominal wall repair that, to our knowledge, for the first time simultaneously characterizes differences in the wound healing trajectories of the fascia and skin. METHODS: Full-thickness dermal flaps were raised on the ventral abdominal walls of rats, and midline fascial celiotomies were completed. The dimensions of the flap were developed so as to have no detrimental effect on skin healing. The dermal flaps were replaced so that the fascial incisions would heal separately from the overlying skin incisions. Animals were killed 7, 14, and 21 days after operation and fascial and dermal wounds were harvested and tested for breaking strength. Fascial and dermal wounds were also compared histologically for inflammatory response, fibroplasia, and collagen staining. RESULTS: Fascial wound breaking strength exceeded dermal wound breaking strength at all time points (9.16 +/- 2.17 vs 3.51 +/- 0.49 N at 7 days, P <.05). Fascial wounds also developed greater fibroblast cellularity and greater collagen staining 7 days after the incision. There was no difference in wound inflammatory response. CONCLUSIONS: Fascial incisions regain breaking strength faster than simultaneous dermal incisions. The mechanism for this appears to involve increased fascial fibroplasia and collagen production after acute injury.


Subject(s)
Abdominal Muscles/surgery , Dermatologic Surgical Procedures , Fasciotomy , Wound Healing , Abdominal Muscles/pathology , Animals , Fascia/pathology , Male , Models, Animal , Rats , Rats, Sprague-Dawley , Skin/pathology , Surgical Flaps , Surgical Wound Dehiscence/pathology , Tensile Strength , Time Factors
5.
J Surg Res ; 95(1): 54-60, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11120636

ABSTRACT

BACKGROUND: Abdominal wall wound failure remains a common surgical problem. The signals that activate normal fibroplastic repair versus regeneration pathways are unknown. Transforming growth factor beta levels rise during incisional healing but fall during hepatic regeneration. Changes in the injured host cytokine milieu may therefore differentially effect abdominal wall repair versus hepatic regeneration. MATERIALS AND METHODS: Forty-eight rats were divided into four groups (n = 12). Groups 1-3 underwent sham celiotomy, 70% hepatectomy, or 80% enterectomy with anastamosis. Incisions from Group 4 were treated with either 1 microg of transforming growth factor beta(2) (TGF-beta(2)) or vehicle following hepatectomy. Isolated fascial and dermal incisions were harvested and tested for breaking strength on POD 7. Serum (TGF-beta(2)) and hepatocyte growth factor (HGF) levels were measured by ELISA. RESULTS: Recovery of incisional wound breaking strength was delayed following hepatectomy but not enterectomy (P<0.002). The inhibitory effect was observed in both the fascia and the dermis of the abdominal wall. TGF-beta(2) levels were depressed in hepatectomy animals on POD 7, while at the same time HGF levels were elevated. Exogenous TGF-beta(2) shifted the healing trajectory of deficient wounds back toward a control pattern. CONCLUSION: Abdominal wall fascial and dermal healing is delayed during hepatic regeneration. Elevated HGF and depressed TGF-beta(2) suggest a host mechanism that prioritizes hepatic parenchymal regeneration over fibroplastic repair (scar). Observations such as these are needed as therapeutic wound healing enters the clinical realm.


Subject(s)
Abdominal Muscles/injuries , Liver Regeneration , Wound Healing , Animals , Body Weight , Eating , Hepatectomy , Hepatocyte Growth Factor/blood , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta/blood
6.
J Surg Res ; 92(1): 11-7, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10864475

ABSTRACT

BACKGROUND: The time required for incisional healing accounts for the majority of postoperative pain and convalescence. Impaired healing prolongs the process further. If a method for accelerating acute incisional wound healing could be developed, patients would benefit from decreased wound failure and an earlier return to their premorbid condition. MATERIALS AND METHODS: In a rat dermal model, cytokine or vehicle infiltration prior to incision was performed using a single dose or four daily doses preincision. Planned incision sites were primed with the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) or platelet-derived growth factor BB (PDGF-BB) in an effort to activate the inflammatory phase of healing prior to wounding. At the time of incision closure, one half of the incisions were treated with transforming growth factor beta(2) (TGF-beta(2)). Incisional sites were biopsied and stained with hematoxylin and eosin and immunohistochemistry for inflammatory cells and fibroblast populations and breaking strength was measured. RESULTS: Priming skin with GM-CSF or PDGF-BB mimicked the early inflammatory phase of wound healing. Macrophage staining (EB1) and fibroblast staining (vimentin) were significantly increased prior to incision. Inflammatory priming as well as priming coupled with TGF-beta(2) at the time of the incision closure synergistically improved breaking strength. CONCLUSION: This study demonstrates that sequential therapy consisting of priming of tissue with an inflammatory cytokine followed by application of a proliferative cytokine at the time of incision closure nearly doubles the breaking strength of an acute wound. By manipulating the inflammatory and early proliferative phases of wound healing with tissue growth factors, it may be possible to accelerate acute wound repair and shift the wound healing trajectory to the left.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Transforming Growth Factor beta/pharmacology , Wound Healing/drug effects , Wound Healing/immunology , Animals , Anticoagulants/pharmacology , Becaplermin , Dermis/cytology , Dermis/drug effects , Dermis/immunology , Fibroblasts/cytology , Injections, Intradermal , Male , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , Rats , Rats, Sprague-Dawley , Surgical Procedures, Operative
7.
Wound Repair Regen ; 8(6): 511-6, 2000.
Article in English | MEDLINE | ID: mdl-11208178

ABSTRACT

Accurate and clinically practical methods for measuring the progress of acute wound healing is necessary before interventions designed to optimize and even accelerate acute wound healing can be applied. Complete wound closure rates and operative wound closure severity are irrelevant to most acute wounds since most are closed at the time of primary tissue repair and remain closed throughout healing. Analogous to chronic wound closure, the rate of increase of incision tensile strength progressively decreases as time passes and 100% unwounded tissue strength is never achieved making the endpoint definition of "healed" vague. Conceptualizing acute wound healing in terms of its design elements with reintegration into a final outcome lends itself to the description of acute wound healing as a mathematical trajectory. Frequently such an equation is a rate expressing the change in an acute healing parameter, most often tensile strength, over time. Such an approach also normalizes misinterpretations in analysis or errors in theory developed by measuring healing parameters at fixed points in time. Distributions of fractional strength gain times (e.g., 85% normal strength) can be determined using statistical methodology similar that used for failure time of survival analysis. Preclinical studies show that acute wound healing trajectories can be shifted to the left from a "normal" or "impaired" curve to an accelerated or more "ideal" curve. A useful method for measuring acute wound healing outcomes is therefore required before the basic science of acute wound healing is inevitably applied to the problem of acute surgical wounds.


Subject(s)
Wound Healing/physiology , Acute Disease , Collagen/metabolism , Humans , Prognosis , Sensitivity and Specificity , Surgical Wound Dehiscence/prevention & control , Tensile Strength , Time Factors
8.
J Gastrointest Surg ; 4(6): 614-9, 2000.
Article in English | MEDLINE | ID: mdl-11307097

ABSTRACT

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


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Metalloendopeptidases/antagonists & inhibitors , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/mortality , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Thiophenes/pharmacology , Adenocarcinoma/pathology , Animals , Biopsy, Needle , Confidence Intervals , Disease Models, Animal , Humans , Immunohistochemistry , Mice , Mice, Nude , Neoplasms, Experimental , Pancreatic Neoplasms/pathology , Reference Values , Statistics, Nonparametric , Survival Rate , Treatment Outcome
9.
Surgery ; 124(2): 218-23; discussion 223-4, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9706141

ABSTRACT

BACKGROUND: The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers. METHODS: We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model. RESULTS: Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P < .01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01). CONCLUSIONS: Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.


Subject(s)
Adenocarcinoma/therapy , Genetic Therapy , Isoenzymes/genetics , Pancreatic Neoplasms/therapy , Protein Kinase C/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Animals , Carcinogenicity Tests , DNA, Antisense/pharmacology , DNA, Complementary/pharmacology , Disease Models, Animal , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Isoenzymes/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Protein Kinase C/metabolism , Protein Kinase C-alpha , RNA, Messenger/genetics , Survival Analysis , Tumor Cells, Cultured/enzymology
10.
Dig Dis Sci ; 42(8): 1783-8, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9286248

ABSTRACT

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet. Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting. Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models, coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P < 0.001). IL-1 beta and TNF-alpha were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle. A significant delay between pancreatic and distant organ cytokine production was always observed. It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific, correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.


Subject(s)
Cytokines/biosynthesis , Pancreatitis/metabolism , Actins/biosynthesis , Acute Disease , Animals , Female , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Liver/metabolism , Lung/metabolism , Male , Mice , Mice, Inbred Strains , Pancreas/metabolism , Pancreatitis/physiopathology , Pancreatitis, Acute Necrotizing/metabolism , Pancreatitis, Acute Necrotizing/physiopathology , Spleen/metabolism , Tumor Necrosis Factor-alpha/biosynthesis
11.
J Surg Res ; 69(2): 367-71, 1997 May.
Article in English | MEDLINE | ID: mdl-9224409

ABSTRACT

Matrix metalloproteinases (MMP) are enzymes responsible for extracellular matrix degradation, a critical component influencing the growth and metastatic potential of cancer. The purpose of this study was to determine the in vitro effects of MMP inhibition on human pancreatic cancer cells and to document its effect on cancer growth in vivo. The effect of MMP inhibition was determined using the MMP inhibitor BB-94 and a moderately differentiated pancreatic cancer cell line (HPAC). In vitro, a dose response curve was generated over 5 days utilizing the MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. In vivo, using an established orthotopic model for pancreatic cancer (LD100 = 80 days), 22 nude mice with orthotopic tumors (30 were implanted) received either BB-94 or vehicle beginning 4 days prior to implantation and continuing to death or sacrifice on Day 70. Mice were weighted weekly. At death/sacrifice, tumors were weighted, volume determined, and metastases/ distant spread documented. In vitro, BB-94 had little effect on HPAC proliferation at 40 ng/ml but achieved progressively greater to near complete inhibition at doses up to 4000 ng/ml while maintaining cell viability. In vivo, BB-94 significantly increased length of survival (69 +/- 0.1 days vs. 56 +/- 3.1 days) and necropsy weight (25.7 +/- 1.67 g vs. 19.8 +/- 1.14 g) while decreasing metastatic rate (1 vs. 20) and tumor size (0.14 +/- 0.02 g vs. 0.65 +/- 0.1 g). MMP inhibition limits HPAC proliferation in a dose-dependent fashion without direct cytotoxic effects in vitro. Mice harboring orthotopic tumors treated with BB-94 demonstrated significant reductions in tumor weight, volume, and metastases which corresponded to increased animal weight and prolonged survival.


Subject(s)
Metalloendopeptidases/antagonists & inhibitors , Pancreatic Neoplasms/pathology , Phenylalanine/analogs & derivatives , Protease Inhibitors/pharmacology , Thiophenes/pharmacology , Animals , Humans , Mice , Neoplasm Metastasis , Neoplasm Transplantation , Pancreatic Neoplasms/enzymology , Phenylalanine/pharmacology , Tumor Cells, Cultured
12.
Ann Surg Oncol ; 3(6): 564-9, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8915489

ABSTRACT

BACKGROUND: The signal transduction pathways important in regulating the growth and differentiation of malignant cells are poorly understood. Recent evidence has implicated activation of the protein kinase C (PKC) family of signaling proteins in pancreatic carcinoma during cytokine-induced cytostasis and differentiation. METHODS: A human pancreatic adenocarcinoma (HPAC) cell line was exposed to tumor necrosis factor-alpha (TNF-alpha; 40 ng/ml) for 6 days. Cytostasis and viability were confirmed by daily MTT [(3(4,5)-dimethyl-thiazol-2-yl) 2,5-diphenyl-tetrazolium bromide] and trypan exclusion assay. Protein fractions were isolated daily and subjected to immunoblot analysis for the normal (terminally differentiated) pancreatic ductal cell marker carbonic anhydrase II (CA II) as well as specific PKC isoforms (alpha, beta, gamma, eta, and zeta). RESULTS: Growth arrest occurred in HPAC cells after exposure to TNF-alpha for 48 h, with viability maintained above 90% throughout the 6-day time course. CA II immunoreactivity was not detected in untreated controls but appeared after 2 days of TNF-alpha exposure, peaking on day 6. Concurrently, TNF-alpha induced the selective downregulation of PKC-alpha, whereas PKC-gamma levels increased. PKC-beta and PKC-eta immunoreactivity did not change. The atypical PKC-zeta isoform developed a doublet banding pattern in response to TNF-alpha, although overall PKC-zeta levels did not change. CONCLUSIONS: TNF-alpha-induced growth arrest and differentiation in HPAC cells is associated with the selective downregulation of PKC-alpha and upregulation of PKC-gamma.


Subject(s)
Carcinoma, Ductal, Breast/enzymology , Carcinoma, Ductal, Breast/pathology , Isoenzymes/analysis , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Protein Kinase C/analysis , Carbonic Anhydrases/analysis , Cell Differentiation/drug effects , Cell Line , Humans , Protein Kinase C beta , Protein Kinase C-alpha , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/pharmacology
13.
Surgery ; 120(3): 515-21, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8784406

ABSTRACT

BACKGROUND: Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host. METHODS: With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily. RESULTS: Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockade (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters. CONCLUSIONS: Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.


Subject(s)
Pancreatitis/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Acute Disease , Animals , Female , Interleukin-1/blood , Interleukin-6/blood , Mice , Receptors, Tumor Necrosis Factor/physiology , Time Factors
15.
Arch Surg ; 130(9): 966-70, 1995 Sep.
Article in English | MEDLINE | ID: mdl-7661681

ABSTRACT

OBJECTIVE: To examine the intrapancreatic production of tumor necrosis factor (TNF) alpha and define its cell of origin during acute pancreatitis. DESIGN: Acute necrotizing pancreatitis was induced in adult male mice by administering cerulein (50 micrograms/kg intraperitoneally four times over 3 hours). Animals were killed at 0, 0.5, 1, 2, 4, 6, and 8 hours, with the severity of pancreatitis established by blind histologic grading and serum amylase, lipase, and TNF levels. The expression of TNF messenger RNA within the pancreas was established by the reverse transcription polymerase chain reaction. Intrapancreatic TNF protein was analyzed by enzyme-linked immunosorbent assay, Western blot, and immunohistochemical methods. RESULTS: Acute pancreatitis was manifest within 1 hour of the first cerulein injection and increased in severity through 8 hours. There was no constitutive expression of TNF messenger RNA within the pancreas, but transcripts were induced within 30 minutes following the onset of pancreatitis, increasing through 4 hours. Intrapancreatic and serum TNF peptide levels became detectable at 1 hour and increased over 6 hours (both P < .001 vs control), with intrapancreatic levels rising faster and attaining concentrations three times higher than time-matched serum levels (P < .01). Immunohistochemical staining demonstrated the progressive infiltration of macrophages into the pancreas that stained heavily for TNF (P < .01 vs control). CONCLUSIONS: Tumor necrosis factor gene expression is induced locally during acute pancreatitis, resulting in large amounts of intrapancreatic TNF with levels consistently higher than those found in the serum. The overall rise in both tissue and serum TNF concentrations correlates directly with the severity of pancreatic damage and inflammation. The infiltrating macrophage appears to contribute most to this process.


Subject(s)
Pancreatitis/genetics , Tumor Necrosis Factor-alpha/biosynthesis , Acute Disease , Animals , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Gene Expression , Immunohistochemistry , Male , Mice , Pancreas/chemistry , Pancreas/metabolism , Pancreas/pathology , Pancreatitis/metabolism , RNA, Messenger/analysis , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/genetics
16.
Ann Surg ; 221(6): 625-31; discussion 631-4, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7794067

ABSTRACT

OBJECTIVE: This study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. SUMMARY BACKGROUND DATA: Previous studies have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known. METHODS: A lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received 100/microL normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time 0; IL-1ra late mice received IL-1ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-alpha, IL-1ra, pancreatic wet weight, and blind histopathologic grading. RESULTS: The 10-day mortality in the untreated control group was 73%. Early and late IL-1ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). Interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all p < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. CONCLUSIONS: Early or late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.


Subject(s)
Cytokines/antagonists & inhibitors , Pancreatitis/drug therapy , Pancreatitis/mortality , Receptors, Interleukin-1/antagonists & inhibitors , Sialoglycoproteins/therapeutic use , Acute Disease , Animals , Choline/administration & dosage , Ethionine/administration & dosage , Female , Interleukin 1 Receptor Antagonist Protein , Mice , Pancreatitis/pathology , Severity of Illness Index
17.
Am Surg ; 61(1): 40-4, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7832380

ABSTRACT

The early diagnosis of acute appendicitis before progression to gangrene or abscess formation is recognized as important to minimize morbidity from this common disease process. As our population ages, the challenge for expedient diagnosis and intervention in older age groups will become more significant. Prompted by recent unexpected complications occurring in elderly patients, we reviewed 100 consecutive admissions with the diagnosis of appendicitis to a tertiary Veterans Administration hospital. All patients were males and were arbitrarily divided into three age groups: less than 50, 50-70, and greater than 70 years of age. There were no patients less than 20 years old. Operative findings were classified as simple acute appendicitis, ruptured or perforated appendicitis, appendicitis associated with intra-abdominal abscess, and finally other when the operative diagnosis differed from appendicitis. Of the 37 patients less than 50 years of age, 28 were found to have simple acute appendicitis, making this by far the most common finding in this age group (P < 0.05). Only two of the 18 patients aged 50-70 with appendicitis demonstrated simple acute appendicitis, with the remainder having progressed to perforation or abscess formation (P < 0.05). Patients greater than 70 years of age were significantly more likely than any other age group to manifest appendicitis associated with intra-abdominal abscess (10 of 19, P < 0.05). Eight patients died in this series, six of whom were more than 70 years of age. In most cases, mortality was directly attributable to infectious complications of perforated appendicitis. There were no deaths in the under 50 age group.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Abdominal Abscess , Appendicitis , Intestinal Perforation , Abdominal Abscess/complications , Abdominal Abscess/diagnosis , Abdominal Abscess/epidemiology , Abdominal Abscess/surgery , Acute Disease , Age Factors , Aged , Aged, 80 and over , Appendicitis/complications , Appendicitis/diagnosis , Appendicitis/epidemiology , Appendicitis/surgery , Cause of Death , Diagnostic Errors , Humans , Incidence , Intestinal Perforation/complications , Intestinal Perforation/diagnosis , Intestinal Perforation/epidemiology , Intestinal Perforation/surgery , Male , Middle Aged , Morbidity , Patient Acceptance of Health Care , Rupture, Spontaneous , Survival Rate
18.
Biochem Biophys Res Commun ; 205(3): 1815-21, 1994 Dec 30.
Article in English | MEDLINE | ID: mdl-7529022

ABSTRACT

TNF is a 17kD cytokine classically known for its cytotoxic effects on malignant cells. More recent cell culture studies demonstrated TNF induced cytostasis associated with the expression of a terminally differentiated phenotype. This was best characterized in malignant hematopoietic models, although a similar action on cells derived from solid tumors is now increasingly recognized. In the present study, six day exposure to TNF (40 ng/ml) stimulated morphologic changes in a human pancreatic adenocarcinoma cell line (HPAC), including increased cellular homogeneity, decreased nuclear to cytoplasmic ratio and detachment from the cell monolayer. Proliferation and DNA synthesis were reversibly inhibited while cellular viability was maintained. Parallel to the changes in morphology and growth was the delayed appearance of carbonic anhydrase II (CA II, E.C. 4.2.1.1), an accepted marker for pancreatic cells of ductal origin. A concomitant increase in the steady-state level of CA II mRNA was also observed over the time-course of TNF exposure. These results suggest a novel role for TNF in the induction of a more terminally differentiated ductal cell phenotype in a human pancreatic carcinoma model.


Subject(s)
Adenocarcinoma/enzymology , Carbonic Anhydrases/biosynthesis , Pancreatic Neoplasms/enzymology , Tumor Necrosis Factor-alpha/pharmacology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Amylases/metabolism , Biomarkers, Tumor/metabolism , Carbonic Anhydrases/genetics , Cell Differentiation/drug effects , Cell Division/drug effects , Chromogranin A , Chromogranins/metabolism , DNA, Neoplasm/biosynthesis , Gene Expression Regulation, Enzymologic/drug effects , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/enzymology , Tumor Cells, Cultured/pathology
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