PubMed Health⌕ Search

Biomedical subjects

M W Flye

Publications and source records attributed to M W Flye.

At least 127 records · Page 7Linked to original sources
PubMed1992

Day-5 protocol liver allograft biopsies document early rejection episodes and are predictive of recurrent rejection.

METHODS: The day-5 posttransplant protocol biopsy specimens and clinical courses of 27 consecutive orthotopic liver transplant recipients followed up at least 6 months were reviewed. RESULTS: Twelve (44%) of 27 patients had histologic evidence of rejection on the day-5 biopsy; 8 (67%) of these 12 patients required OKT3 for reversal of the rejection. No significant differences in biochemical liver test results, bile output, or cyclosporine levels were observed between this group and the 15 patients (56%) without histologic evidence of rejection on day 5. Eight (67%) of the 12 patients with rejection had recurrent rejection episodes, with one recurrence each in six patients, two recurrences in one patient, and three recurrences in one patient. Of the 15 patients without rejection on day 5, nine (60%) subsequently had rejection at 10 days, 14 days, and 1 1/2, 3 1/2, 4, 5, and 11 months after transplantation. Only one (11%) of these nine patients had a recurrent rejection episode. There were no differences in the incidence of posttransplant cytomegalovirus infections between the two groups. Two cases of posttransplant lymphoma were seen; they developed in two patients without rejection on the day-5 biopsy. No patients or allografts were lost to acute or chronic rejection. No complications occurred as a result of the day-5 protocol biopsy. CONCLUSION: The day-5 protocol biopsy is useful in detecting rejection episodes that may not otherwise be clinically apparent.

Adult↗
PubMed1992

Endotoxin stimulates interleukin-6 production by human Kupffer cells.

Interleukin-6 (IL-6) induces acute-phase protein synthesis in human hepatocytes. We evaluated whether the contiguous hepatic macrophages, human Kupffer cells (HKC), produce IL-6 in response to an inflammatory stimulus. HKC were harvested from collagenase-digested normal liver biopsies and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture, 5 x 10(5) HKC were repleted with fresh media with or without 2.5 micrograms/ml of endotoxin (LPS). Parallel cultures contained polymyxin-B (10 micrograms/ml) or antihuman-IL-6 antibody (4 units/ml). Timed supernatants were collected and IL-6 levels (ng/ml) measured (B9.9 proliferative bioassay). Data analysis was by the paired Student's t test. Unstimulated HKC produced negligible IL-6 levels (less than 0.150 ng/ml). Endotoxin invoked early and sustained HKC production of IL-6, which was completely (P less than 0.001) abrogated by the addition of the anti-IL-6 antibody. Polymyxin B, an LPS-inhibitor, also blocked (P less than 0.001) IL-6 production, indicating the specificity of the response to the inflammatory stimulus. This is the first evidence that HKC can produce IL-6 in response to LPS. Local intrahepatic production of IL-6 may provide a necessary paracrine signal for HKC to amplify directly neighboring hepatocyte acute-phase responses during inflammation in man.

Cells, Cultured↗
PubMed1992

Prostaglandin E2 production during hepatic regeneration downregulates Kupffer cell IL-6 production.

The liver possesses the remarkable ability to regenerate to its original size after a 70% partial hepatectomy. There has been little effort to characterize the Kupffer cells' role in this unique mammalian reparative physiologic phenomenon. The capacity of rat Kupffer cells (KC) isolated at specific intervals after partial hepatectomy to produce interleukin-6 (IL-6) and prostaglandin E2 (PGE2) in response to endotoxin was evaluated in standard RPMI-1640 (1200 microM L-arginine) and arginine-depleted RPMI-1640 (10 microM L-arginine) media. Regenerating liver KC 48 to 120 hours after partial hepatectomy responded to endotoxin stimulation with a significantly greater (p less than 0.05) production of IL-6 in standard RPMI-1640. Because Kupffer cells function in an environment where high arginase activity results in negligible L-arginine levels, the 10 microM L-arginine RPMI-1640 was used to simulate the true hepatic microenvironment. Production of IL-6 by regenerating liver KC was further increased (p less than 0.05) by placing these same KC in 10 microM L-arginine RPMI-1640 tissue culture media. During the same period, regenerating liver KC produced significantly (p less than 0.01) more PGE2 than sham-operated KC in both standard and low-arginine media. When the cyclo-oxygenase inhibitor indomethacin (1 x 10(-5) M) was added to cultures, the PGE2 production was inhibited, and IL-6 production was upregulated (p less than 0.05) in arginine-depleted cultures. The authors conclude that during hepatic regeneration KC IL-6 production is elevated but controlled in an autoregulatory fashion by KC PGE2 production.

Animals↗
PubMed1992

Beneficial effect of syngeneic pancreatic islet transplantation on liver atrophy and hepatocellular function after portacaval shunt.

BACKGROUND: Hepatic insufficiency, which continues to be a source of morbidity after portacaval shunt (PCS), can be prevented by syngeneic pancreatic islet transplantation into the portal vein before PCS. This study investigated the ability of syngeneic pancreatic islet transplantation after PCS to prevent hepatic atrophy and rescue hepatocellular function. METHODS: Approximately 1200 to 1400 syngeneic rat pancreatic islets were transplanted through a heparinized catheter into the left lobes of the liver 3, 7, and 21 days after end-to-side PCS. Normal rats received no treatment, and PCS control rats received PCS only, without islet transplantation. Hepatocellular function (caffeine clearance) and hepatic blood flow (indocyanine green clearance) were analyzed at 42 and 49 days after PCS. On day 51 after PCS, the left and right lobes of the liver were divided, weighed, and sectioned for histologic studies. RESULTS: Caffeine clearance in the animals at 3 days (p less than 0.05) and at 7 days (p less than 0.05) after end-to-side PCS was significantly improved versus control PCS animals, indicating that hepatocellular function could be rescued after creation of a PCS. Indocyanine green clearance of all groups with PCS was significantly (p less than 0.001) decreased versus normal animals, showing that hepatic blood flow was uniformly decreased by PCS in all groups. The weight of the transplanted left lobes was significantly greater than the untransplanted right lobes of the groups at 3 days (p less than 0.01) and at 7 days (p less than 0.05) after end-to-side PCS compared with control animals, indicating that liver atrophy was prevented in the islet-transplanted lobes but not in those lobes without a transplant. CONCLUSIONS: Islet transplantation early after PCS can prevent liver atrophy and significantly improve hepatocellular function.

Animals↗
PubMed1991

Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis.

Endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF-alpha) have been implicated in the pathogenesis of sepsis-induced adult respiratory distress syndrome. To evaluate the possible interaction of the hepatic-pulmonary macrophage axis in the adult respiratory distress syndrome, we compared the kinetics of immunosuppressive prostaglandin E2, TNF-alpha, and interleukin 6 production in LPS-stimulated Kupffer cells and alveolar macrophages (AMs). Interleukin 6 production by Kupffer cells was significantly higher than for equal numbers of AMs. Kupffer cell TNF-alpha levels peaked early before decreasing as regulatory prostaglandin E2 levels rose. In contrast, AM TNF-alpha levels rose sharply and remained significantly higher than for Kupffer cells throughout culture coincident with negligible prostaglandin E2 production. Kupffer cell sequestration of LPS may normally invoke a coordinated cytokine response able to locally induce acute-phase hepatocytes. In hepatic failure, however, LPS spillover to the lung may promote adult respiratory distress syndrome by inducing unregulated AM TNF-alpha production within the pulmonary microenvironment.

Animals↗
PubMed1991

Kupffer cell tumor necrosis factor-alpha production is suppressed during liver regeneration.

Mammalian liver regeneration following resection invokes intrinsic hepatic responses which result in rapid tissue repair. The role of soluble immune cytokines in this phenomenon is not known. The capacity of Kupffer cells (KC) from regenerating liver to produce the potent cytokine TNF-alpha was evaluated. Twenty-four hours after 70% partial hepatectomy (PHx) or sham operation, Kupffer cells were harvested from collagenase-digested Wistar-Furth rat livers and purified (greater than 95% by phagocytosis) by adherence. Following overnight culture with or without the cyclooxygenase inhibitor indomethacin (10 microM), 5 x 10(5) KC were repleted with fresh media with or without 2.5 micrograms/ml lipopolysaccharide (LPS). Supernatant TNF-alpha activities (units/ml) were measured using the L929 fibroblast lysis assay. With LPS, sham KC TNF-alpha levels were significantly higher (P less than 0.001) than those for PHx KC. Indomethacin significantly increased PHx KC TNF-alpha levels, but did not affect those for sham KC, suggesting autoregulation by arachidonic acid cyclooxygenase metabolites following PHx. We conclude that KC TNF-alpha production is suppressed following PHx by a mechanism apparently regulated by eicosanoid metabolism. During the stress of hepatic regeneration, a coordinated limitation of excessive TNF-alpha responses by PHx liver KC may naturally protect the host.

Animals↗
PubMed1991

Infarction in focal nodular hyperplasia of the liver. A case report.

An unusual case of focal nodular hyperplasia of the liver with infarction is presented. The patient, a 16-year-old girl with a three-year history of oral contraceptive use, presented with a two-week history of intermittent abdominal pain. Focal nodular hyperplasia of the liver and the role of estrogens in the development of this lesion are discussed.

Administration, Oral↗
PubMed1991

Liver transplantation for hepatoblastoma. The American experience.

The current role of liver transplantation in treating malignant tumors of the liver is uncertain, except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.

Carcinoma, Hepatocellular↗
PubMed1991

Intragraft delivery of 16, 16-dimethyl PGE2 induces donor-specific tolerance in rat cardiac allograft recipients.

The stable prostaglandin E2 analogue, 16,16-dimethyl PGE2 (di-M-PGE2) was continuously infused by osmotic pump directly into rat heterotopic cardiac allografts. Intragraft delivery of 20 micrograms/kg/day di-M-PGE2 for 2 weeks completely prevented graft rejection for more than 150 days (n = 10), while untreated Buffalo recipients rejected Lewis cardiac allografts within 8 days after transplantation (mean survival time = 7.4 +/- 0.5 days, n = 5). When given for only 1 week, 20 micrograms/kg/day had a partial effect, since 60% of recipients accepted grafts long-term and 40% experienced rejection by day 14 (n = 5). In contrast, systemic intravenous administration of 20 micrograms/kg/day di-M-PGE2 for 2 weeks could not prolong graft survival (MST = 7.0 +/- 0.0 days, n = 3), and the higher dose of 200 micrograms/kg/day resulted in death by day 2 (n = 5). Long-term BUF recipients of LEW cardiac allografts accepted LEW donor strain skin grafts for more than 35 days while rejecting third-party Wistar Furth skin grafts in a normal fashion (MST = 7.3 +/- 0.5 days, n = 3), indicating the induction of donor-specific tolerance. Long-surviving LEW cardiac allografts retransplanted into naive BUF recipients were rejected within 7 days (MST = 6.7 +/- 0.5 days, n = 3), indicating no change in graft immunogenicity. Therefore, a 14-day infusion of di-M-PGE2 directly into a strongly MHC-mismatched cardiac allograft uniformly has resulted in long-term engraftment and the development of recipient donor-specific tolerance.

16,16-Dimethylprostaglandin E2↗
PubMed1991

Restoration of lymphocyte proliferation and CTL generation by murine rIL-2 after treatment of allogeneic stimulator cells by ultraviolet B irradiation, heat, or paraformaldehyde.

Following a 5-day mixed lymphocyte culture (MLC), C3H/HeJ (H-2k) splenocytes stimulated with DBA/2 (H-2d) gamma-irradiated splenocytes (2000 rads) are specifically cytotoxic in a 4-hr 51Cr-release assay to P815 (H-2d) target cells (62 +/- 2% cytolysis) but not to third-party EL4 (H-2b). However, when the DBA/2 stimulator cells were treated with heat inactivation (45 degrees C for 1 hr), fixed with 1% paraformaldehyde (15 min), or irradiated with ultraviolet-B light (10(4) J/M2), no cell proliferation or cytolytic activity developed in the MLCs. The levels of IL-1, IL-2, and IL-6 from the supernatants of MLC using stimulators undergoing either of the three treatments were markedly decreased compared with that from gamma-irradiated stimulators. Both cell proliferation and specific cytolysis were restored in a dose-dependent fashion by the addition of murine rIL-2 to the MLCs. If the stimulator cells were first activated with 5 micrograms/ml pokeweed mitogen or lipopolysaccharide for 2 days, the subsequent treatment with heat, paraformaldehyde, or UV-B did not significantly affect the development of cytolysis (54-70% cytolysis). Suppressor cells were not detected when cells from the nonresponsive MLCs (2.5 x 10(6) cells) were added to an MLC freshly prepared with gamma-irradiated stimulator cells, or were injected intraperitoneally (50 x 10(6) cells) into naive mice 2 days before recovery and in vitro sensitization of splenocytes. Therefore, modification of the stimulating alloantigen can prevent the release of cytokines that function as an essential second signal in the development of the proliferative response and subsequent cytolysis. The cytokine found to be essential for restoration of this response is IL-2.

Animals↗
PubMed1991

Arginine-specific suppression of mixed lymphocyte culture reactivity by Kupffer cells--a basis of portal venous tolerance.

Portal venous administration of alloantigen abrogates the DTH response and prolongs heart and kidney allograft survival. Within the hepatic microenvironment, negligible L-arginine levels result from the effects of the highest tissue arginase activity of any organ (25 times greater than kidney). This study evaluated the effects of arginine availability on Kupffer cell immune function in the rat mixed lymphocyte culture. When 5 x 10(5) Wistar-Furth unfractionated lymph node cells (LNC) were cultured with 5 x 10(5) irradiated Lewis LNC in standard RPMI-1640 medium containing 1200 microM L-arginine, the proliferative response was not effected by the addition of 1 x 10(5) WF KC. However, when L-arginine-depleted medium (6 microM) was used, the MLC response was markedly reduced by the addition of KC. This was specific to arginine since media depletion of L-lysine, a similar basic amino acid, did not affect MLC/KC responses. When syngeneic WF KC were added as antigen-presenting cells to fractionated stimulator and responder T lymphocytes, WF/LEW MLC proliferation was restored in standard and L-lysine-depleted media, but did not increase in L-arginine-depleted RPMI 1640 medium. These responses correlated with a fivefold increase in KC prostaglandin-E2 (PGE2) production in the L-arginine-depleted medium. These findings support the hypothesis that diminished immune responsiveness in the low-arginine hepatic environment is effected, at least in part, by locally increased production of the immunosuppressant prostaglandin-E2.

Animals↗
PubMed1991

Low-attenuation periportal collar in transplanted liver is not reliable CT evidence of acute allograft rejection.

Recent reports indicate that the presence or absence of a periportal low-attenuation rim ("periportal collar" sign) on CT scans is of variable reliability in predicting rejection after liver transplantation. To study this matter further, we reviewed 178 CT scans in 68 patients (74 allografts) after hepatic transplantation. One hundred twenty-one scans were obtained within 7 days of liver biopsy. The presence or absence of a central or peripheral periportal collar on these scans was correlated with the presence or absence of acute rejection found at biopsy. A central periportal collar was defined as an abnormally large amount of low-attenuation material surrounding the main portal vein, the right portal vein, or the left portal vein. A peripheral periportal collar was defined as a low-attenuation area surrounding a portal vein branch distal to the left or right portal veins. A weak, but statistically significant correlation between the presence of a peripheral periportal collar and acute allograft rejection was shown in patients in whom CT scans were obtained within 3 days of biopsy. However, the sensitivity, specificity, accuracy, and positive predictive value of the presence of a peripheral collar in this group were 60%, 67%, 64%, and 63%, respectively. The sensitivity, specificity, accuracy, and positive predictive value of the presence of a central collar in patients scanned within 3 days of biopsy were 74%, 35%, 54%, and 52%, respectively. Negative predictive values of peripheral and central collars were 65% and 59%, respectively. Our study shows that a periportal collar is seen more commonly in patients with recently transplanted allografts (mean interval after transplantation, 46 days for peripheral collars and 57 days for central collars) and in patients with ascites. The presence of a central or peripheral periportal collar on CT is not sufficiently sensitive, specific, or accurate to reliably diagnose or exclude acute allograft rejection.

Adolescent↗
PubMed1991

A biologic basis for limited Kupffer cell reactivity to portal-derived endotoxin.

Despite continuous exposure to gut-derived endotoxin (lipopolysaccharide) under normal conditions, Kupffer cells (KC) fail to generate detrimental cytokine responses. KC function within a unique microenvironment in which high hepatic arginase activities (25 times greater than those activities in the kidney) result in negligible local L-arginine levels. To evaluate the relevance of this profound arginine deficiency on the physiologic function of KC, the kinetics of tumor necrosis factor (TNF-alpha) production and autoregulatory eicosanoid prostaglandin E2 (PGE2) production were compared in lipopolysaccharide-stimulated KC cultured with (1200 mumol/L) and without (10 mumol/L) L-arginine media. In (+)arginine culture the KC TNF-alpha production peaked early before decreasing as PGE2 production increased. In (-)arginine culture, however, KC TNF-alpha production was significantly (p less than 0.01) reduced, whereas PGE2 production was amplified (p less than 0.01). When cyclooxygenase blockade with indomethacin completely prevented KC production of PGE2 in (-)arginine culture, TNF-alpha production was upregulated (p less than 0.001 vs (-)arginine; p not significant vs (+)arginine). These arginine-specific depression of TNF-alpha responses appeared unique to KC because both TNF-alpha and PGE2 levels increased when peritoneal, pleural, and alveolar macrophages were stimulated by lipopolysaccharide in (-)arginine medium. This PGE2-dependent autoregulation of potentially harmful lipopolysaccharide-induced TNF-alpha responses may reflect an evolutionary adaptation by KC to their local hepatic environment and strategic anatomic position in the portal circuit, which optimally removes endotoxin and naturally protects the host.

Animals↗
PubMed1991

Kupffer cell prostaglandin-E2 production is amplified during hepatic regeneration.

Prostaglandin-E2 increases in liver tissue after partial hepatectomy and stimulates DNA synthesis in primary cultures of hepatocytes. This study evaluated the capacity of Kupffer cells isolated at various intervals after partial hepatectomy to produce prostaglandin E2 in response to bacterial endotoxin. This stimulator of Kupffer cells is a normal endogenous component of portal venous blood. After partial hepatectomy (6 to 48 hr), when hepatic regeneration rates were greatest, regenerating liver Kupffer cells demonstrated a significantly greater capacity to produce prostaglandin E2 in response to bacterial endotoxin than did equal numbers of Kupffer cells from time-matched, sham-operated control animals. However, by 12 days after partial hepatectomy, when liver mass had been more than 83% restored, regenerating liver Kupffer cell prostaglandin E2 production had decreased to levels produced by sham KC. We postulate that high levels of Kupffer cell-derived prostaglandin E2 provide a critical paracrine signal fundamental to the initiation and control of growth by neighboring hepatocytes during liver regeneration.

Animals↗