Several models of tumor necrosis factor (TNF)/TNFreceptor 1 (TNF-R1)-dependent liver injury in mice were investigated with respect to caspase-3-like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T-cell-activating agents (i.e., agonistic anti-CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-sensitized mice caused TNF/TNF-R1-dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF-mediated hepatotoxicity dependent on both TNF-R1 and TNF-R2. Hepatic caspase-3-like proteases were activated in GalN/TNF, GalN/anti-CD3, or GalN/SEB-treated mice, but not in Con A-treated mice. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-val-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxicity in all GalNdependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF-R1-dependent, but not TNF-R2-dependent, activation of caspase-3-like proteases, and zVADfmk prevented animals from Con A-mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A-and GalN/Con A-induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase-3-like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driven hepatocyte apoptosis involves activation of caspase-3-like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver. (HEPATOL-OGY 1999;30:1241-1251.) Activation of T lymphocytes appears to be the initial event in the pathophysiology of a variety of autoimmune liver diseases (e.g., chronic active hepatitis) or viral hepatitis. 1 This lymphocyte activation and the ensuing interactions of these cells with macrophages leads to a systemic cytokine response. The continuous release of proinflammatory cytokines such as tumor necrosis factor (TNF) or interferon gamma (IFN-␥) into the circulation is currently held responsible for the onset of pathological symptoms and the clinical manifestation of a variety of immunologically mediated liver diseases. [2][3][4][5] Several animal models of cytokine-dependent liver tissue destruction allow the study of mechanisms of T-lymphocyte activation in relation to the extent and time course of subsequent hepatic injury. In two commonly used models, D-galactosamine (GalN)-sensitized mice are injected with T-cell-activating anti-CD3 monoclonal antibodies, 6 or with the superantigen, staphylococcal enterotoxin B (SEB). 7 These treatment regimens both result in severe liver injury 8,9 characterized by histological features of apoptosis as well as internucleosomal DNA fragmentation. 9 In contrast to these GalN models, naive mice, when injected with the T-cell mitogen, concanavalin A (Con A), develop an acute, partly apoptotic, hepatic injury that is subsequently ove...
Neoplasms of the nervous system, whether spontaneous or induced, are infrequent in laboratory rodents and very rare in other laboratory animal species. The morphology of neural tumors depends on the intrinsic functions and properties of the cell type, the interactions between the neoplasm and surrounding normal tissue, and regressive changes. The incidence of neural neoplasms varies with sex, location, and age of tumor onset. Although the onset of spontaneous tumor development cannot be established in routine oncogenicity studies, calculations using the time of diagnosis (day of death) have revealed significant differences in tumor biology among different rat strains. In the central nervous system, granular cell tumors (a meningioma variant), followed by glial tumors, are the most common neoplasms in rats, whereas glial cell tumors are observed most frequently in mice. Central nervous system tumors usually affect the brain rather than the spinal cord. Other than adrenal gland pheochromocytomas, the most common neoplasms of the peripheral nervous system are schwannomas. Neural tumors may develop in the central nervous system and peripheral nervous system from other cell lineages (including extraneural elements like adipose tissue and lymphocytes), but such lesions are very rare in laboratory animals.
We have tested two surfactant preparations with the same phospholipid (PL) composition, containing recombinant surfactant protein-C (rSP-C surfactant) and without SP-C (plain PL surfactant). The effects of rSP-C surfactant were compared with the bovine-derived surfactant preparations Alveofact, bLES, and Infasurf in a lung lavage model, with surfactant given 1 h after the last lavage. The effects of surfactant treatment on histopathologic changes (e.g., hyaline-membrane formation) and improvement of oxygenation were compared with changes in untreated controls. The surfactants were given in doses of 25, 50, and 100 mg PL/kg body weight. At 120 min after treatment, only the protein-containing surfactants showed a statistically significant increasing dose dependence with respect to improving oxygenation. The values were 318 +/- 120 mm Hg, 443 +/- 58 mm Hg, and 480 +/- 43 mm Hg (mean +/- SD) for the three doses of rSP-C surfactant and 105 +/- 81 mm Hg, 100 +/- 69 mm Hg, and 131 +/- 108 mm Hg for the three doses of PL surfactant. The respective values for Alveofact were 104 +/- 81 mm Hg, 105 +/- 93 mm Hg, and 260 +/- 143 mm Hg; for bLES 373 +/- 138 mm Hg, 441 +/- 88 mm Hg, and 467 +/- 43 mm Hg; and for Infasurf 146 +/- 96 mm Hg, 284 +/- 178 mm Hg, and 436 +/- 70 mm Hg. The oxygen values of controls remained low, at 74 +/- 46 mm Hg. Only the protein-containing surfactants dose-dependently inhibited the formation of hyaline membranes. We conclude that rSP-C surfactant is at least as effective as bovine-derived surfactants. Furthermore, the data imply that the difference between plain PL surfactant preparations and bovine-derived surfactant preparations containing both SP-B and SP-C can be overcome by addition of SP-C.
Synthetic surfactants allow examination of the effects of specific components of natural surfactant. To determine whether surfactant containing apoprotein C, dipalmitoyl-phosphatidylcholine, phosphatidylglycerol, and palmitic acid restores gas-exchanging function in acute lung injury (ALI), we administered such surfactant (in doses of 50 or 100 mg/kg and in volumes from 1 to 6 ml/kg) or phospholipid (PL) alone, by intratracheal instillation, to pigs with ALI induced by massive saline lavage. Animals ventilated with 100% O(2) and receiving 1, 2, 4, or 6 ml/kg of 50 mg/kg recombinant surfactant apoprotein C (rSP-C) surfactant or 2 ml/kg of 50 mg/kg PL (control) had mean arterial PO(2) values, 4 h after treatment, of 230, 332, 130, 142, or 86 Torr, respectively. Animals receiving 1, 2, or 4 ml/kg of 100 mg/kg rSP-C surfactant or 2 ml/kg of 100 mg/kg PL (control) had mean arterial PO(2) values of 197, 214, 148, or 88 Torr, respectively. Surfactant PL distribution was homogeneous. Hyaline membrane formation was reduced in treated animals. Thus, in this model of ALI, rSP-C with PL has the capacity to improve gas exchange and possibly modify lung injury.
The direct carcinogenic effects of sidestream (SS) and mainstream (MS) smoke condensates of a filtered commercial brand of blond cigarettes were compared using a lifetime mouse skin tumorigenicity assay on female NMRI mice. Each cigarette was smoked by a smoking machine under the standard conditions, and the separately collected SS and MS smoke condensates were extracted with acetone/methanol as described elsewhere. These were tested for carcinogenicity on an area of 1-1.5 cm shaved skin of mice on the lower back. The mice were treated with half of each dose (5, 10 or 15 mg) twice a week, for only 3 months. No substance was used as promoter or as an additional initiator of carcinogenicity. No statistically significant difference was found when the life spans of MS-treated and untreated animals were compared. In contrast, the life spans of SS-treated mice were significantly (P less than 0.01) shorter than those of MS-treated animals or those of all three negative control groups together. The observed carcinogenic effects were based on tumours and lesions found only on the site of application of the test material. Of 210 mice (effective number, 129) serving as the negative controls, 3 developed skin lesions but no tumours. Of 210 MS-treated mice (effective number, 177), 7 developed tumours (4 malignant and 3 benign) and 35 had a uniform type of precancerous skin lesions. The numbers of tumours or lesions were not increased dose-dependently. Of 210 SS-treated animals (effective number, 182), 30 developed tumours (16 malignant and 14 benign) and 56 had a uniform type of precancerous skin lesion. The initiation of these latter lesions was found to be dose-dependent (P less than 0.001). The SS-treated animals developed two to six times more skin tumours than the MS-treated mice. Comparing the negative controls with the MS- or SS-treated animals, the overall carcinogenic effect observed was statistically significant. Comparing the MS- with SS-treated animals, the overall carcinogenic effect of SS was much higher than that of MS (P less than 0.001).
1 In a previous paper we showed that an SP-C containing surfactant preparation has similar activity as bovine-derived surfactants in a rat lung lavage model of the adult respiratory distress syndrome. In this study surfactant was given ten minutes after the last lavage (early treatment). In the present investigation we were interested how di erent surfactant preparations behave when they are administered 1 h after the last lavage (late treatment). 2 Four protein containing surfactants (rSP-C surfactant, bLES, Infasurf and Survanta) were compared with three protein-free surfactants (ALEC, Exosurf and the phospholipid (PL) mixture of the rSP-C surfactant termed PL surfactant) with respect to their ability to improve gas exchange in this more stringent model when surfactant is given one hour after the last lavage. For better comparison of the surfactants the doses were related to phospholipids. The surfactants were given at doses of 25, 50 and 100 mg kg 71 body weight. The surfactants were compared to an untreated control group that was only ventilated for the whole experimental period. 3 Tracheotomized rats (8 ± 12 per dose and surfactant) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min 71 , inspiration expiration ratio of 1 : 2, peak inspiratory pressure of 28 cmH 2 O at positive endexpiratory pressure (PEEP) of 8 cmH 2 O. Animals were ventilated for one hour after the last lavage and thereafter the surfactants were intratracheally instilled. During the whole experimental period the ventilation was not changed. 4 Partial arterial oxygen pressures (PaO 2 , mmHg) at 30 min and 120 min after treatment were used for statistical comparison. All protein containing surfactants caused a dose-dependent increase of the reduced PaO 2 values at 30 min after treatment. The protein-free surfactants showed only weak dosedependent increase in PaO 2 values at this time. This di erence between the protein-containing and the protein-free surfactants was even more pronounced when comparing the PaO 2 values at 120 min after treatment. Only rSP-C surfactant, bLES and Infasurf showed a dose-dependent increase in PaO 2 at this time.5 With this animal model of late treatment it is possible even to di erentiate between bovine derived surfactants. The di erences between protein-containing and protein-free surfactants become even more pronounced. From the comparison of rSP-C surfactant with bovine-derived surfactants and the PL surfactant without rSP-C, it can be concluded that addition of rSP-C is su cient to achieve the same activity as that of natural surfactants.
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