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PubMed2003

Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation.

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

Animals↗

PubMed1963

Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. II. Lymphoma 6C3HED cells cultured in a medium devoid of L-asparagine lose their susceptibility to the effects of guinea pig serum in vivo.

Cells of the original line of lymphoma 6C3HED, which regularly prove susceptible to the effects of guinea pig serum in vivo, were cultured in Eagle's medium devoid of L-asparagine; after a latent period of 2 or more weeks, during which time the cell population declined markedly, some of the cells began to proliferate, and thereafter continued vigorous growth. On implantation into mice the proliferating cells were found, however, to have completely and permanently lost their susceptibility to the effects of guinea pig serum. By contrast, when cultures of the original line of 6C3HED cells were prepared in Eagle's medium to which L-asparagine was added in a concentration of 20.0 mg/liter or more, they proliferated vigorously from the beginning; after long periods of growth in the enriched medium in vitro they remained susceptible to the effects of guinea pig serum upon test in vivo. Other amino acids, purines, and pyrimidines were unable to substitute for L-asparagine in this relation. Furthermore, a variant subline of 6C3HED cells which had become insensitive to guinea pig serum under in vivo conditions did not require L-asparagine for growth in tissue culture. It seems plain from the findings as a whole, that in 6C3HED cells, L-asparagine dependence in vitro is associated with the in vivo character of guinea pig serum sensitivity, and conversely L-asparagine independent variants are insusceptible to the effects of guinea pig serum. The implications of the findings complement those of a companion paper in which direct evidence is provided that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects.

Amino Acids↗

PubMedDate not supplied

Immunity to reinfection and immunization of male guinea pigs against urethral infection with the agent of guinea pig inclusion conjunctivitis.

BACKGROUND AND OBJECTIVES: There is little information available on immunity of males to chlamydial infection after recovering from a primary urethral infection or after immunization with chlamydial antigen. The guinea pig model of genital infection using the chlamydial agent of guinea pig inclusion conjunctivitis was utilized to evaluate the protective immune response in these circumstances. GOAL: To determine whether immunity to reinfection develops after a primary urethral infection and whether immunity develops as a result of immunization with inactivated chlamydiae. STUDY DESIGN: Groups of five male guinea pigs each in two separate experiments were infected in the urethra with chlamydiae and challenged with a fresh inoculum at either 30, 75, or 150 days after infection. The course of the challenge infection was then determined. Similarly, guinea pigs were immunized subcutaneously with ultraviolet-inactivated chlamydial elementary bodies and the course of urethral infection was determined when inoculated 2 weeks after immunization. RESULTS: Male guinea pigs were highly resistant to reinfection after a primary urethral infection. Animals that were immunized with inactivated chlamydiae generally became infected upon challenge, but the intensity of the infection was markedly reduced. CONCLUSIONS: Male guinea pigs possess protective mechanisms that make them more resistant to repeat chlamydial genital infection for a longer period of time than is seen in female guinea pigs. In addition, immunization of males with inactivated chlamydial antigen by a parenteral route is able to elicit a protective response to urethral infection with chlamydiae.

Animals↗

PubMed1999

In vitro activity of the ketolide HMR 3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia.

The activities of HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin for 97 Legionella spp. isolates were determined by microbroth dilution susceptibility testing. Growth inhibition of two Legionella pneumophila strains grown in guinea pig alveolar macrophages was also determined. The concentrations required to inhibit 50% of strains tested were 0.06, 0.02, 0.25, 0.03, and 0.02 microg/ml for HMR 3647, HMR 3004, erythromycin, clarithromycin, and levofloxacin, respectively. BYEalpha broth did not significantly inhibit the activities of the drugs tested, as judged by the susceptibility of the control Staphylococcus aureus strain; however, when Escherichia coli was used as the test strain, levofloxacin activity tested in BYEalpha broth was fourfold lower. HMR 3647, HMR 3004, erythromycin, and clarithromycin (0.25 and 1 microg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 0.5 to 1 log10, but regrowth occurred over a 2-day period. HMR 3647, erythromycin, and clarithromycin appeared to have equivalent intracellular activities which were solely static in nature. HMR 3004 was more active than all drugs tested except levofloxacin. In contrast, levofloxacin (1 microg/ml) was bactericidal against intracellular L. pneumophila and significantly more active than the other drugs tested. Therapy studies with HMR 3647 and erythromycin were performed in guinea pigs with L. pneumophila pneumonia. When HMR 3647 was given (10 mg/kg of body weight) by the intraperitoneal route to infected guinea pigs, mean peak plasma levels were 1.4 microg/ml at 0.5 h and 1.0 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.4 h. All 16 L. pneumophila-infected guinea pigs treated with HMR 3647 (10 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days after antimicrobial therapy, as did all 16 guinea pigs treated with the same dose of HMR 3647 given twice daily. Fourteen of 16 erythromycin-treated (30 mg/kg/dose given intraperitoneally twice daily) animals survived, whereas 0 of 12 animals treated with saline survived. HMR 3647 is effective against L. pneumophila in vitro, in infected macrophages, and in a guinea pig model of Legionnaires' disease. HMR 3647 given once daily should be evaluated as a treatment for Legionnaires' disease in humans.

Animals↗

PubMed2001

In vitro activity of ABT-773 against Legionella pneumophila, its pharmacokinetics in guinea pigs, and its use to treat guinea pigs with L. pneumophila pneumonia.

The activity of ABT-773 was studied against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia. The ABT-773 MIC at which 50% of isolates are inhibited (MIC(50)) for 20 different Legionella sp. strains was 0.016 microg/ml, whereas the MIC(50)s of clarithromycin and erythromycin were 0.032 and 0.125 microg/ml, respectively. ABT-773 (1 microg/ml) was bactericidal for two L. pneumophila strains grown in guinea pig alveolar macrophages. In contrast, erythromycin and clarithromycin had easily reversible static activity only. Therapy studies of ABT-773 and erythromycin were performed with guinea pigs with L. pneumophila pneumonia. When ABT-773 was given to infected guinea pigs by the intraperitoneal route (10 mg/kg of body weight), mean peak levels in plasma were 0.49 microg/ml at 0.5 h and 0.30 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 0.55 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was 0.65 microg. h/ml. For the same drug dose, mean levels in the lung were 15.9 and 13.2 microg/g at 0.5 and 1 h, respectively, with a half-life of 0.68 h and an AUC(0-24) of 37.0 microg. h/ml. Ten of 15 L. pneumophila-infected guinea pigs treated with ABT-773 (15 mg/kg/dose given intraperitoneally once daily) for 5 days survived for 9 days post-antimicrobial therapy, as did 14 of 15 guinea pigs treated with erythromycin (30 mg/kg given intraperitoneally twice daily) for 5 days. All of the ABT-773-treated animals that died appeared to do so because of drug-induced peritonitis rather than overwhelming pneumonia. None of 12 animals treated with saline survived. ABT-773 is as effective as erythromycin against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease. These data support studies of the clinical effectiveness of ABT-773 for the treatment of Legionnaires' disease.

Animals↗

PubMed1976

Comparison of guinea pig cytomegalovirus and guinea pig herpes-like virus: growth characteristics and antigentic relationship.

The growth characteristics of guinea pig cytomegalovirus (GPCMV) and guinea pig herpes-like virus (GPHLV) in cell cultures were compared. Guinea pig fibroblast cells were highly susceptible to infection with both viruses, whereas guinea pig kidney cells were sensitive only to GPHLV. No cytopathic effect was observed in the latter cell system after infection with GPCMV,nor was there an increase in virus titer, although the cirus persisted in the kidney cells for 2 to 3 weeks postinfection. Electron microscope studies showed nonvirion tubular structures in GPCMV -infected fibroblast cells, but not in GPHLV- infected cells. Large packages of enveloped nuclear virus particles were commonly seen in GPHLV -infected cells, especially kidney epithelial cells, but none were found in the GPCMV -infected fibroblasts. Complete enveloped extracellular virus particles were present in both virus-cell systems. Both viruses showed narrow host spectra and replicated well only in guinea pig cells although GPHLV multiplied to some degree in rabbit cells. No antigenic relationship could be demonstrated between the two viruses using antisera specific for each virus that was produced in rabbits and guinea pigs. Rabbits produced high neutralizing antibody titers to GPHLV, whereas guinea pigs were the animals of choice for GPCMV antiserum production.

Animals↗

PubMed1989

Role of cell-mediated immunity in the resolution of secondary chlamydial genital infection in guinea pigs infected with the agent of guinea pig inclusion conjunctivitis.

Guinea pigs which have recovered from a genital infection with the agent of guinea pig inclusion conjunctivitis demonstrate strong immunity to reinfection for a short period of time but then become susceptible to reinfection. The secondary infection is markedly shortened in duration and decreased in intensity. Previous studies have indicated an important role for humoral immunity in resistance to and in recovery from reinfection. However, the contribution of cell-mediated immunity to immunity toward or recovery from a secondary infection is not clear. Guinea pigs were infected in the genital tract with guinea pig inclusion conjunctivitis and were challenged at either 30 or 75 days after the primary infection. Prior to challenge, one group of animals were injected with rabbit anti-guinea pig thymocyte serum (ATS) while control groups received either normal rabbit serum or no treatment. Treatment was continued daily for the course of the experiment. On day 30, ATS-treated guinea pigs had a slightly higher rate of reinfection, and generally the infection persisted longer than in controls. On day 75, all animals became reinfected upon challenge, but control animals resolved their infections in 3 to 9 days. In contrast, most ATS-treated animals remained infected throughout the course of the experiment. Although the animals became reinfected, the levels of chlamydiae were much lower than those observed during the primary infection. ATS treatment abrogated T-cell responses, but serum and secretory antibody responses remained normal. Histopathological examination revealed some decrease in mononuclear infiltration of endocervical and uterine tissues in ATS-treated animals. These data indicate that previously infected guinea pigs require both cell-mediated immunity and humoral immunity for resolution of a challenge infection.

Animals↗

PubMed1962

Influence of guinea pig plasma factors on phagocytosis of Pasteurella pestis. II. Plasma from plague-infected guinea pigs.

Stanziale, W. G. (Fort Detrick, Frederick, Md.) and J. D. White. Influence of guinea pig plasma factors on phagocytosis of Pasteurella pestis. II. Plasma from plague-infected guinea pigs. J. Bacteriol. 83:182-186. 1962.-The phagocytosis enhancing property of normal guinea pig plasma was altered during experimental plague infection. The most notable changes occurred in the plasma from afebrile, moribund animals and from those convalescing from acute infection. The plasma of the moribund guinea pigs, which was obtained 7 to 8 days after exposure to Pasteurella pestis, inhibited phagocytosis to a considerable degree. Plasma from convalescent guinea pigs enhanced phagocytosis to a higher degree than the plasma of normal animals. In contrast, plasma from recovered guinea pigs in which cultural or serological evidence of infection was not demonstrated enhanced phagocytosis to a degree equivalent to that of normal plasma. Plasma taken from guinea pigs during the febrile phase of plague infection enhanced phagocytosis to a lower degree than did normal plasma.

Animals↗

PubMed1975

Characterization of murine sarcoma virus transformation of guinea pig cells and activation of an RNA tumor-like virus from nonproducer guinea pig cells.

Guinea pig embryo (GEP) cells were transformed in vitro by the Kirsten strain of mouse sarcoma virus (Ki-MSV). The transformed cells were found to release infectious virus continuously and produced high titers of group-specific (gs) complement-fixing (CF) antigen characteristics of the murine sarcoma-leukemia virus complex. Foci of transformed cells were similar in appearance to those obtained with Ki-MSV in mouse and rat cells. The transformed cells produced RNA dependent DNA polymerase and type C virus particles with a density of approximately 1.15 g/ml in sucrose gradients by 3H-uridine labeling. The transformed cells produced tumors when transplanted into newborn guinea pigs. A number of focus-derived clonal lines from Ki-MSV transformed cells were isolated and characterized. All the focus-derived lines were found to be either producers or nonproducers (NP). The NP guinea pig cells produced neither infectious virus nor viral antigens of the murine sarcoma-leukemia virus complex although they were morphologically indistinguishable from virus-releasing MSV transformed GPE lines and produced tumors when transplanted into newborn guinea pigs. However, the sarcoma virus genome could be rescued in these NP cells by cocultivation with "helper" murine leukemia virus (MuLV) releasing GPE cells. Particles resembling guinea pig leukemia virus were activated from guinea pig NP cells or cultured normal guinea pig cells following chemical treatment. These particles were approximately 100 nm in the mature form and had a density of 1.16-1.17 g/ml. They contained RNA dependent DNA polymerase activity.

Animals↗

PubMed2002

Guinea pig GnRH: localization and physiological activity reveal that it, not mammalian GnRH, is the major neuroendocrine form in guinea pigs.

The isolation of GnRH cDNA from guinea pig hypothalamus predicted a novel form of GnRH with two unique amino acid substitutions relative to all known forms of this essential decapeptide. The predicted substitution at amino acid 2 in guinea pig (gp) GnRH was particularly intriguing because of the proposed importance of position 2 for binding and activation of the GnRH receptor. In the present study, gpGnRH was synthesized, and a specific antibody was generated and used to assess translation of the gpGnRH transcript. The localization of intensely labeled gpGnRH-positive cell bodies and processes in tissue sections through the preoptic area and hypothalamus argue that gpGnRH is the major neuroendocrine form of GnRH in guinea pigs. Guinea pig GnRH stimulated LH release in guinea pigs and increased LH output from guinea pig pituitary fragments, thus demonstrating biological activity in this species. In contrast, gpGnRH demonstrated little ability to stimulate LH release in rats, a species known to possess the highly conserved mammalian GnRH receptor. These findings suggest that: (1) the amino acid substitutions in gpGnRH impede binding to and/or activation of the mammalian GnRH receptor, and (2) the unique amino acid substitutions in gpGnRH are accompanied by changes in the guinea pig GnRH receptor.

Animals↗

PubMed2000

[Culture of endotheliocytes derived from guinea-pig common carotid artery and establishment of guinea-pig donor model].

Since endotheliocyte strains of guinea-pig and inbred strains of guinea-pig are not easily obtained, it is impossible to ensure the consistence of antigenicity between endotheliocytes and donor organs when endotheliocytes are used as an inductor in the research of immunological tolerance. So it is necessary to establish the guinea-pig endotheliocyte-donor model. One side of common carotid arteries was removed and reversed. After collagenase digestion, culture of endotheliocytes was performed. And the survival time of guinea-pig was observed. Cultured cells were confirmed as endotheliocytes by the study of morphology, immunohistochemistry and electron microscopy. The two-month-survival of guinea-pigs was 92% (103/112). The establishment of guinea-pig endotheliocyte-donor model can provide the foundation for the research of guinea-pig endotheliocyte and immunological tolerance.

Animals↗

PubMed1997

Recombinant guinea pig and human RANTES activate macrophages but not eosinophils in the guinea pig.

To characterize the biologic activities of potential mediators of allergic inflammation, we have cloned, expressed, and purified guinea pig RANTES (gpRANTES). cDNA for gpRANTES was cloned from Con A-stimulated guinea pig spleen cells. A high level of gpRANTES expression in Escherichia coli was achieved by mutation of a human RANTES (hRANTES) expression construct to obtain a 68-amino acid protein identical with the predicted guinea pig amino acid sequence, assuming an equivalent amino terminus as the human protein. Purified gpRANTES was an effective stimulus of human eosinophils as assessed by increases in intracellular free calcium in fura-2-loaded cells and chemotactic responses in vitro. gpRANTES exhibits similar potency and efficacy to hRANTES. In marked contrast, neither gpRANTES nor hRANTES was able to activate guinea pig peritoneal eosinophils in these assays, even in the presence of IL-5. However, gpRANTES was found to be a potent stimulator of guinea pig peritoneal macrophages. Following tracheal instillation of gpRANTES, a dose-dependent increase in macrophages, but not eosinophils, was observed in gpBAL. Macrophage accumulation was detectable by 6 h and sustained for at least 48 h. These results indicate that RANTES in the guinea pig may have a different cellular selectivity than that described in the human, which may be important in the use of animal models in the analysis of allergic disorders. These selectivities do not appear to be accounted for by differences in guinea pig and human RANTES sequences.

Amino Acid Sequence↗

PubMed2000

Pigs shift too: foraging strategies and spatial memory in the domestic pig.

In a previous experiment, we showed that domestic pigs, Sus scrofa, unlike many other species, performed accurately in a spatial memory task, where visits to a previously baited food trough were rewarded (win-stay). We investigated whether pigs have a predisposition for this strategy, by comparing their performance in a radial arm maze under either win-stay (N=10) or win-shift (N=10) reward contingencies. Contrary to our earlier results, only one of the animals in the win-stay condition was able to reach the imposed criterion level of accuracy. The performances of the other win-stay pigs did not deviate from random. All pigs in the win-shift condition reached criterion by day 25 of the experiment, and performed better than expected by chance. Analysis of the types of errors made matched our a priori predictions that shift movements would occur more frequently, especially within visits to the maze. We suggest that the difference in learning rates may reflect the fact that win-stay pigs needed to use two different rules, stay between trials and shift within trials, while win-shift pigs only needed to use the shift rule. In our previous study, win-stay pigs did not experience a conflict of rules and this may have facilitated stay learning. We found evidence of a recency effect in win-shift animals and a primacy effect in the win-stay group. However, we discuss the unsuitability of these specific terms in this type of experiment, and propose an alternative interpretation of the results. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed2000

Presence of the LEE (locus of enterocyte effacement) in pig attaching and effacing Escherichia coli and characterization of eae, espA, espB and espD genes of PEPEC (pig EPEC) strain 1390.

In the present study, attaching and effacing Escherichia coli (AEEC) O45 isolates from post-weaning pigs with diarrhoea were examined for the presence of the LEE (locus of enterocyte effacement) using various DNA probes derived from the LEE of human enteropathogenic E. coli (EPEC) strain E2348/69. The LEE fragment was conserved among the eae -positive pig isolates. The attaching and effacing activity of PEPEC (pig EPEC) O45 isolates is highly correlated with the presence of the LEE. Nevertheless, for some PEPEC isolates, the insertion site of the LEE is different or has diverged during evolution. The presence of the LEE fragment in PEPEC isolates provides further evidence that the LEE region is conserved among AEEC of different animal origins. In addition, the nucleotide sequence of the region containing the eae gene and esp genes of a pig AEEC isolate, strain 1390, was determined. Among examined Eae proteins, Eae of strain 1390 showed the highest similarity with Eae belonging to the beta intimin group such as the Eae of rabbit AEEC. Moreover, all pig strains that produced attaching and effacing lesions in piglets and pig ileal explants belonged to the beta intimin group. The deduced amino acid sequences of the EspA, EspB and EspD proteins of strain 1390 showed particularly strong homology to those of AEEC strains presenting a beta intimin allele. Thus, pig AEEC possess the LEE sequences, and for the strain 1390, sequences of the eae and esp regions are related to those of other AEEC, in particular, strains presenting a beta intimin allele, such as the rabbit AEEC.

Adhesins, Bacterial↗

PubMed1982

Temperature independence of the alkaline Bohr effect in pig red cells and pig haemoglobin solutions.

The influence of temperature on the oxygen affinity and the alkaline Bohr effect of pig red cells and pig hemoglobin solutions has been compared to that of human adult red cells and human adult hemoglobin. Pig red cells and pig Hb evidence a lower affinity for oxygen in various conditions of pH, temperature and salt concentration, in the presence as well as in the absence of organic phosphates. It has been observed that the alkaline Bohr effect of pig Hb was reduced by 20-25% compared to Hb A0 and independent of changes in temperature, contrary to human Hb A0. Titrations of pig Hb with C1- indicate a lower heterotropic effect of this anion at low concentration of the salt. It is concluded that this may be the origin of the temperature independence of the alkaline Bohr effect in pig Hb. Conversely, the temperature dependence of the alkaline Bohr effect of Hb A0 should be related to the oxygen-linked binding of C1- at the alpha 1-alpha 2 interface.

Adult↗

PubMed1994

Detection of pig farms with Ornithodoros erraticus by pig serology. Elimination of non-specific reactions by carbohydrate epitopes of salivary antigens.

Ornithodoros erraticus is the European vector of African Swine Fever. It is therefore essential to know on which pig farms the tick is present in order to prevent contact with swine. Currently, studies are being made to ascertain this through the detection of anti-O. erraticus antibodies in the sera of swine, using three extracts from the salivary glands of the parasite (SGE): a complete extract (SGE-1), a soluble antigens extract (SGE-2), and a tissue antigens extract (SGE-3). The results of the present work show that SGE-2 gives the best differentiation between swine bitten by O. erraticus and unbitten swine in the enzyme-linked immunosorbent assay (ELISA). Using this extract, an optical density (OD) five-fold higher than the basal OD indicates that the pigs carry anti-O. erraticus antibodies. A serological study carried out in Salamanca with 8083 sera from 1756 pig farms revealed the presence of the parasite on 135 farms. However, during this study we noticed that some sera of unbitten animals gave false-positive reactions. Western blot analysis of SGE-2 of these false-positive sera demonstrated the same bands (except for two) as the real anti-O. erraticus sera. We observed, in ELISA and Western blot analysis, that such false-positive sera only recognised carbohydrate epitopes on SGE-2. This reactivity disappeared on deglycosylated SGE-2 (SGE-2-P). Therefore, SGE-2-P is the antigen that confers the greatest specificity to serology. In this study it was also observed that the low levels of anti-O. erraticus antibodies found in some cases may be because the swine were bitten some months previously on a different farm or that the current farm harboured only a few specimens of O. erraticus, so pig-tick contact is unlikely and hence the pigs either only develop a primary response or the time between contacts is very long and the levels of antibodies fall. Since pigs could be bitten on a different farm, the presence of low levels of anti-O. erraticus antibodies in pig sera do not necessarily indicate the presence of the tick on the farm where sampling was carried out.

African Swine Fever↗

PubMed1989

Nephropathy in the mature pig after the irradiation of a single kidney: a comparison with the immature pig.

The right kidney of 11 mature 10-month-old Large White female pigs was irradiated with single doses of 9.8-14.0 Gy of 60Co gamma rays. Individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using 99mTc-DTPA and 131I-hippuran renography for periods up to 24 weeks after irradiation. Renal function was assessed either as a functional index, FI (FI = irradiated/unirradiated kidney function), or as the individual kidney GFR and ERPF. The radiation-induced changes after the irradiation of a single kidney (unilaterally irradiated--UI) of mature pigs were compared with those previously observed in 14-week-old immature pigs. Irradiation resulted in a dose-dependent reduction in the FI for both GFR and ERPF. However, these reductions were significantly less than those previously seen in immature pigs. Within 2 weeks of irradiation GFR increased in both the irradiated and the unirradiated kidneys in each animal, compared with unirradiated age-matched control kidneys. No marked changes in renal hemodynamics were seen in mature animals after a single dose of 9.8 Gy. This was in marked contrast to the pronounced reduction in the GFR and ERPF in the irradiated kidney previously observed in immature animals irradiated with an equivalent single dose of X rays. After higher doses, the irradiated kidney in mature pigs showed a dose-dependent reduction in GFR and ERPF. However, the extent of this reduction was significantly less than that seen in immature animals. There was no apparent difference in the response of the unirradiated kidneys in mature or immature pigs. The ED50 values, based on a probit fit to the data for the proportion of functional tests in which the irradiated kidney showed a greater than or equal to 50% reduction in GFR or ERPF, were higher in the mature animals; for example for ERPF the ED50 values were 11.76 +/- 0.28 Gy and 7.67 +/- 0.34 Gy for mature and immature animals, respectively. Thus, the UI kidney in mature pigs appears to be less radiosensitive than the UI kidney in immature animals.

Aging↗

PubMed2006

A novel strategy for preventing human CD8+ cytotoxic T lymphocyte-mediated cytotoxicity against pig endothelial cells by overexpression of pig cellular FLICE-like inhibitory protein (c-FLIP) gene.

Human CD8+ cytotoxic T lymphocyte (CTL)-mediated cytotoxicity in xenograft recipients is an important obstacle for successful xenotransplantation of pig organs into humans. In our previous study, we demonstrated that xenocytotoxicity of human CD8+ CTL detrimental to pig endothelial cells (PEC) is mediated mainly by the Fas/FasL apoptotic pathway. Furthermore, we developed new methods to prevent this CTL killing by extracellular remodeling using overexpression of human decoy Fas antigen and membrane-bound human FasL on pig xenograft cells. The cellular FLICE-inhibitory protein (c-FLIP), a caspase-8 inhibitor that lacks the cysteine domain, is a negative regulator of death receptor-mediated apoptosis. c-FLIP proteins exist as long (c-FLIP(L)) and short (c-FLIPs) splice variants, both capable of protecting cells from death receptor-mediated apoptosis. In this report, we have demonstrated that both pig c-FLIPs and pig c-FLIP(L) significantly inhibit human CD8+ CTL-mediated xenocytotoxicity toward stably transfected PEC, although the expression level of pig Fas antigen on cell surface was not changed. These data suggested that intracellular remodeling with overexpression of pig c-FLIP in xenograft cells may decrease the innate cellular responses against xenografts, facilitating long-term xenograft survival.

Animals↗