Survival of two patients with severe δ-aminolaevulinic acid dehydratase deficiency porphyria

The course of -aminolaevulinic acid dehydratase activity was studied over the 23 years in erythrocytes of two male patients. The enzyme activity was originally 1–2%, which then increased to 8% of normal levels several years after clinical manifestation of the acute hepatic porphyria syndrome. Urinary excretions of -aminolaevulinic acid and coproporphyrin III were excessively increased in the two patients with compound-heterozygous -aminolaevulinic acid dehydratase deficiency porphyria.     

Analysis of lymphocyte subsets in patients with aplastic anemia before and during immunosuppressive therapy

Summary To define the contribution of T-lymphocyte subsets in the development of aplastic anemia (AA), T-cell subpopulations including T cells, T cells, and TCS1-positive T cells, were analyzed by cytophotometry in the peripheral blood (PB) and bone marrow (BM) of patients with AA before and after 6 weeks of therapy with anti-lymphocyte globulin (ALG), methylprednisolone, and cyclosporin A (CSA). In nine patients with AA a significant decrease of PB- and BM-derived T cells was observed after 6 weeks of therapy as compared with normal controls. At diagnosis, the CD4/CD8 ratio in PB and BM of the patients did not differ from the ratio in the control population; however, a reversed ratio (< 1) was present in PB as well as in BM after weeks of therapy. Interestingly, lymphocytes expressing the T-cell receptor (TCR) were significantly decreased both before (PB 1.2±0.1%; BM 0.8±0.1%) and after 6 weeks of therapy (PB 0.7±0.1%; BM 0.7±0.1%) as compared with healthy controls (PB 2.4±0.2%; BM 2.3±0.2%). However, the proportion of the -T-cell subpopulation expressing the TCS1 phenotype was markedly increased before (PB 42±3.5%; BM 31±3%) and especially after 42 days of therapy (PB 77±12%; BM 45±2%) as compared with that in normal subjects (PB 19±2%; BM 9.7±0.8%). At present, follow-up is under evaluation to correlate these findings with hematological response. The pathophysiological significance of the observed alterations within the T-cell subsets and especially the T-cell populations will require further functional analyses, in particular since TCS1-positive T cells exhibit autoimmunological capacity.Presented at the annual meeting of the German Society for Hematology and Oncology, 4–7 October 1992, Berlin     

Volume control during periodic changes of blood volume in the alert rat

Summary Blood (3.4–13.5% of blood volume) was pumped in and out of the circulation of rats at different rates and period lengths during continuous measurements of blood conductivity (reciprocally related to hematocrit) and arterial pressure. Hct followed the same zig-zag course as the induced changes of blood volume in every case, indicating that fluid shifts (v) between interstitium and intravascular space closely follow blood volume changes. As the het increase during reinfusion was not as great as the preceding decrease, hct dropped continuously during the 20–90 minutes of experimentation, so that a final volume increase (v) by about 4% was calculated, which was confirmed by a corresponding decrease of plasma protein concentration. Both final v and v during periodic volume change (% B.V.) were greater when arterial pressure dropped. v was directly related to % B.V. but not to its rate of change. Heart rate dropped slightly at the end of the reinfusion periods, whereas it rose to control at the end of the withdrawal periods. The results were regarded as evidence of blood volume regulation proportional to the absolute volume of blood lost in non-hypotensive hemorrhage.Supported by DFG-grant AZ 3/3     

Porphyrin synthesis and metabolism in iron deficiency anaemia. I. In-vivo-studies

Summary The results of studies done to ascertain whether the rate of protoporphyrin synthesis from -aminolaevulic acid is decreased in iron deficiency anaemia and whether iron is essential for the synthesis of the intermediate compounds in the porphyrin metabolism are reported. By measuring the urinary -amino-laevulic acid, porphobilinogen, coproporphyrin and uroporphyrin excretion and the faecal coproporphyrin and protoporphyrin excretion a decrease in the rate of porphyrin synthesis was demonstrated in cases of idiopathic hypochromic anaemia. The relative increase in the urinary porphobilinogen excretion points to a partial block of porphyrin synthesis from porphobilinogen. Iron treatment normalises the porphyrin metabolism.

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Zusammenfassung Die Ergebnisse von Untersuchungen zur Feststellung, ob die Höhe der Protoporphyrinsynthese aus -Aminolävulinsäure bei Eisenmangelanämie geringer ist und ob Eisen für die Synthese von Zwischenprodukten im Porphyrinstoffwechsel wesentlich ist, werden berichtet. Durch das Messen von -Aminolävulinsäure im Harn, Porphobilinogen-, Koproporphyrin- und Uroporphyrinausscheidung im Harn und die fäkale Ausscheidung von Koproporphyrin und Protoporphyrin wurde ein Absinken der Höhe der Porphyrinsynthese bei Fällen von idiopathischer hypochromer Anämie nachgewiesen. Der relative Anstieg in der Porphobilinogenausscheidung im Harn deutet auf eine Teilblockierung der Porphyrinsynthese von Porphobilinogen. Eisenbehandlung normalisiert den Porphyrinstoffwechsel.

     

Further identification of protein kinase C isozymes in mouse epidermis

In the current study, the protein kinase C (PKC) isozymes present in mouse epidermis have been identified using immunological and chromatographic methods. Six PKC isozymes, PKC, PKC, PKC, PKC, PKC, and PKC, were identified in unfractionated epidermal preparations by protein immunoblotting. The subcellular distribution and presence of these isozymes was further verified by hydroxyapatite (HA) chromatography with the exception of PKE, which could not be detected following HA chromatography. The five PKC isozymes recovered following HA chromatography were detected in both epidermal cytosol and particulate fractions, although PKC was found in a much higher proportion relative to the other PKC isozymes in the particulate fraction using histone H1 as the substrate. The biochemical properties of the epidermal PKC isozymes partially purified by HA chromatography agreed with those reported for other tissues and further supported their immunological identification in epidermal preparations. The activities of HA chromatography peaks corresponding to PKC, PKC, and PKC were found to be dependent on both Ca²⁺ and phosphatidylserine (PtdSer), whereas, the activities of HA peaks corresponding to PKC and PKC were Ca²⁺-independent but PtdSer-dependent. The HA peak corresponding to PKC also displayed a characteristic biphasic modulation by arachidonic acid (activation at low, inactivation at high concentrations) and inactivation by preincubation with PtdSer. PKC activity was also characteristic, in that it was dependent on PtdSer and was not increased by the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate. Some differences in substrate specificity were also observed between the epidermal PKC isozymes. The presence of multiple isozymes of PKC in mouse epidermis suggests that the different isozymes may play distinct roles in signal transduction and tumor promotion in this tissue.Abbreviations PKC protein kinase C - HA hydroxyapatite - PtdSer phosphatidylserine - TPA 12-O-tetradecanoylphorbol 13-acetate This work was supported by USPHS grants CA 38871 (J.D.), CA 57596 (J.D.) and core grant CA 16672     

A modified spectrophotometric assay for porphobilinogen deaminase: its application in the detection of both carriers and patients with acute intermittent porphyria

Summary A spectrophotometric method for porphobilinogen deaminase assay in erythrocytes is described. This test is determinant for the definite diagnosis of acute intermittent porphyria. In the method described, -aminolevulinic acid is used as substrate. Mercaptoethanol and zinc ions are introduced to maintain -aminolevulinic acid dehydratase in optimal conditions and to guarantee thein vitro production of porphobilinogen. An incubation temperature of 45°C leads to the production of uroporphyrins, which are measured spectrophotometrically at 405 nm, giving reproducible results. The assay can be performed easily in any clinical laboratory and is valuable for detecting both patients and carriers of acute intermittent porphyria.     

Characterization of an acute T lymphoblastic leukemia expressing the γ/δ T-cell receptor

Summary Leukemic cells of a 20 year old patient, suffering from acute lymphoblastic leukemia, were characterized by surface marker and functional analysis. A significant cell population within this type of leukemia expresses concomitantly the CD4 and CD8 antigen on the same cell and might represent a new differentiation stage of T-cells with the / receptor. The leukemic cells show a distinct pattern of growth response to mitogens and lymphokines, which might correlate to their differentiation stage. Moreover, a natural killer-like activity can be induced in these cells by IL-2.Abbreviations FITC fluorescein isothiocyanate - PE phycoerythrin - IL-2 interleukin 2; - / TCR gamma/delta T cell receptor - NK natural killer - PBL peripheral blood lymphocytes - T-ALL acute T lymphoblastic leukemia - ConA concanavalin A - PMA phorbol myristate acetate - BM bone marrow - IL-2R IL-2 receptor - TdT terminal deoxynucleotidyl transferase Supported by the Deutsche Forschungsgemeinschaft (DFG Wi-728/3-1)     

Porphyrin synthesis and metabolism in iron deficiency anaemia: II. in vitro studies

Summary The results ofin vitro studies on the rate of porphobilinogen and porphyrin synthesis in iron deficient human red blood cells are reported. It was found: 1. that the synthesis of porphobilinogen from -aminolaevulic acid is virtually normal; 2. that in iron deficient red blood cells -aminolaevulic acid follows the same metabolic paths as in normal red blood cells; 3. that the synthesis of porphyrin from porphobilinogen is partly inhibited, the amount of porphyrin formed being appreciably decreased; 4. that the administration of iron normalises the rate of porphyrin synthesis from porphobilinogen without interfering with the synthesis of this pyrrole.

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Zusammenfassung Die Autoren berichtenüber die Ergebnisse von In-vitro-Untersuchungen über die Höhe der Porphobilinogen- und der Porphyrinsynthese in menschlichen Erythrozyten mit Eisenmangel. Es zeigte sich, 1. daß die Synthese von Porphobilinogen aus -Aminolacvulinsäure praktisch normal ist; 2. daß in Erythrozyten mit Eisenmangel die Aminolaevulinsäure dem gleichen Stoffwechselweg folgt wie in normalen roten Blutkörperchen; 3. daß die Synthese von Porphyrin aus Porphobilinogen zum Teil gehemmt und die Menge des gebildeten Porphyrins erheblich verringert ist; 4. daß die Gabe von Eisen die Höbe der Porphyrinsynthese aus Porphobilinogen normalisiert ohne die Synthese diese Pyrolls zu stören.

     

γ/δ Receptor-expressing T-cell clones from a cutaneous T-cell lymphoma suppress hematopoiesis

Summary Recently we described a cutaneous T-cell lymphoma expressing the / T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patient's bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating / T-lymphoma cells we established T-cell clones bearing the / T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these / T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of / T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-,since it was detectable in high amounts in the SN of these / T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN- antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-, which is secreted in high amounts from / T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.Abbreviations TCR T-cell receptor - IFN- interferon- - SN supernatant - placenta CM placenta conditioned medium - BM bone marrow - CFU-GM myeloid/monocyte colony formation - NK cells natural killer cells - Ab antibody M. Wilhelm was supported by theDeutsche Forschungsgemeinschaft (DFG Wi 728-2)     

Impaired alveolar gas exchange in acute pancreatitis

We evaluated the alveolar–arterial oxygen difference (A-a) and the ratio between P_ao₂ and the fractional concentration of inspired oxygen (P/F) in acute pancreatitis. Eleven patients had mild uncomplicated disease, six showed acute abdominal fluid collections, six had acute abdominal collections and asymptomatic x-ray lung involvement, three presented transient dyspneic episodes, and four had severe acute pancreatitis requiring prolonged oxygen therapy. In the uncomplicated disease, respiratory function was normal; in the six patients with abdominal collections only, A-a increased by 50% and P/F decreased by 20–30%; in the six patients with abdominal collections and asymptomatic x-ray lung involvement, A-a increased by 50–70% and P/F decreased by 40%; the three patients with dyspneic episodes showed a twofold increase in A-a and a 40% decrease in P/F; the four patients with severe pancreatitis had a two- to threefold increase in A-a and a 40–50% decrease in P/F. Hence respiratory function is normal only in uncomplicated pancreatitis; in the presence of complications, disturbance of gas exchange always occurs, requiring careful control and treatment.     

Detection of clonality by polymerase chain reaction in childhood B-lineage acute lymphoblastic leukemia

Summary DNA-based PCR with various sets of primers for TCR /, and Ig heavy chain (IgH) genes were used to study clonality in childhood B-lineage acute lymphoblastic leukemia. Amplification of the IgH CDR-III was observed in 75 of 120 analyzed cases (62.5%). From all analyzed groups, the IgH gene rearrangement was most often observed in pre-B ALL (85.7%) and was rather rare in null-ALL (34.5%). TCR delta gene rearrangement was the most common, and was observed in 77 patients (64.2%). The typical pattern of rearrangements was defined as anincomplete V2 to D3, V2 to D2, or D3 to D3 to D2 recombination product. Rearrangements of TCR gamma gene we observed in 61 cases (50.8%). TCR gamma gene rearrangements were detected predominantly in null-ALL and early B-ALL (55.2% and 60%, respectively) and were rather rare in other groups. Of all eight V segments of VI group, the most frequent gene usage concerns regions V2, V4, and V7. We have confirmed that IgH gene amplification, together with TCR gamma and delta gene amplification, provides a rapid, sensitive approach to assessing clonality in ALL almost in 100% of cases.This work was financed by KBN grants 4.0551.91.01 and 6.6346.92.03     

Local and Systemic Liberation of Proinflammatory Cytokines in Ulcerative Colitis

Determination of plasma and tissue cytokinelevels in inflammatory bowel disease have frequentlyresulted in conflicting data. In the present study wedetermined in patients with ulcerative colitis (UC), the levels of the proinflammatory cytokinesinterleukin (IL)-1, IL-6, interferon(IFN)-, and tumor-necrosis factor (TNF)-liberated by peripheral blood mononuclear cells (PBMC)and lamina propria mononuclear cells (LPMC) after 48-hrculture with pokeweed mitogen (PWM). IL-1, IL-6,IFN- and TNF- in the supernatant weredetected by ELISA. Results show low basal levels ofIL-1 secretion by PBMC and LPMC, and a considerableincrease after mitogen stimulation. Basal IL-6production by PBMC was higher in UC patients than incontrols [2029 pg/ml, CI₉ (–165 to4223) vs 572 pg/ml (–383 to 1527) respectively, P = 0.05] and also afterPWM activation [14,995 pg/ml (7759 -22230) vs 6598 pg/ml(3240-9956), respectively, P = 0.05]. In LPMC, nodifferences in IL-6 secretion were observed. TNF- in activated PBMC of patients with UC was notsignificantly increased in relation to control (P =0.09). No constitutive secretion of IFN- wasobserved in mononuclear cells. IFN- levelssecreted by activated LPMC were lower in patients withUC than in controls [1571 pg/ml (–108 to 3251) vs7953 pg/ml (3851-12,055), respectively, P = 0.03]. Theseresults suggest that IL-6, IL-1, and TNF- participate as mediators in the inflammatoryphenomena observed in UC. Further studies are necessaryto evaluate the role of IFN- in thiscondition.     

TCR1+ large granular lymphocyte proliferation in rheumatoid arthritis

The T-lymphoproliferative syndrome is characterized by a proliferation of large granular lymphocytes (LGL). It is often associated with neutropenia, and in 30% of cases with rheumatoid arthritis (RA). Phenotypic analysis has demonstrated that in most cases of RA with T-proliferative disease, the LGL represent T cells with a clonal rearrangement of the / T cell receptor (TCR2). Here, three patients with / TCR1⁺ LGL proliferation suffering from long-standing arthritis and neutropenia are described. The first patient with RA showed an expansion of a heterogeneous CD2⁺ CD16⁺ CD56^- LGL population, of which 30% coexpressed TCR1 with V1 rearrangement. The second patient with ankylosing spondylitis and RA was suffering from proliferation of TCR1⁺ (V9^-, V1^-), CD2⁺ CD16^- CD56^- LGL with low coexpression of CD8. The third patient with RA was suffering from a proliferation of TCR1⁺ (V1⁺, V9^-) CD4^- CE8^- CD16^- CD56^- lymphocytes. On the basis of these unusual findings, the pathogenetic role of TCR1⁺ T cells in RA is discussed.     

Problems of reduced heme synthesis in reticulocytes with impaired globin synthesis

Summary The mechanism by which heme synthesis is inhibited in reticulocytes with inhibited globin synthesis is not yet established. Evidence was found that the accumulated free heme does not inhibit the activity of -aminolaevulic acidsynthetase. The very early inhibition of heme synthesis may be caused by the effect of uncompleted globin chains or amino acids on the -aminolaevulic acidsynthetase or some other enzymes of the porphyrin biosynthetic chain. The accumulated free heme, the presence of which in reticulocytes with inhibited globin synthesis has been indirectly proved may reduce the iron entry to the reticulocytes which in turn can influence the synthesis of heme especially in the later periods of incubation. A feedback inhibitory effect of accumulated free heme at some critical site on the enzymes of the porphyrin biosynthetic chain cannot still be quite excluded.

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Zusammenfassung Der Mechanismus, mit dem die Häm-Synthese bei Retikulozyten mit gestörter Globulinsynthese gehemmt wird, ist noch nicht geklärt. Es wurden Anzeichen dafür gefunden, daß die akkumulierten freien Häme die Aktivität der -Aminolävulinsäuresynthetase nicht behindern. Die sehr frühe Hemmung der Häm-Synthese kann durch die Wirkung unvollständiger Globinketten oder Aminosäuren auf die -Aminolävulinsäuresynthetase oder einige andere Enzyme der biosynthetischen Porphyrinkette verursacht werden. Die akkumulierten freien Häme, deren Anwesenheit in Retikulozyten mit gehemmter Globinsynthese indirekt nachgewiesen wurde, können den Eintritt von Eisen in die Retikulozyten reduzieren, was wiederum die Synthese der Häme, besonders in den späteren Inkubationszeiten beeinflussen kann. Eine hemmende Rückkoppelungswirkung akkumulierter freier Häme an irgendeiner kritischen Stelle der Enzyme der biosynthetischen Prophyrinkette kann nicht ganz ausgeschlossen werden.

     

Oligosaccharides accumulated in the bovineβ-mannosidosis kidney

Summary The phenotype of bovine-mannosidosis (-mannosidase deficiency), recently identified in Salers cattle, is similar to the caprine form of the disease (Abbittet al., 1991). This investigation was designed to characterize accumulated kidney oligosaccharides in bovine-mannosidosis. Oligosaccharides were extracted from the kidney of an affected Salers calf and purified by chromatographic techniques. The amount of accumulating oligosaccharides in 1 g of wet tissue was about 21µmol. Structures of derivatized oligosaccharides were characterized by high-performance liquid chromatography, mass spectrometry, methylation analysis and sequential exoglycosidase digestions. The major accumulating oligosaccharides were Man1-4GlcNAc and Man1-4GlcNAc1-4GlcNAc. Oligosaccharides accumulating in minor amounts were Man1-4GlcNAc1-4Man1-4GlcNAc, Man1-6Man1-4GlcNAc1-4GlcNAc and Man1-4GlcNAc1-4Man1-4GlcNAc1-4GlcNAc. As in caprine-mannosidosis, oligosaccharides with terminal-mannose residues and cleaved as well as uncleaved chitobiose linkages were identified in bovine-mannosidosis kidney. The accumulating oligosaccharides in tissue were thus identical in bovine and caprine-mannosidosis; however, the source of the novel oligosaccharides remains to be determined.     

Celiac Disease Without Villous Atrophy

Current diagnostic criteria of celiac disease require small bowel villous atrophy, although the damage develops gradually. We therefore searched for evidence of disease in 10 adults suspected to have celiac disease, but evincing only minor mucosal inflammation and increase in ⁺ cells without villous atrophy. Twenty untreated celiac and 27 nonceliac patients served as biopsy controls. CD3⁺, ⁺, and ⁺ cells were increased in patients with only minor mucosal lesions, but less than in celiac patients. The inflammation resolved on gluten-free diet, and abdominal symptoms were alleviated. Eight of 10 had positive endomysial, seven gliadin, and nine tissue transglutaminase antibodies; all normalized on diet. Eight patients had osteopenia; HLA DQ2 was found in all. Minor mucosal lesions with an increase in ⁺ intraepithelial lymphocytes were suggestive of celiac disease. Our patients showed a clinical, histological, and serological recovery on diet; risk of osteopenia speaks in favor of dietary treatment.     

Elliptocytosis associated with an abnormal α glycophorin

Summary A case of elliptocytosis associated with an undescribed abnormal glycophorin (GP) is reported. Using immunoblotting techniques, a clear-cut minor band 6 was detected emerging just behind the monomer of GP (band 6) when probed with anti- GP antiserum. It also reacted with anti-peptide C antiserum, suggesting that this new band with a molecular weight of 24 K is related to the structural alteration of GP and not GP. The erythrocyte membrane proteins of the patient exhibited a quite normal pattern, with a normal spectrin/ spectrin ratio, but the reaction with anti-protein 4·1 serum confirmed the increase in proteolytic susceptibility of her protein 4·1. The results of DNA mapping implied that the abnormality may be due to a short deletion of the heterozygote. The significance of deviation involving the GP and protein 4·1 to the elliptocytic change of erythrocyte shape is briefly discussed.This work was supported by grant no. HL-21016 from the National Institutes of Health, Bethesda, MD     

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats

Background Gabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl₄)-induced liver injury in rats.Methods Acute hepatic failure was induced by administration of CCl₄ intragastrically to male Sprague–Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats.Results Gabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24h after the administration of CCl₄ (0.2ml/100g rat weight). Plasma tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl₄ (0.5ml/100g rat weight) from 0% to 20%.Conclusions Gabexate mesilate treatment attenuated CCl₄-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.     

Early infiltration of arterial intima by activated dendritic γ/δ T-cells in ligated human arteries: An ultrastructural and immunocytochemical study

To clarify the role of immune mechanisms in the vascular response to injury in humans, the sequence, subset and activation status of lymphocytes infiltrating acutely ischemic arteries were studied. Thirty-five branches of mesenteric arteries removed from 8 men during surgery—22 of which were ligated for 0.5–4 hours—were examined ultrastructurally and immunocytochemically. The ligated arteries showed early intimal infiltration by activated T-cells, the predominant subset of which was dendritic, / T-cell receptor (TCR)-bearing and phenotyped CD3+, CD4-, and CD8-. Their activated status is shown by strong HLA-DR positivity, expression of interleukin-2 receptors, increased expression of lymphocyte function antigen-1, and frequent lymphocyte-macrophage interactions. Intimal macrophage infiltration consisted of single cells in the earlier biopsy specimens and clusters of cells in the later ones. These findings suggest that an early immune mechanism initiated by activated / dendritic T-cells, and amplified later by macrophages, may play a pivotal role in the inflammatory response after acute arterial injury.     

Effect of FR167653 on Small Bowel Ischemia-Reperfusion Injury in Dogs

IL-1 and TNF- are known to be pleiotropiccytokines associated with various inflammatoryconditions such as small intestinal injury afterischemia-reperfusion. FR167653 has been characterized asa potent suppressant of IL-1 and TNF-production. The effect of FR167653 on intestinalreperfusion injury was investigated in a warm ischemiamodel of the canine gut. Sixteen mongrel dogs weredivided into two groups: a control group and a FR groupto which FR167653 was administered. Both the superiormesenteric artery and vein were clamped for 2 hr.Arterial pH, hepatic venous hemoglobin oxygensaturation, intramucosal pH, and the survival rate werewell maintained in the FR group in comparison with thecontrol group after reperfusion. FR167653 inhibited theexpression of IL-1 mRNA. Histologically,ischemia-reperfusion injury was more severe in the control groupthan the FR group. This study suggests that FR167653inhibits proinflammatory cytokines and amelioratesischemia-reperfusion injury of the smallintestine.