Long-acting PGE2 and Lisinopril Mitigate H-ARS.

Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.

Mucosal ulcerogenic action of monochloramine in rat stomachs: effects of polaprezinc and sucralfate.

Effects of a novel zinc compound polaprezinc [N-(3-aminopropionyl)-L-histidinatozinc] and sucralfate on the mucosal ulcerogenic responses induced by monochloramine (NH2Cl) were examined in rat stomachs. Oral administration of NH2Cl (>60 mM) produced severe lesions in unanesthetized rat stomachs, with concomitant increase of lipid peroxidation. These lesions were aggravated by sensory deafferentation but not affected by pretreatment with indomethacin or L-NAME. The mucosal ulcerogenic response to NH2Cl was significantly inhibited by oral pretreatment with either dmPGE2 (10 microg/kg), capsaicin (30 mg/kg), or NOR-3 (3 mg/kg), the NO donor. Gastric lesions induced by NH2Cl were also inhibited by prior oral administration of polaprezinc (3-30 mg/kg) as well as sucralfate (30 and 100 mg/kg). The protective effect of polaprezinc was not affected by any pretreatments such as indomethacin, L-NAME, or sensory deafferentation, while that of sucralfate was significantly mitigated in the presence of either indomethacin or L-NAME. On the other hand, mucosal exposure to NH4OH (60 mM) caused a marked PD reduction in ex vivo stomachs made ischemic by bleeding from the carotid artery, followed by severe gastric lesions. These ulcerogenic and PD responses caused by NH4OH plus ischemia were also attenuated by prior application of polaprezinc, while dmPGE2 and sucralfate prevented such lesions without affecting the reduced PD response. These results suggest that: (1) NH2Cl generated either exogenously or endogenously damages the gastric mucosa, (2) both polaprezinc and sucralfate protect the stomach against injury caused by NH2Cl, and (3) the mechanisms underlying the protective action of sucralfate may be partly mediated by both endogenous PGs and NO but may be different from those of polaprezinc.

Repair of rat gastric mucosa: effect of 16,16-dimethyl prostaglandin E2.

Prostaglandins protect the gastric mucosa against a variety of injurious agents and may accelerate the recovery of the gastric mucosa following damage. In previous studies prostaglandins were given prior to the injurious agent, so it was not possible to distinguish their potential effects on accelerating repair or reducing initial damage. We have investigated the effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on the repair of the gastric mucosa after injury induced by several injurious agents. dmPGE2 was given orally 15 min prior to aspirin or sodium salicylate, or 30 min after aspirin, sodium salicylate, or ethanol. dmPGE2 delivered prior to injury reduced the aspirin-induced fall in mucosal potential difference (PD), but had no effect on that induced by sodium salicylate. dmPGE2 administered after ASA injury significantly increased recovery of PD (P < 0.05), but did not alter the rate of recovery of PD with other damaging agents. Histological damage was decreased in rats treated with dmPGE2 after aspirin compared to aspirin-only-treated rats (P < 0.02). Exogenous dmPGE2 protects and restores gastric mucosal integrity after aspirin damage but has no effect on the repair of sodium salicylate and ethanol injured mucosa, suggesting that repair of the gastric mucosa after aspirin damage is enhanced by dmPGE2 due to its ability to prevent ongoing damage, rather than directly enhancing repair processes.

Protective effects of potato extracts and 16,16-dimethyl prostaglandin E2 on the induction of hepatic foci by cotreatment of gamma radiation and diethylnitrosamine.

We investigated the effect of potato extracts and 16,16-dimethyl prostaglandin E2 (DiPGE2) on the induction of glutathione S-transferase P-positive (GST-P+) altered hepatic foci in newborn Sprague-Dawley rats given single treatment with 60Co gamma irradiation and diethylnitrosamine (DEN) alone or in sequential combination. Intraperitoneal injection of 0.15 mumol/g body weight of DEN 1 hour after gamma radiation significantly increased the frequencies of GST-P+ hepatic foci compared to DEN or gamma radiation alone and DEN injection 1 hour before irradiation (p < 0.001). Potato extract was given at a dose of 2 mg/ml in drinking water for 3 weeks and DiPGE2 given at a dose of 10 micrograms/mouse 30 minutes before irradiation. Potato extracts and DiPGE2 decreased significantly the number (p < 0.001), area (p < 0.001) and Dmax (p < 0.05) of GST-P+ hepatic foci compared to the corresponding control. These results suggest that potato extracts and DiPGE2 have radio-protective potential and further studies for underlying mechanisms will be necessary.

Attenuation of acetaminophen hepatitis by prostaglandin E2. A histopathological study.

Acute acetaminophen hepatitis was produced in three groups of five rats given 1600 mg/kg by gavage. The protective effect of 16,16-dimethyl prostaglandin E2, 200 micrograms/kg administered subcutaneously 30 min later, was compared to the protective effect of N-acetylcysteine 1 g/kg similarly administered. All animals were killed at 24 hr, and liver tissues were compared histologically to the damage found in acetaminophen-treated controls and untreated anatomic controls. Serum transaminase values at 24 hr exceeded 1000 units in the acetaminophen control group, averaged 658 units in the acetylcysteine treated group, and were near normal (75 units) in the prostaglandin treated group (P < 0.02). Liver samples (1 cm3) were removed terminally at 24 hr. Liver damage was assessed without reference to precedent history. Histopathologically, damage was most severe in the acetaminophen control group, mainly in pericentral lobular zones. The prostaglandin-treated group showed considerably less damage, which was confined to the hepatic vein area. The acetylcysteine-treated group showed an intermediate degree of damage. We conclude that dmPGE2, given 30 min after ingestion of acetaminophen was found to be more effective in limiting liver damage than NAC in this rat model.

Pepsin hydrolysis of the adherent mucus barrier and subsequent gastric mucosal damage in the rat: effect of diosmectite and 16,16 dimethyl prostaglandin E2.

BACKGROUND AND OBJECTIVE: The gastroduodenal mucus layer is progressively eroded at its luminal surface as a consequence of pepsin mucolysis. Diosmectite binds to gastric mucus and modifies its rheological properties. Prostaglandins are well-known mucus secretagogues. The aim of this study is to describe interactions of diosmectite and 16,16 dimethyl prostaglandin E2 on adherent gastroduodenal mucus and pepsin mucolysis in the rat. METHODS: Instillation of pepsin (1 or 2 mg.mL-1 at pH1 or pH2) into the pylorus ligated stomach of anaesthetised rats resulted in progressive disruption of the adherent mucus layer and a large, significant, increase in soluble degraded mucin compared to that following instillation of HCl pH1 or pH2. Pepsin (2 mg.mL-1), instillation over 2 hours, but not HCl alone, consistently resulted in small focal, haemorrhagic mucosal lesions, significant bleeding into the lumen and histologically, localised punctate ulcers in an otherwise intact epithelium. Diosmectite (500 mg.kg-1) and 16,16 dimethyl prostaglandin E2 were given by oro-gastric intubation. RESULTS: Diosmectite, given 30 minutes beforehand, inhibited breakdown of the adherent gastric mucus barrier by pepsin in vivo. When administered up to 16 hours prior to the experiment, diosmectite prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage. Substantial amounts of diosmectite (39.6 micrograms/mm2, equivalent in volume to layer 93 microns thick) were bound to the gastric mucosa 30 minutes after administration. Diosmectite (100:1 by weight to enzyme) completely inhibited pepsin hydrolysis of protein in vitro. Topical 16,16 dimethyl prostaglandin E2, 5 micrograms.kg-1 increased the thickness of the adherent mucus layer by two-fold. Both doses of the prostaglandin prevented pepsin induced gastric mucosal haemorrhage and histological epithelial damage. CONCLUSIONS: These results show that both diosmectite and prostaglandin increase the effectiveness of the mucus barrier against mucosal damage by pepsin in vivo.

Effect of prostaglandins and superoxide dismutase administration on oxygen free radical production in experimental acute pancreatitis.

Oxygen free radicals and prostaglandins are implicated in the pathophysiology of acute pancreatitis, although their mechanisms of action remain unclear. We have studied the effect of administration of exogenous 16,16-dimethyl prostaglandin E2 and superoxide dismutase on oxygen free radical production in acute pancreatitis. For this purpose, five experimental rat groups were studied: group I, control; group II, sodium taurocholate-induced acute pancreatitis; group III, same as group II but with previous administration of 16,16-dimethyl prostaglandin E2; group IV, same as group II but with previous administration of indomethacin; and group V, same as group II but with previous administration of superoxide dismutase. In sodium taurocholate-treated rats, xanthine dehydrogenase is completely converted to xanthine oxidase within the first 5 min with subsequent oxygen free radical production while in 16,16-dimethyl prostaglandin E2-treated rats this enzyme transformation does not occur. In the superoxide dismutase-treated group xanthine oxidase activation is partially prevented. These data suggest that xanthine oxidase is the main source of oxygen free radicals, which contribute to extending the cellular damage in sodium taurocholate-induced acute pancreatitis.

Reduction of short-term radiation lethality by biological response modifiers given alone or in association with other chemical protectors.

The advantages gained by a combined treatment of different chemical protectors on short-term lethality of X-irradiated adult male mice have been studied. The following compounds were given alone or in a mixture of two or three compounds: 16,16-dimethyl PGE2 (PGE2), cysteine (Cys), glucan, glutathione (GSH), 5-hydroxytryptamine (5-HT), mercaptoproprionylglycine (MPG), or WR-2721. The survival of mice treated before X irradiation with the optimal dose of each radioprotector given separately shows that WR-2721 and 5-HT yield the best protection with dose reduction factors (DRFs) of 2.2 and 1.7, respectively. Cysteine, glucan, PGE2, MPG, and GSH, with DRFs of 1.4, 1.4, 1.2, 1.1, and 1.1, respectively, are less efficient radioprotectors. When PGE2 was combined with a low dose of WR-2721 (200 mg/kg), the protection increased in a synergistic way. The increase in protection offered by a combination of PGE2 with Cys, glucan, GSH, or 5-HT is less marked and the effect obtained is only additive. A synergistic action is also obtained with a combination of WR-2721 (200 mg/kg) and 5-HT (8 mg/kg) (DRF 2.7).

Cytoprotective drugs in the prevention of ethanol-induced experimental gastric mucosal damage: a morphological study.

Various so-called "cytoprotective" agents (sucralfate, carbenoxolone, 16,16-dimethyl-PGE2, sulglycotide and Maalox TC) have been tested on rats, with the aim of quantifying their capability to prevent ethanol-induced gastric mucosal damage. Rats fasted for 48 hours received 1 ml of 80% ethanol by oral gavage, after prior oral treatment with placebo or one of the above-mentioned drugs u.i.d. for 5 consecutive days. Six hours after ethanol administration, the animals were sacrificed and the stomach was removed and processed for computerized macroscopic assessment of the damaged surface and for structural (light microscopy) and ultrastructural (scanning and transmission electron microscopy) studies. The results obtained demonstrate that ethanol injury caused extensive mucosal necrosis of the glandular region of the stomach, an event that was effectively reduced in rats treated with 16,16-dm-PGE2, carbenoxolone or sulglycotide. These drugs appeared to preserve the mucosa, with morphology comparable to that of normal noninjured rats - in contrast to the other drugs investigated. These data confirm the cytoprotective properties of sulglycotide in particular, which was the most potent agent for preventing the development of ethanol-induced acute lesions of the gastric mucosa.

Monitoring of serum markers for fibrosis during CCl4-induced liver damage. Effects of anti-fibrotic agents.

Liver fibrosis was induced in rats by repeated peritoneal injections of carbon tetrachloride (CCl4) over a period of 2-11 weeks. Serum procollagen III peptide (SPIIINP), prolidase (SP) and alanine aminotransferase (SALT) levels were monitored during the period of induction. The extent of fibrosis was semi-quantitatively estimated after collagen staining, and the anti-fibrotic effects of 16,16-dimethyl prostaglandin E2 (DMPGE2), colchicine, and zinc sulphate were studied. SPIIINP and SP were increased the first 2 weeks after CCl4 administration and peaked at 6 weeks. Alterations in SPIIINP and SP correlated well to the semi-quantitative histological score of liver sections during the first 6 weeks, and SP was positively related to SPIIINP throughout the whole induction period. DMPGE2 decreased SPIIINP, SP and SALT significantly in addition to a markedly decreased formation of liver collagens. Colchicine had a similar but less dramatic effect, whereas zinc sulphate only reduced SPIIINP without influencing liver damage. In conclusion SPIIINP seems to be a valuable indicator of liver fibrogenesis, and SP may play a limited role in indicating accelerated collagen metabolism in the liver. DMPGE2 obviously inhibited the production of collagens induced by CCl4. Colchicine also had an apparent effect on liver fibrosis, whereas zinc sulphate merely seemed to postpone it.

The effects of 16, 16 dimethyl prostaglandin E2 therapy alone and in combination with low-dose cyclosporine on rat small intestinal transplantation.

The use of prostaglandin E (PGE) in the setting of allotransplantation both clinically and experimentally has been suggested because PGE has significant immunosuppressive effects and potentially could lessen the toxic effects of cyclosporine. In the present study, we examined the immunosuppressive effects of 16,16 dimethyl prostaglandin E2 (dmPGE2) alone and in combination therapy with low-dose CsA to assess the clinical course, histology and expression of monocyte/macrophage procoagulant activity (PCA) following small intestinal transplantation in a heterotopic model of rat allograft rejection. Therapy with low-dose CsA (1 mg/kg) failed to prevent rejection and all animals reached a terminal state by day 26. In contrast, animals treated with high-dose CsA (10 mg/kg) showed no clinical or histological evidence of rejection and all animals survived. The dmPGE2 (100 micrograms/kg/twice daily) delayed the onset of rejection, but all animals developed severe rejection and subsequently died. Treatment of animals with low-dose CsA (1 mg/kg) in combination with dmPGE2 (100 micrograms/kg twice daily) resulted in a delay in the onset (P = 0.05) and a reduction in the intensity of allograft rejection (P = 0.0001) compared with either agent used alone. Monocyte/macrophage procoagulant activity levels correlated with the degree of rejection in all animals (P = 0.03). There was a statistically significant relationship between PCA levels and the time of onset of rejection and histologic grade of rejection in all groups. The data presented here, therefore, demonstrate a beneficial role for long-term combination therapy with CsA and PGE in small intestinal transplantation and strongly suggest a role for allogeneic induction of PCA in the pathogenesis of rejection.

Modulation of thioacetamide-induced hepatocellular necrosis by prostaglandins is associated with novel histologic changes.

Cytoprotective effects of the prostaglandins 16,16-dimethyl PGE2 (dmPGE2) and PGF2 alpha tromethamine (PGF2 alpha) were evaluated in the rat model of acute hepatocellular necrosis induced by thioacetamide (TAA). dmPGE2 (100 micrograms/kg SC 8 hourly) did not induce a significant increase in survival when started after the onset of TAA-induced fulminant hepatic failure. However, priming with dmPGE2 (100 micrograms/kg SC 30 min before TAA) reduced TAA-induced elevations in serum ALT (684 +/- 68 (SEM) vs 274 +/- 135 IU/1, p less than 0.01). This phenomenon did not occur if dmPGE2 was administered after TAA or by the IP route. Modulation of TAA-induced centrizonal hepatocellular necrosis by dmPGE2 was associated with a striking increase in centrizonal ballooning of hepatocytes (p less than 0.01), and, as assessed by stereology, less hepatocellular necrosis and degenerative changes. PGF2 alpha, which in contrast to dmPGE2 does not act via cAMP, had no effect on TAA-induced changes in serum ALT or hepatic histology. These findings suggest that dmPGE2 decreases hepatocellular necrosis by activating surface membrane adenylate cyclase and consequently stimulating cAMP. Ballooning of hepatocytes could occur secondary to these membrane events and appears to be a marker of dmPGE2-induced cytoprotection in this model.

Topical or systemic 16, 16 dm prostaglandin E2 or WR-2721 (WR-1065) protects mice from alopecia after fractionated irradiation.

Our previous studies in mice demonstrated that systemic or topical 16,16 dm PGE2 protected against single dose radiation-induced hair loss. We have now investigated prostaglandin, or WR-2721, protection against murine alopecia produced by varying doses and schedules of fractionated radiation. On days one to eight after hair was plucked from the thighs of B6D2F1 mice, groups of 6 animals each were given daily exposures of 4.0 or 4.5 Gy for 5 days; 2.5, 3.5, 4.5 or 5.5 Gy for 10 days; or 2 Gy for 15 days. One hour before irradiation each mouse received 10 microgram 16,16 dm PGE2, either by subcutaneous injection into the neck or topical application, 8 mg WR-2721 by injection, or 0.3 mg WR-1065 by topical application. Three weeks later counts of regrowing hairs were recorded from excised skin samples. For the radioprotectors used, hair regrowth was increased 25-100% in the various radiation groups in comparison to irradiated-only control sites. In some studies with the radioprotector given systemically, WR-2721 afforded slightly greater radioprotection than 16,16 dm PGE2. The two compounds were essentially equally radioprotective in the topical application studies. Since both systemic and topical applications of the agents tested enhanced hair regrowth following radiation, we conclude that clinical use of these compounds may provide some protection of hair follicles, and perhaps other tissues, lying within a radiation therapy field.

Morphological and functional gastric cytoprotection by prostaglandin in rats receiving absolute ethanol orally.

Pretreatment with prostaglandins at non-antisecretory doses protects the gastric mucosa, including the parietal cells, from deep necrosis produced by intragastric administration of necrotising agents such as absolute ethanol. Whether the parietal cells also retained their ability to secrete acid when rats were pretreated with a prostaglandin, in spite of exposure to ethanol, was investigated. Gastric acid secretion was abolished 4 hours after ethanol, and secretion returned to control values only after 5-6 days. Pretreatment with a single, non-antisecretory dose of 16, 16-dimethyl prostaglandin E2 (dm PGE2) maintained acid secretion, in spite of exposure to absolute ethanol. Absolute ethanol caused histological changes - extensive gastric mucosal necrosis (through the muscularis mucosae), oedema, haemorrhages, polymorphonuclear infiltration, and formation of granulation tissue - that were maximal 24-48 hours after ethanol and persisted for 2 to 4 weeks. None of these changes were present in animals treated with the prostaglandin. It is concluded that a single oral pretreatment with dmPGE2 protects the gastric mucosa against not only the morphological damage of absolute ethanol (preventing necrosis, haemorrhages, and polymorphonuclear infiltration) but also the functional damage (maintaining the acid secretory function of parietal cells).

Subcutaneous or topical administration of 16,16 dimethyl prostaglandin E2 protects from radiation-induced alopecia in mice.

Alopecia, a common sequel of radiation treatment of brain tumors, increases patient stress to the extent that refusal of treatment may occur. The expectation that loss of hair will be prevented, or that regrowth will occur, is extremely important to patients. To investigate prostaglandin-induced radiation protection against alopecia, the hair of B6D2F1 male mice was plucked from the right thigh and surrounding area to induce anagen. Fourteen days later, mice were injected subcutaneously in the neck with 10 micrograms 16,16 dm PGE2 in 0.2 ml of vehicle, or with the vehicle alone. In another group of previously plucked mice, 16,16 dm PGE2 in the same concentration, or the vehicle was applied topically. One hour later, graded single doses from 6.5 to 12.5 Gy 137Cs gamma irradiation were given to groups of six animals. On day 21 post-plucking, all animals were killed and a portion of the irradiated site was excised. The average hair counts per field in irradiated animals were 85 +/- 4 (6.5 Gy), 25 +/- 5 (8.5 Gy), and 5.5 +/- 0.7 (10 Gy). Animals receiving the prostaglandin systemically had values of 60 +/- 10 (6.5 Gy), 54 +/- 3 (8.5 Gy), 66 +/- 6 (10 Gy), and 30.1 +/- 8 (12.5 Gy). Topical application of the prostaglandin resulted in protection that yielded 52 +/- 3 (8.5 Gy), 34 +/- 4 (10 Gy), and 3.2 +/- 0.9 (12.5 Gy) hairs per field. Both systemic and topical application of 16,16 dm PGE2 protected from some degree of radiation-induced alopecia, which supports the conclusion that prostaglandins may be useful in the protection of hair follicles in patients treated with radiation for brain tumors.

Inhibition of butyric acid-induced colitis in mice by 16,16-dimethyl prostaglandin E2.

A standard colitic lesion was induced in male BKA mice by intrarectal administration of butyric acid (7.5%, 0.1 ml, 10 sec contact). Animals were killed after 5 h and the 'colitic score', increase in colonic tissue water ('oedema') and colonic tissue content of myeloperoxidase (MPO, a marker for neutrophils) were determined. Drug was administered intrarectally in 0.2 ml saline 20 min before colitis induction. In colitic animals given vehicle alone, all these parameters increased (P less than 0.05) compared to the non-colitic controls. In colitic animals given 16,16-dimethyl PGE2 (0.2-20000 micrograms/kg), colitic score was reduced (P less than 0.05) at all dose levels when compared with vehicle-treated colitic animals. The oedema and MPO showed a dose-related reduction (r = -0.895 and -0.904 respectively). In mouse colon 16,16-dimethyl PGE2 showed a protective action against butyric acid-induced colitic damage.

Prevention of 4-pentenoic acid-induced liver injury in rats by 16,16-dimethyl PGE2.

16,16-Dimethyl PGE2 (dmPGE2) is known to protect against cellular damage in various tissues. Histological and biochemical approaches were used to examine the effect of this prostaglandin on hepatocellular damage in an experimental Reye's syndrome model produced in rats by 4-pentenoic acid. Chronic intraperitoneal administration of 4-pentenoic acid induced an accumulation of fatty droplets throughout the hepatic lobules along with mitochondrial abnormalities including swelling, disappearance of christae, and heterogeneity of matrix. These abnormalities were more intense in the marginal zone and successively decreased nearer to the central vein. Such hepatic abnormalities were markedly reduced by the combined administration of dmPGE2 with 4-pentenoic acid. Biochemical examination confirmed that dmPGE2 was able to inhibit the accumulation of hepatic triglyceride seen after the treatment with 4-pentenoic acid alone. These results indicated that dmPGE2 can prevent characteristic hepatocellular damage in this experimental Reye's syndrome model, suggesting that the involvement of prostaglandins should be taken into account in discussing the etiology and management of this syndrome.

Effects of milk, prostaglandin, and antacid on experimentally induced duodenitis in the rat. Use of myeloperoxidase as an index of inflammation.

Ulcerogenesis of the duodenal mucosa frequently involves an inflammatory reaction with infiltration of leukocytes. Measurement of neutrophil myeloperoxidase activity might thus be a sensitive indicator of damage, before visible lesions occur. To test this possibility, a rat model for duodenal injury was used where fasted animals were treated with indomethacin and histamine-diHCl. Twenty-four hours after indomethacin treatment, duodenal tissues were collected for histochemical staining and biochemical assay for myeloperoxidase activity. Indomethacin- and histamine-challenged rats had significantly elevated myeloperoxidase activity compared to unchallenged controls (P less than 0.05) for both histochemistry and biochemistry. There was also a significant correlation between these two parameters (r = 0.68, P less than 0.001). The duodenal injury model then was used to test the effectiveness of known gastric protective agents. Results indicated that milk and buttermilk did not aggravate or protect against duodenal injury, while antacid and prostaglandin did significantly protect against inflammation (P less than 0.02). We concluded that measurement of myeloperoxidase activity is a sensitive and potentially useful estimate of duodenal injury that can be valuable in assessing ulcerogenesis and healing.

16,16-Dimethyl prostaglandin E2 and/or syngeneic bone marrow transplantation increase mouse survival after supra-lethal total body irradiation.

We evaluated the effects of 16,16-dimethyl prostaglandin E2 (dm-PGE2), with and without syngeneic bone marrow transplantation (BMT) on the survival and hematopoietic recovery of mice given 14-20 Gy total body irradiation (TBI). Survival of mice given combined dm-PGE2 and BMT was improved significantly over that of mice given either treatment alone. The 30-day survival after 14, 15, 16 or 18 Gy TBI for combined treatment was 97, 90, 20 or 10 percent, respectively. The corresponding 30-day survival rates for mice given BMT alone were 69, 60, 7 or 0 percent, respectively. For dm-PGE2 alone, 30-day survival was 63, 20, 10 or 0 percent, respectively. Deaths in both dm-PGE2 treated groups generally occurred after day 10 whereas deaths in the BMT group occurred before day 10. All irradiated controls were dead on or before day 10; after larger doses, deaths clustered around day 5. After 20 Gy TBI, all mice in all groups were dead by day 7. Studies of white blood cell recovery 1-9 days after 14 Gy TBI showed improvement with BMT, whereas dm-PGE2 did not enhance recovery. Nucleated cells per humerus, spleen weight, and spleen iron uptake (erythropoiesis) were also improved by BMT but not dm-PGE2.