Biomedical subjects

J Werner

Publications and source records attributed to J Werner.

At least 73 records · Page 4Linked to original sources

PubMed2000

Assessment of the chronotropic response at the anaerobic threshold: an objective measure of chronotropic function.

The evaluation of the heart rate response to exercise is important for the diagnosis of chronotropic incompetence and the assessment of a rate responsive algorithm of sensor-controlled pacemakers. The aim of the present study was to examine a classification of the chronotropic response at an individually moderate exercise level. Sixteen pacemaker patients (patient group, age 62.9 +/- 7.6 years) with sick sinus syndrome and 15 age-matched healthy subjects (control group, age 57.6 +/- 9.4 years) underwent a maximum cardiopulmonary exercise test on a treadmill after a protocol with individually selected incremental steps. To analyze the patients' intrinsic heart rate response, the rate responsive mode of the pacemaker was switched off. Chronotropic incompetence was diagnosed in eight patients whose maximal heart rate was < 80% of the age-predicted heart rate. The heart rate at the anaerobic threshold was significantly lower in the chronotropically incompetent subgroup than in the chronotropically competent patients and the healthy subjects (85.9 +/- 6.6 beats/min vs 100.3 +/- 9.9 beats/min and 112.9 +/- 11.7 beats/min, respectively). The chronotropic slope of the heart rate reserve as a function of the metabolic reserve was significantly higher in the control group than in the patient groups with either mild or severe chronotropic incompetence (0.94 +/- 0.17 vs 0.64 +/- 0.08 and 0.43 +/- 0.14, respectively). Furthermore, the chronotropically incompetent response could be divided into a linear type with and without a threshold, an exponential, and a logarithmic type. The anaerobic threshold was an objectively detectable breakpoint at an individually moderate exercise level that could be used for characterization of chronotropic function. At the anaerobic threshold, a physiological heart rate response was about 220--age--50 beats/min. A deviation of more than 10 beats/min below this physiological value characterized chronotropic incompetence.

Algorithms↗

PubMed2000

[Psychotherapeutic and psychosocial therapy in general practice. Results of demonstration project on quality management in psychosocial primary care].

Since 1987, psychosocial primary care (PPC) provided by General Practitioners, are reimbursed by German health insurances. The aim of the psychosocial primary care is to improve recognition and treatment of mental disorders in the primary care sector. As a part of a eight-center national demonstration program on quality management in the outpatient services, General Practitioners (n = 191) from 5 regions participated in the study. 1341 treatment episodes of patients with predominately psychosocial strain were documented. Differences between psychosocial strain, treatment and outcome were determined by analyses of variance. Men and patients beyond the age of 65 were underrepresented. Psychosocial treatments were offered more often to those patients, who had the highest level of anxiety and depression. Patients with physical illness, with pain and without psychological attribution to the illness belief were offered less psychosocial interventions and reached a worse outcome. The study outcome helps to improve training programs as to recognition and treatment of psychosocial problems in primary care. Male and generally elderly patients with somatic symptoms and lack of psychological attribution need a special psychosocial intervention to improve the outcome.

Adult↗

PubMed2000

Vascular structure and microcirculation of experimental pancreatic carcinoma in rats.

OBJECTIVE: To study angiogenesis and microcirculation in experimental pancreatic carcinoma. DESIGN: Open experimental study. SETTING: 2 University hospitals, Germany and USA. ANIMALS: 16 male Lewis rats. INTERVENTIONS: Induction of a duct-like pancreatic cancer in the pancreas and peritoneum by interposition of fragments of tumour between 2 inert transparent polymethylmethacrylate plates. MAIN OUTCOME MEASURES: Microcirculation in the tumour and interaction between leucocytes, tumour, and endothelium investigated by intravital microscopy. RESULTS: The density of vessels in the carcinoma was significantly less than in normal pancreatic tissue (p = 0.0004). The vasculature of the tumour was characterised by a lack of differentiation in architecture of vessels, formation of sinusoidal and lacunar vessels and sudden changes in diameter of vessels. Red blood cell velocity differed among tumour vessels, but mean values were similar to those of normal exocrine pancreas. The mixed lymphocyte culture test indicated that the cell line DSL6A was immunogenic. However, high-affinity leucocyte-endothelium-interaction was significantly reduced in the tumour's microcirculation after both orthotopic and heterotopic implantation (p = 0.002). Rates of apoptosis were suppressed in heterotopic tumours compared with orthotopic ones. Tumour growth was faster in heterotopic tumours. CONCLUSIONS: Experimental duct-like pancreatic carcinoma can be differentiated from normal pancreas by: chaotic arrangement of vessels with loss of differentiation of architecture and heterogeneous distribution; the formation of sinusoidal or lacunar vessels; lower vascular density with similar erythrocyte velocity; increase in mean diameter of vessels; reduced leucocyte-endothelium interaction despite confirmed immunogeneity independent of wall shear rates. The site of implantation influences apoptosis and growth rates.

Animals↗

PubMed2000

Cigarette smoke enhances ethanol-induced pancreatic injury.

Alcohol induces pancreatic ischemia, but the mechanisms promoting pancreatic inflammation are unclear. We investigated whether cigarette smoke inhalation is a cofactor in the development of ethanol-induced pancreatic injury. Cigarette smoke was administered to anesthetized rats alone or in combination with intravenous ethanol infusion. Control animals received either saline or ethanol alone. Pancreatic capillary blood flow and leukocyte-endothelium interaction in postcapillary venules were evaluated by intravital microscopy. Leukocyte sequestration was assessed by measurement of myeloperoxidase activity in pancreatic tissue, and pancreatic injury evaluated by histology. Ethanol decreased pancreatic blood flow progressively over 90 minutes (p < 0.001 vs. baseline), but neither leukocyte-endothelium interaction nor leukocyte sequestration was altered. Cigarette smoke alone reduced pancreatic blood flow temporarily (p < 0.01 vs. baseline) and increased leukocyte-endothelium interaction (roller p < 0.001, sticker p < 0.01 vs. baseline). Cigarette smoke potentiated the impairment of pancreatic capillary perfusion caused by ethanol, and both the number of rolling leukocytes and myeloperoxidase activity levels were increased compared to ethanol or nicotine administration alone (p < or = 0.05 and p < or = 0.01, respectively). This study demonstrates that ethanol induces pancreatic ischemia and that cigarette smoke leads to both temporary pancreatic ischemia and minimal leukocyte sequestration. Cigarette smoke potentiates the amount of pancreatic injury generated by ethanol alone. Smoking therefore seems to be a contributing factor in the development of alcohol-induced pancreatitis in the rat model.

Animals↗

PubMed2000

Absence of herpesvirus DNA by polymerase chain reaction in ocular fluids obtained from immunocompetent patients.

OBJECTIVE: To assess the prevalence of herpesvirus DNA in ocular fluids obtained from healthy patients undergoing vitreoretinal surgery. BACKGROUND: Polymerase chain reaction (PCR) has been used to detect herpesvirus DNA in patients with acute retinal necrosis and cytomegalovirus retinitis. Little is known regarding the prevalence of detectable herpesvirus DNA in ocular fluids collected from healthy seropositive patients with no clinical evidence of viral retinitis. METHODS: Seventy-five intraocular specimens (35 aqueous and 40 vitreous samples) were collected from 75 patients undergoing scleral buckling or vitrectomy. Using a PCR-based assay, the authors tested each specimen for the presence of herpesvirus genome DNA with primers specific for cytomegalovirus, Epstein-Barr virus, herpes simplex virus types 1 and 2, and varicella zoster virus. Serologic testing for immunoglobulin G (IgG) and IgM levels corresponding to each of the herpesviruses was also performed. RESULTS: Of the 75 samples tested, none was found to harbor herpesvirus DNA. The assay did not give false-positive results in patients with active intraocular inflammation. The sensitivity of the assay was 0.08 infection-forming units for cytomegalovirus, 0.6 tissue culture infectious doses for herpes simplex virus, 0.5 infected-cell equivalents for Epstein-Barr virus, and 0.03 focus-forming units for varicella zoster virus. The percentage of patients with positive herpesvirus serology ranged from 86% to 100% and was consistent with rates observed in the general population. CONCLUSIONS: The prevalence of herpesvirus DNA detectable by PCR techniques in ocular fluids appears to be quite low despite the high proportion of patients who tested positive for herpesvirus antibodies. Therefore, a positive result obtained in a patient presenting with vitreoretinal inflammation should be regarded as significant.

Adolescent↗

PubMed2000

Influence of gastrointestinal hormones on tumor microcirculation of experimental pancreatic cancer in the rat.

BACKGROUND/AIMS: Gastrointestinal hormones influence the microcirculation in the normal pancreas. In the present study, we studied the effect of cerulein and somatostatin on pancreatic cancer microcirculation after orthotopic and nonorthotopic tumor implantation. METHODS: In 36 male Lewis rats (150-180 g) induction of a ductlike pancreatic cancer was achieved by intrapancreatic or intraperitoneal tumor fragment interposition between two inert transparent polymethyl methacrylate plates. After 4 weeks, intravital microscopy of the tumor microcirculation was performed in a temperature-controlled immersion chamber. The animals received 5 microg/kg cerulein or 3 mg/kg somatostatin for 1 h intravenously. The erythrocyte velocity in normal pancreatic capillaries or in tumor vessels was measured. RESULTS: The erythrocyte velocity in the capillaries of the normal pancreas was 1.01 +/- 0.11 mm/s at baseline and increased to 1.64 +/- 0.09 mm/s after cerulein stimulation (p = 0.007). Pancreatic cancer vessels demonstrated no increase in erythrocyte velocity after orthotopic (baseline 0.95 +/- 0.14 mm/s, after 1 h 0.86 +/- 0.13 mm/s; n.s.) and nonorthotopic tumor implantation (baseline 0.91 +/- 0.12 mm/s, after 1 h 0.95 +/- 0.14 mm/s; n.s.) after cerulein stimulation. Somatostatin decreased the erythrocyte velocity both in normal pancreas (baseline 0.87 +/- 0.02 mm/s, after 1 h 0.60 +/- 0.07 mm/s; p = 0.01) and in pancreatic cancer (baseline 0.85 +/- 0.20 mm/s, after 1 h 0.63 +/- 0.18 mm/s; p = 0.02) after orthotopic tumor implantation. There was no effect of somatostatin after nonorthotopic tumor implantation (baseline 0.90 +/- 0.10 mm/s, after 1 h 0.88 +/- 0.14 mm/s; n.s.). CONCLUSION: These data suggest that pancreatic cancer microcirculation lacks physiological blood flow control by stimulatory hormones, in contrast to the normal pancreas.

Animals↗

PubMed2000

Differences in the fatty acid composition of fatty acid ethyl esters in organs and their secretions.

BACKGROUND: Fatty acid ethyl esters (FAEE) are nonoxidative ethanol metabolites that have been shown to be long term markers of ethanol intake and have been implicated as mediators of ethanol-induced cell injury. Previous studies have indicated that the fatty acid composition of the FAEE found in the plasma of human subjects after ethanol ingestion is predominantly ethyl palmitate and ethyl oleate. This raised the possibility that there is some selectivity toward the fatty acid used for FAEE to be exported from the liver into the blood. METHODS: To address the hypothesis that the fatty acid composition of FAEE secreted from organs, such as the liver and pancreas, differs from the fatty acid composition of FAEE in the organs, this study was performed using rats that received ethanol by intra-arterial infusion. RESULTS: It was found that the fatty acids in FAEE differed significantly in plasma versus liver, bile versus liver, and pancreatic secretions versus pancreas. CONCLUSIONS: These results indicate that organs selectively export certain FAEE species.

Animals↗

PubMed1999

Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats.

BACKGROUND & AIMS: Intracellular activation of trypsinogen is currently believed to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluated the significance of interstitial protease release and activation in this process. METHODS: In rats with cerulein-induced pancreatitis, concentrations of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular trypsinogen was induced by intravenous infusion of enterokinase, which does not enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soybean trypsin inhibitor (acinar cell nonpermeable) was administered to distinguish the effects of intracellular or extracellular protease activation. RESULTS: In cerulein pancreatitis, trypsinogen levels increased prominently and were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP increases in lymph and blood and in severe necrohemorrhagic pancreatitis. Gabexate mesilate as well as soybean trypsin inhibitor significantly decreased TAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups. CONCLUSIONS: In secretagogue-induced pancreatitis, large amounts of trypsinogen are present in the interstitium and drain via the portal and lymphatic circulation. Activation of this extracellular trypsinogen induces hemorrhagic necrosis in a setting of mild edematous pancreatitis. This phenomenon may be the central event in the progression to fulminant necrotizing pancreatitis.

Animals↗

PubMed1999

Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen-activated protein kinase occurs independently of IGF-I receptor kinase activation and IRS-1 tyrosine phosphorylation.

The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated through the insulin receptor. These cells, however, also have high-affinity binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the other hand, was ineffective at concentrations equivalent to the lowest effective insulin dose, although stimulation was observed with concentrations 100-fold higher. Similar results were obtained when glucose uptake was measured. Western blot analysis demonstrated that tyrosine phosphorylation patterns produced by insulin and IGF-I differed. In particular, phosphorylation of insulin receptor substrate-1 (IRS-1) was evident after treatment with insulin, but not after treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated receptor tyrosine kinase activity. In contrast with these results, both insulin and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and activity at a concentration of 10 nM. The correlation between insulin-dependent and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis of phosphorylated MAP kinase kinase (MEK). These results suggest that phosphorylation of IRS-1 is essential for both cell proliferation and glucose metabolism, but is uncoupled from the MAP kinase cascade. Furthermore, stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase activity.

Animals↗

PubMed1999

Multi-loop control of liquid cooling garment systems.

In this study the effects of multi-loop control of liquid cooling garments (LCGs) under exercise heat stress conditions were investigated by experiments and theoretical analysis. A triple-loop LCG, by which the torso, arms and legs could be independently cooled, was used in the two series of experiments carried out in a hot environment (35 degrees C/40% RH). The experiment consisted of rest, exercise on an ergometer at 70 W and exercise at 110 W. In the first experiment, each water inlet temperature (TWI) was adjusted according to the local thermal sensation. In the second experiment, TWI for the torso including arms and TWI for the legs were regulated by a skin temperature controller with set-point adjustment via heart rate. The experiments showed that a multi-loop LCG is more effective than a single-loop LCG in providing thermal sensation and comfort adjusted to the requirements of the different parts of the body, and that a skin temperature controller could be applied to a multi-loop system. The theoretical analysis was carried out using a mathematical model of thermoregulation. The results showed that a strong cooling of the surface over the working muscles (legs) provided the greatest thermoregulatory advantage during low body exercise, because most of the heat generated within the working muscles can be removed directly by heat conduction to the skin. Optimization of a human/LCG system could be attained by an optimal configuration and control. However, an optimal configuration always depends on the application purpose of an LCG system.

Adult↗

PubMed1999

Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1.

OBJECTIVE: To analyze the time points and levels of the expression of adhesion molecules in the pancreas and lung in pancreatitis of different severities, and to assess whether treatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) can reduce local and systemic complications. BACKGROUND: The outcome of severe acute pancreatitis relates to its pulmonary and septic complications. Leukocyte adhesion and infiltration, both mediated by ICAM-1, are central events in the pathogenesis of necrotizing pancreatitis. METHODS: Expression of ICAM-1 at different time points was assessed by immunohistochemistry and Western blot analysis in pancreas and lungs from rats with mild edematous or severe necrotizing pancreatitis. ICAM-1 expression was correlated with leukocyte infiltration and histologic changes. The possible therapeutic effect of monoclonal antibodies against ICAM-1 was assessed by measuring pancreatic and lung injury. RESULTS: In edematous pancreatitis, increased ICAM-1 expression in pancreas was evident by 6 hours but did not occur in lung. In contrast, ICAM-1 was upregulated at 3 hours in the pancreas and at 12 hours in lung in necrotizing pancreatitis. Increased expression of ICAM-1 preceded leukocyte infiltration. Treatment of severe necrotizing pancreatitis with monoclonal antibodies against ICAM-1 decreased both local pancreatic injury and systemic lung injury compared with untreated controls. CONCLUSIONS: Upregulation of ICAM-1 and subsequent leukocyte infiltration appear to be significant mediators of pancreatic and pulmonary injury in pancreatitis, and both the onset and extent correlate with severity. The time course should permit effective prevention of tissue damage by treatment with ICAM-1 antibodies.

Acute Disease↗

PubMed1999

Restoration of cardio-circulatory regulation by rate-adaptive pacemaker systems: the bioengineering view of a clinical problem.

In the past, the development of rate-adaptive (sensor-controlled) pacemaker systems seems to have been determined primarily by the availability, compatibility and other properties of the technical sensor. This paper, however, focuses on the system-physiological aspect in an attempt to answer the question to what extent physiological cardiovascular control is restored by the pacemaker system. This is a question which should be asked before attempting to design a sensor-controlled system and especially before designing multisensor systems with infinite combinations. Four categories are defined: direct bridging ("shunting"), open loop systems, closed systems using cardiorespiratory or metabolic coupling and those using cardiac signals. Further subdivisions are shown. From the bioengineering as well as from the physiological viewpoint a system should preferably not combine sensors from one and the same of these categories. At present direct bridging is available only for the atrioventricular (AV)-block, so that for sick-sinus-syndrome (SSS) patients feedback control via cardiac signals ("inotropic" pacemaker) comes nearest the goal without, however, ideally bridging the gap. Open-loop systems should no longer be developed as single-sensor systems. A well developed activity sensor, however, which quickly pinpoints the most prominent stressor of cardiovascular control is best suited to complement another sensory system achieving closed-loop control. New and promising concepts orientated toward direct bridging are the analysis of monophasic action potentials and the "dromotropic" concept, both of which seek direct correlation with the "chronotropic" information not available in SSS patients.

Adaptation, Physiological↗

PubMed1999

Influence of the pacing rate on the atrioventricular conduction time during aerobic and anaerobic exercise: basic concepts for a dromotropically controlled rate responsive pacemaker.

The dromotropic pacemaker concept needs a rate responsive algorithm in which the pacing rate is controlled by the atrioventricular conduction time (AVCT). To develop basic concepts for such a rate responsive algorithm, the influence of the pacing rate on the AVCT was investigated. Seven patients (62 +/- 7.8 years) with sick sinus syndrome and intact atrioventricular conduction underwent two cardiopulmonary exercise tests (CPX) on a treadmill. According to the determination of the anaerobic threshold (AT) and the patients maximum capacity in the first incremental CPX the work rate for two exercise levels below and above the AT were chosen for the second constant workload CPX. The calculation of the optimal pacing rate (HRopt) was based on the oxygen uptake (VO2) during exercise after reaching steady-state conditions. According to the increase of the VO2 from 14.8 +/- 2.3 mL/min per kilogram during aerobic work (38.3 +/- 16.0 W) to 19.4 +/- 4.7 mL/min per kilogram during anaerobic work (80.6 +/- 32.3 W), the HRopt was calculated to be 98.6 +/- 6.9 beats/min and 116.4 +/- 4.7 beats/min. Starting from HRopt, the pacing rate was increased (overpacing) and decreased (underpacing) by about 5 beats/min every minute. At optimal pacing rate the AVCT decreased significantly from 233.0 +/- 30.5 ms during aerobic work and to 226.4 +/- 27.3 ms during anaerobic work (P < 0.05). Whereas overpacing induced a significant prolongation of the AVCT during aerobic work (4.17 +/- 1.78 ms per 10 beats/min) and anaerobic work (3.84 +/- 1.60 ms per 10 beats/min), underpacing yielded a significant shortening of the AVCT by about 4.49 +/- 2.64 ms per 10 beats/min during aerobic work and 4.75 +/- 1.87 ms per 10 beats/min during anaerobic work (P < 0.01). The slopes of the regression lines of the relationship between AVCT and pacing rate were not significantly. different. Based on the reciprocal relationship of heart rate (HR) and AVCT, basic concepts may be established for a dromotropic rate responsive algorithm.

Aged↗

PubMed1999

Relationship between atrioventricular delay and oxygen consumption in patients with sick sinus syndrome: relevance to rate responsive pacing.

To develop a dromotropic-controlled rate adaptive algorithm for patients with sick sinus syndrome (SSS) and intact AV conduction, 14 pace-maker patients with SSS underwent cardiopulmonary exercise testing (CPX). During exercise, the pace-maker was programmed in an AAT mode without rate adaptation, whereby 3 patients developed supraventricular arrhythmia and 11 patients kept sinus rhythm. Chronotropic incompetence (CI) at heart rate (HR) < 95 beats/min at the anaerobic threshold (AT) was found in five patients. In patients with chronotropic competence (CC), the HR increase was significantly greater than in CI patients (rest: 73.2 +/- 12.6 vs. 64.2 +/- 4.0 beats/min;AT:101.2 +/- 6.2 vs. 82.0 +/- 5.1 beats/min;peak: 135.2 +/- 10.7 vs. 103.2 +/- 10.9 beats/min). There was no significant difference in the AVD between CC and CI patients (rest: 167.7 +/- 38.6 vs. 170.8 +/- 22.5 ms, AT: 156.2 +/- 30.7 vs. 163.6 +/- 21.6 ms, peak: 144.7 +/- 29.0 vs. 152.4 +/- 15.0 ms). The correlation coefficient between HR increase and VO2 was +1.0 and between AVD decrease and VO2 - 1.0 in both groups. An increase in pacing rate from 75 beats/min to 120 beats/min without exercise (overpacing) led to a prolongation of the AV interval of about 30.6 +/- 14.2 ms. Based on this closed loop control with negative feedback, a dromotropic rate adaptive algorithm for patients with SSS and intact AV conduction could be developed.

Aged↗

PubMed1999

Microbial desulfurization of alkylated dibenzothiophenes from a hydrodesulfurized middle distillate by Rhodococcus erythropolis I-19.

Rhodococcus erythropolis I-19, containing multiple copies of key dsz genes, was used to desulfurize alkylated dibenzothiophenes (Cx-DBTs) found in a hydrodesulfurized middle-distillate petroleum (MD 1850). Initial desulfurization rates of dibenzothiophene (DBT) and MD 1850 by I-19 were 5.0 and 2.5 micromol g dry cell weight(-1) min(-1), more than 25-fold higher than that for wild-type bacteria. According to sulfur K-edge X-ray absorption near-edge structure (XANES) analysis, thiophenic compounds accounted for >95% of the total sulfur found in MD 1850, predominantly Cx-DBTs and alkylated benzothiophenes. Extensive biodesulfurization resulted in a 67% reduction of total sulfur from 1,850 to 615 ppm S. XANES analysis of the 615-ppm material gave a sulfur distribution of 75% thiophenes, 11% sulfides, 2% sulfoxides, and 12% sulfones. I-19 preferentially desulfurized DBT and C1-DBTs, followed by the more highly alkylated Cx-DBTs. Shifting zero- to first-order (first-order) desulfurization rate kinetics were observed when MD 1850 was diluted with hexadecane. Apparent saturation rate constant (K(0)) and half-saturation rate constant (K(1)) values were calculated to be 2.8 micromol g dry cell weight(-1) min(-1) and 130 ppm, respectively. However, partial biocatalytic reduction of MD 1850 sulfur concentration followed by determination of initial rates with fresh biocatalyst led to a sigmoidal kinetic behavior. A competitive-substrate model suggested that the apparent K(1) values for each group of Cx-DBTs increased with increasing alkylation. Overall desulfurization rate kinetics with I-19 were affected by the concentration and distribution of Cx-DBTs according to the number and/or lengths of alkyl groups attached to the basic ring structure.

Alkylation↗

PubMed1999

Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury.

Pancreatic proteases are secreted in acute pancreatitis, but their contribution to associated lung injury is unclear. Applying models of mild edematous (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycholic acid) pancreatitis in rats, we showed that both trypsinogen and trypsin concentrations in peripheral blood, as well as lung injury, correlate with the severity of the disease. To isolate the potential contribution of proteases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intravenous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activation worsened lung injury in mild pancreatitis. In vitro incubation of leukocytes with trypsinogen showed that stimulated leukocytes can convert trypsinogen to trypsin. In conclusion, this study demonstrates that the occurrence and severity of pancreatitis-associated lung injury (PALI) corresponds to the levels of circulating trypsinogen and its activation to trypsin. Neutrophils are involved in both protease activation and development of pulmonary injury.

Acute Disease↗

PubMed1999

Chemotactic peptide uptake in acute pancreatitis: correlation with tissue accumulation of leukocytes.

Chemotactic peptides bind specifically to receptors on leukocyte membranes. This property makes them prospective vehicles to evaluate inflammation and infection. We used two well-established models of acute pancreatitis to quantitate the binding of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine-lysine (fMLFK) to leukocytes and its correlation to degree of organ inflammation. Uptake of the (99m)Tc-labeled nicotinyl hydrazine-derivatized chemotactic peptide analog fMLFK-HYNIC was measured in blood, pancreas, lung, and muscle specimens in rats with edematous or necrotizing pancreatitis and was compared with neutrophil sequestration assessed by myeloperoxidase activity and histology. Chemotactic peptide uptake in the pancreas was increased in mild and severe pancreatitis compared with controls, with higher levels in severe than in mild disease, and correlated with tissue myeloperoxidase activity (r = 0.7395, P < 0.001). Increased pulmonary uptake only in severe pancreatitis reflected pancreatitis-induced neutrophil sequestration in the lungs. Muscle uptake was unchanged compared with controls. Edema formation did not affect chemotactic peptide uptake. The data suggest that uptake of chemotactic peptides can contribute to quantitative assessment of neutrophils in localized inflammatory processes and is independent of associated edema formation or microcirculatory compromise.

Animals↗

PubMed1999

Reduced basal and stimulated leukocyte adherence in tumor endothelium of experimental pancreatic cancer.

BACKGROUND: The interaction between immunocompetent cells and tumor endothelium is essential for an effective immunological response. In the present study, we evaluated resting and CD11b/CD18-mediated leukocyte adhesion in tumor vessels of experimental pancreatic cancer and in healthy pancreatic venules in the rat. METHODS: Solid tumor fragments (1 mm3) were interposed intrapancreatically between inert transparent polymethylmetacrylate plates for intravital microscopy (n = 12) by which tumor microcirculation, leukocyte-tumor-endothelium interaction, and the effect of the chemoattractants N-formyl-methioninleucylphenylalanine (fMLP) and platelet-activating factor (PAF) on leukocyte adherence was investigated. RESULTS: Leukocyte adhesion in pancreatic tumor vessels was significantly reduced compared to healthy pancreatic venules. Both fMLP and PAF dramatically increased leukocyte adherence in normal pancreatic venules. No change in leukocyte adhesion was present in tumor vessels after exposure to these chemotactic substances. CONCLUSION: Resting and stimulated integrin-dependent leukocyte adhesion is strongly reduced in malignant vessels of experimental pancreatic cancer, which may be an important mechanism to escape immune control.

Animals↗