Pentoxifylline and tumour necrosis factor-induced lung injury.
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Animals↗
Biomedical subjects
P Zabel
Publications and source records attributed to P Zabel.
[Therapy of sarcoidosis].
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Contraindications↗
Elimination of radiolabelled recombinant human insulin-like growth factor binding protein-3 from the circulation, and its distribution amongst organs and tissues in adult male rats.
Most insulin-like growth factor-I (IGF-I) in blood is found in complex with IGF binding protein-3 (IGFBP-3). An additional association of IGFBP-3 with an acid-labile subunit is thought to severely limit its ability to cross the vascular endothelium. However, it is not clear whether IGFBP-3 which is not complexed to acid-labile subunit can gain access to tissues and contribute to the transcapillary transport of IGF-I. We have investigated the concentration time profile of 125I-labelled recombinant, non-glycosylated human IGFBP-3 in the rat circulation, its appearance within various organs, urine, and in peritoneal lavage fluid. Radiolabelled IGFBP-3 was administered as a single infusion over 1 min into the catheterized jugular vein of male Wistar rats. Blood was sampled from the femoral artery, and urine by cannulation of the bladder for up to 3 h. The peritoneal cavity was cannulated to allow for the collection of lavage fluid. In a separate series of animals various organs were collected up to 3 h following administration of 125I-labelled IGFBP-3, and the content of radiolabel estimated by gamma spectrometry. Radiolabelled IGFBP-3 was rapidly cleared from the circulation initially (half-life 25 min), however from 70 min life to 3 h the levels of radiolabel remained constant. Neutral gel filtration on Sephadex G200 revealed that 1 h following administration the majority of the [125I]IGFBP-3 existed within a complex of 100-120 kDa, likely to represent an association with the acid-labile subunit. Radioactivity was detected in urine within 30 min of IGFBP-3 administration, was maximally present at 60 min, but declined thereafter. A proportion of the radiolabel in urine represented degraded protein fragments of IGFBP-3, although only 8% of the administered radiolabel was excreted within urine over 3 h. Within 10 min of entry into blood 125I-labelled IGFBP-3 was found within peritoneal lavage fluid. Most of the radiolabel was accumulated within the kidneys, liver, stomach and intestine up to 3 h after administration. However, while the hepatic and renal content were maximal after 30 min, stomach content continued to rise over 1 h, and stabilized at 15% of administered dose for up to 3 h. The results suggest that when not in complex with the acid-labile subunit, IGFBP-3 can rapidly cross capillary endothelia from blood to extravascular compartments. While kidney and liver are likely sites of excretion and degradation, a substantial proportion of IGFBP-3 is also accumulated by gastrointestinal tissues.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Isolation of a 6.2 kb genomic fragment carrying the Adh1 gene of tomato and its expression in transgenic tobacco.
An 11 kb Eco RI genomic fragment containing the alcohol dehydrogenase (Adh1) gene was cloned. Cross-hybridization with three Adh2 cDNA clones suggested that the entire coding region of the Adh1 gene was contained on a 6.2 kb Xba I/Hind III subfragment. Using RFLP linkage analysis, the genomic clone was mapped on chromosome 4 between the markers TG 182 and TG 65 in a position corresponding to the Adh1 locus. To further confirm the Adh1 origin of the genomic clone, tobacco plants were transformed with the 6.2 kb Xba I/Hind III genomic subfragment. Isozyme analysis demonstrated that in transgenic tobacco plants functional tomato specific ADH-1 homodimers were synthesized as well as heterodimers composed of tobacco and tomato subunits.
Alcohol Dehydrogenase↗
Long-range physical maps of two loci (Aps-1 and GP79) flanking the root-knot nematode resistance gene (Mi) near the centromere of tomato chromosome 6.
The root knot nematode resistance gene Mi in tomato has been mapped in the pericentromeric region of chromosome 6. With the objective of isolating Mi through a map-based cloning approach, we have previously identified and ordered into a high-resolution genetic linkage map a variety of tightly linked molecular markers. Using pulsed-field gelelectrophoresis and various rarely cutting restriction enzymes in single, double and partial digestions, we now report long-range physical maps of the two closest flanking markers, acid phosphatase-1 (Aps-1) and GP79, which span over 400 and 800 kb, respectively. It is concluded that the physical distance between both markers is larger than predicted on the basis of genetic linkage analysis. Furthermore, two RFLP markers (H3F8 and H4H10) which map genetically to the same locus as Aps-1 do not show physical linkage, indicating severe suppression of recombination in this region of the chromosome. Finally, no evidence was obtained showing the presence of a CpG island near Aps-1.
Acid Phosphatase↗
Inhibition of endogenous TNF formation by pentoxifylline.
During the last decade cytokines were recognized as focal components in acute and chronic inflammatory processes. The growing knowledge about these agents stimulated efforts to pharmacologically control their synthesis and action in clinical situations. Various rational approaches to these issues including selective antibodies or receptor antagonists are at present under clinical investigation. Recently, in our institute evidence was raised that pentoxifylline is able to suppress the synthesis of tumor necrosis factor-alpha in cell cultures, and in vivo, and to protect experimental animals against endotoxin shock. Extended studies in human experimental endotoxemia showed that pentoxifylline decreased circulating TNF without affecting endogenous formation of interleukins. The potency of this drug to interfere with TNF synthesis could also be demonstrated in cases of acute and chronic cytokine release-syndromes such as OKT3 first-dose reaction and severe pulmonary tuberculosis, respectively. In conclusion, we suggest that pentoxifylline may improve therapeutic strategies in septic syndrome and other diseases in which TNF represents a causative pathophysiological factor.
Animals↗
Integration of the classical and molecular linkage maps of tomato chromosome 6.
In the past, a classical map of the tomato genome has been established that is based on linkage data from intraspecific Lycopersicon esculentum crosses. In addition, a high density molecular linkage map has recently been constructed using a L. esculentum x L. pennellii cross. As the respective maps only partially match, they provide limited information about the relative positions of classical and molecular markers. In this paper we describe the construction of an integrated linkage map of tomato chromosome 6 that shows the position of cDNA-, genomic DNA- and RAPD markers relative to 10 classical markers. Integration was achieved by using a L. esculentum line containing an introgressed chromosome 6 from L. pennellii in crosses to a variety of L. esculentum marker lines. In addition, an improved version of the classical linkage map is presented that is based on a combined analysis of new linkage data for 16 morphological markers and literature data. Unlike the classical map currently in use, the revised map reveals clustering of markers into three major groups around the yv, m-2 and c loci, respectively. Although crossing-over rates are clearly different when comparing intraspecific L. esculentum crosses with L. esculentum x L. pennellii crosses, the clusters of morphological markers on the classical map coincide with clusters of genomic- and cDNA-markers on the molecular map constructed by Tanksley and coworkers.
Chromosome Mapping↗
[Therapeutic strategies against mediators of septic shock].
The growing knowledge on the pathophysiological role of cytokines in septic shock stimulated efforts to control their synthesis and action pharmacologically in clinical situations. Among the various compounds elaborated by monocytes/macrophages in response to endotoxins, tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1) have been recognized to be of particular importance for endotoxic effects. Therefore, therapeutic strategies in septic shock may benefit from antagonism or inhibition of these mediators. Anti-TNF-antibodies as well as pentoxifylline, an inhibitor of TNF synthesis, attenuated lethality provoked by endotoxin or sepsis in experimental animals. Furthermore, application of IL-1 receptor antagonist was able to counteract endotoxicity in animals. Based on these promising findings, controlled clinical studies have been started to define the precise clinical efficacy of the a.m. therapeutic strategies.
Animals↗
[Circadian rhythm in cytokines].
The well-known human circadian rhythm (CR) in body temperature may be due to CR in endogenous pyrogens such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF). We, therefore, investigated the daily variation in spontaneous and LPS-induced monokine release by peripheral blood cells (whole blood assay) in 10 healthy volunteers. Spontaneous release of monokines (IL-1, IL-6, TNF) showed a simultaneous significant peak at noon, whereas LPS-induced release of IL-1 and IL-6 was strictly correlated with the CR in body temperature with its significant maximum at 8.00 p.m. Since LPS-induced release of TNF showed a significant peak at 4.00 a.m., interleukins and TNF seem to be independently regulated. CR in IL-1 and IL-6 release are suggested to be responsible for the CR in body temperature.
Adult↗
Suppression of OKT3-induced tumor necrosis factor alpha formation by pentoxifylline in renal transplant recipients.
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Enzyme-Linked Immunosorbent Assay↗
[Tumor necrosis factor alpha in lung diseases].
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Adrenal Cortex Hormones↗
The root-knot nematode resistance gene (Mi) in tomato: construction of a molecular linkage map and identification of dominant cDNA markers in resistant genotypes.
A dominant allele at the Mi locus on chromosome 6 of tomato (Lycopersicon esculentum Mill) confers resistance to three species of root-knot nematodes (Meloidogyne). The resistance, which is associated with a localized necrotic response, was originally introduced into tomato from the wild species Lycopersicon peruvianum. As a step towards the molecular cloning of Mi, we have identified closely linked DNA markers from both cDNA and genomic DNA libraries as restriction fragment length polymorphisms (RFLPs). DNA from tomato populations segregating for nematode resistance was analyzed to generate a high-resolution genetic map of this region. Additional information on gene order was obtained by comparing the size of the introgressed L. peruvianum chromosomal segment within a collection of nematode-resistant tomato lines. Among the four cDNA markers that are tightly linked to Mi, three are dominant, i.e. L. peruvianum-specific. One cDNA marker corresponds to a gene family comprising 20-30 members, one of which is diagnostic for all nematode-resistant genotypes tested. The presence of non-homologous sequences around the Mi gene may contribute to the suppression of recombination in this region of the genome in crosses heterozygous for Mi. The potential of 'walking' from closely linked markers to Mi is discussed.
Animals↗
[Pentoxifylline--an inhibitor of the synthesis of tumor necrosis factor alpha].
The growing knowledge on the pathophysiological role of cytokines in acute and chronic inflammatory processes stimulated efforts to control their synthesis and action pharmacologically in clinical situations. Recently, in our institute evidence was raised that pentoxifylline (POF) is able to suppress the synthesis of tumor necrosis factor-alpha (TNF) in cell cultures, in vivo, and to protect experimental animals against endotoxin shock. Studies in human experimental endotoxemia showed that pentoxifylline decreased circulating TNF without affecting endogenous formation of interleukins. The potency of this drug to interfere with TNF synthesis could also be demonstrated in cases of acute and chronic cytokine release syndromes such as OKT3 first-dose reaction and severe pulmonary tuberculosis, respectively. We suggest that POF may improve therapeutic strategies in various diseases in which TNF was identified as a causative pathophysiological factor.
Adult↗
Acid phosphatase-1(1), a tightly linked molecular marker for root-knot nematode resistance in tomato: from protein to gene, using PCR and degenerate primers containing deoxyinosine.
With a view to cloning the root-knot nematode resistance gene Mi in tomato by chromosome walking, we have developed a molecular probe for the tightly linked acid phosphatase-1 (Aps-1) locus. The acid phosphatase-1 allozyme (APS-1(1], encoded by the Aps-1(1) allele originating from Lycopersicon peruvianum, was purified to apparent homogeneity from tomato roots and suspension cells. Microsequencing of CNBr and tryptic peptides generated from APS-1(1) provided a partial amino acid sequence, which accounted for approximately 23% of the protein and revealed two stretches of homology with soybean proteins KSH3 and VSP27, comprising 22 matches within 26 amino acid residues. The partial amino acid sequence information enabled us to isolate a 2.4 kb genomic Aps-1(1) sequence by means of the polymerase chain reaction (PCR), primed by degenerate pools of oligodeoxyribonucleotides, synthesized on the basis of the amino acid sequences. Synthesis of the 2.4 kb PCR product was specific for genomic templates carrying the L. peruvianum Aps-1(1) allele. Crucial to the priming specificity and the synthesis of the 2.4 kb genomic sequence was the use of degenerate primer pools in which the number of different primer species was limited by incorporating deoxyinosine phosphate residues at three and four base ambiguities. In using cDNA as a template, a 490 bp sequence was obtained, indicating a high proportion of intron sequences in the 2.4 kb genomic Aps-1(1) sequence. The Aps-1(1) origin of the PCR product was confirmed by RFLP (restriction fragment length polymorphism) analysis, using both a chromosome 6 substitution line and a pair of nearly isogenic lines, differing for a small chromosomal region around the Aps-1/Mi loci.
Acid Phosphatase↗
Genetic and molecular characterization of an Adh-1 null mutant in tomato.
Treatment of tomato seeds with ethyl methanesulphonate (EMS) followed by allyl alcohol selection of M2 seeds has led to the identification of one plant (B15-1) heterozygous for an alcohol dehydrogenase (Adh) null mutation. Genetic analysis and expression studies indicated that the mutation corresponded to the structural gene of the Adh-1 locus on chromosome 4. Homozygous Adh-1 null mutants lacked ADH-1 activity in both pollen and seeds. Using an antiserum directed against ADH from Arabidopsis thaliana, which cross-reacts with ADH-1 and ADH-2 proteins from tomato, no ADH-1 protein was detected in seeds of the null mutant. Northern blot analysis showed that Adh-1 mRNA was synthesized at wild-type levels in immature seeds of the null mutant, but dropped to 25% in mature seeds. Expression of the Adh-2 gene on chromosome 6 was unaffected. The potential use of the Adh-1 null mutant in selecting rare transposon insertion mutations in a cross with "mutable" Adh-1+ tomato lines is discussed.
Alcohol Dehydrogenase↗
Cyclosporin for hypereosinophilic syndrome.
The idiopathic hypereosinophilic syndrome (HES) comprises a heterogeneous group of disorders with unknown pathogenesis characterized by persistent peripheral blood and bone marrow eosinophilia and eosinophil infiltrates of multiple organs, leading to severe organ dysfunction. Lymphokine-mediated T-lymphocyte control of human eosinophilic granulopoiesis is though to play a major role in the pathogenesis of HES. Treatment of this disease with cyclosporin-A (CSA) therefore appears to be sensible. We report the case of a patient with a severe HES who failed to respond adequately to glucocorticoid treatment. With additional CSA therapy, disease activity showed a favorable remission and eosinophil counts rapidly decreased to the normal range and remained normal even after reduction of the methylprednisolone dosage to 7.5 mg daily. To date his remission has continued for more than 6 months. In the meantime we have confirmed the beneficial effects of CSA in two other cases of HES. This suggests that CSA treatment is justified, at least in combination with glucocorticoids, in severe cases of HES to prevent the side effects of a long-lasting high-dose glucocorticoid therapy.
Adult↗
Release of mediators from human gastric mucosa and blood in adverse reactions to benzoate.
A study was carried out on 29 patients to investigate the amount of histamine liberation and release of platelet-activating factor and 6-keto-prostaglandin F1 alpha from gastric mucosa and whole blood or mononuclear cells by sodium benzoate. The patients suffered from asthma (10), atopic dermatitis (7) and chronic urticaria (4). 8 patients with unrelated, non-immunologic diseases served as controls. In the oral provocation test (OPT) 3 patients experienced a recurrence of their original disease, whilst 1 asthmatic patient reacted with abdominal disorder. The release of histamine and prostaglandin from mucosa was significantly increased by sodium benzoate in comparison to the spontaneous release observed in patients. The mucosa of the control persons did not react to sodium benzoate. Furthermore, there was a significant difference in prostaglandin release between patients with positive OPT and the control persons. No difference could be found between patients with negative OPT and those with positive OPT. Additionally, in the mediator release from whole blood or mononuclear cells there was no obvious difference apparent. These results suggest a possible involvement of prostacyclin and histamine in adverse reactions to benzoate. Due to the sensitivity of the method, a mediator release from mucosa can already be demonstrated in a preclinical state of the pseudoallergic reaction in the absence of clinical symptoms.
6-Ketoprostaglandin F1 alpha↗
Effects of pentoxifylline in endotoxinemia in human volunteers.
The following effects of pentoxifylline in endotoxinemia in man could be demonstrated: 1. Il-6 release and Il-6 mediated effects such as clinical responses and leukocytosis are not inhibited by POF treatment. 2. TNF-alpha release is suppressed which might be the most important result, because TNF seems to play the major role in the pathophysiological events of endotoxinemia. Furthermore, pentoxifylline is able to counteract the initial leukocytopenia caused by sticking of leukocytes in the microcirculation. 3. De-novo-synthesis of cytokines by monocytes ex vivo is totally abolished. This may possibly reflect the in vivo situation. In conclusion, beneficial effects of pentoxifylline in respiratory distress syndrome, multi-organ failure and septic shock are suggested. Furthermore, our data indicate that endotoxin-induced formation of Il-6 and TNF-alpha are regulated independently in vivo.
Endotoxins↗