16-16-dimethylprostaglandin-e2 and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cough; Cysteine; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Epoprostenol; Guinea Pigs; Leukotrienes; Male; Methacholine Chloride; Receptors, Prostaglandin E

Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor sensitization. Blocking COX2/PGE2/EP4 signaling at an earlier stage of inflammation or injury is crucial for preventing the transition from acute pain to a chronic state.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Axonal Transport; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ganglia, Spinal; Glycoproteins; Hyperalgesia; Lectins; Male; Neuralgia; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Sensory Receptor Cells; Time Factors; Versicans

We examined the effect of lafutidine, a histamine H(2) receptor antagonist with a mucosal protective action mediated by capsaicin-sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats.. Animals were given loxoprofen (10-100 mg/kg p.o.) and killed 24 h later. Lafutidine (10 and 30 mg/kg), cimetidine (100 mg/kg) or famotidine (30 mg/kg) was given twice p.o. at 0.5 h before and 6 h after loxoprofen. Omeprazole (100 mg/kg) was given p.o. once 0.5 h before. Ampicillin (800 mg/kg) was given p.o. twice at 24 h and 0.5 h before loxoprofen, while 16,16-dimethyl prostaglandin E(2) (dmPGE(2); 0.01 mg/kg) was given i.v. twice at 5 min before and 6 h after.. Loxoprofen dose-dependently produced hemorrhagic lesions in the small intestine, accompanied by invasion of enterobacteria and increased inducible nitric oxide synthase (iNOS) expression as well as myeloperoxidase activity in the mucosa. The ulcerogenic response to loxoprofen (60 mg/kg) was significantly prevented by lafutidine (30 mg/kg), similar to dmPGE(2) and ampicillin, and the effect of lafutidine was totally attenuated by ablation of CSN. Neither cimetidine, famotidine nor omeprazole had a significant effect against these lesions. Lafutidine alone increased mucus secretion and reverted the decreased mucus response to loxoprofen, resulting in suppression of bacterial invasion and iNOS expression. In addition, loxoprofen downregulated Muc2 expression, and this response was totally reversed by lafutidine mediated by CSN.. Lafutidine protects the small intestine against loxoprofen-induced lesions, essentially mediated by the CSN, and this effect may be functionally associated with increased Muc2 expression/mucus secretion, an important factor in the suppression of bacterial invasion.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Anti-Bacterial Agents; Anti-Ulcer Agents; Capsaicin; Cimetidine; Disease Models, Animal; Enterobacteriaceae; Famotidine; Histamine H2 Antagonists; Intestinal Mucosa; Intestine, Small; Male; Mucin-2; Nitric Oxide Synthase Type II; Omeprazole; Peptic Ulcer; Peroxidase; Phenylpropionates; Piperidines; Proton Pump Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sensory Receptor Cells

Enteroscopic observation has clearly demonstrated that non-steroidal anti-inflammatory drugs/low-dose aspirin (usually enteric-coated) induces hemorrhagic lesions, including ulcers and bleeding, in the small intestine of patients at a high incidence. Such intestinal lesions induced by NSAIDs have been confirmed in animal experiments. With aspirin, however, it has long been believed that it is difficult to induce any damage in the intestinal mucosa of laboratory animals. Therefore, we established a new method of inducing intestinal hemorrhagic lesions in rats by injecting aspirin into the proximal duodenum.. Under ether anesthesia, aspirin (50-200 mg/body), suspended in 2% methylcellulose (with or without 0.1 N HCl), was injected into the proximal duodenum of normally fed or 20-h non-fed rats (male Sprague-Dawley, 9 weeks old). At 1 h after treatment, the animals were killed with ether and the entire small intestine was removed for histological examination. In some experiments, 1% Evans blue was injected (i.v.) into the rats 1 h after aspirin treatment to visualize the lesions. An image analyzer determined the total area of the intestinal lesions. Oral proton pump inhibitors and histamine H(2)-receptor blockers were given 1 h before aspirin injection. 16,16-dimethyl prostaglandin E(2) (dmPGE(2)) was given s.c. 30 min before aspirin injection.. Aspirin alone clearly induced severe lesions (including bleeding and ulcers) mainly in the jejunum at 100% incidence. Total score of lesions per rat obtained by histological examination was similar to the damaged area quantified with the dye method. Dose-related induction of lesions by aspirin was confirmed both by the histological and dye methods. The irritable effect of aspirin suspended in 0.1 N HCl solution was the same as that of aspirin alone; 0.1 N HCl alone induced only minor lesions in the intestine. Both proton pump inhibitors and histamine H(2)-receptor blockers, at doses that inhibit gastric acid secretion, had no or little effect on aspirin-induced intestinal lesions. Pretreatment with dmPGE(2) (3, 10, 30 microg/kg) showed significant prevention of both aspirin- and HCl/aspirin-induced intestinal lesions.. This new aspirin lesion model will be useful for screening defensive drugs against aspirin-induced intestinal lesions and to elucidate the underlying mechanism.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenal Ulcer; Duodenum; Histamine H2 Antagonists; Injections; Intestinal Mucosa; Jejunum; Male; Microscopy, Electron, Scanning; Peptic Ulcer Hemorrhage; Proton Pump Inhibitors; Rats; Rats, Sprague-Dawley

The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis.. Animals were given indomethacin (10 mg/kg s.c.) and killed at various time points. To impair the healing of these lesions, a small dose of indomethacin (2 mg/kg p.o.) or AE3-208 (EP4 antagonist: 3 mg/kg i.p.) was given once daily for 6 days after the ulceration was induced, with or without the co-administration of AE1-329 (EP4 agonist: 0.1 mg/kg i.p.).. Indomethacin (10 mg/kg) caused severe damage in the small intestine, but the lesions healed rapidly decreasing to approximately one-fifth of their initial size within 7 days. The healing process was significantly impaired by indomethacin (2 mg/kg) given once daily for 6 days after the ulceration. This effect of indomethacin was mimicked by the EP4 antagonist and reversed by co-administration of the EP4 agonist. Mucosal VEGF expression was upregulated after the ulceration, reaching a peak on day 3 followed by a decrease. The changes in VEGF expression paralleled those in mucosal cyclooxygenase-2 expression, as well as prostaglandin E(2) (PGE(2)) content. Indomethacin (2 mg/kg) downregulated both VEGF expression and angiogenesis in the mucosa during the healing process, and these effects were significantly reversed by co-treatment with the EP4 agonist.. The results suggest that endogenous PGE(2) promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Indomethacin; Intestinal Mucosa; Intestine, Small; Male; Membrane Proteins; Naphthalenes; Neovascularization, Physiologic; Peptic Ulcer; Phenylbutyrates; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; RNA, Messenger; Severity of Illness Index; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E(2) (PGE(2)) synthetic analog 16,16-dimethyl-PGE(2) (dmPGE(2)) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE(2) dose of 30 microg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-alpha, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE(2) co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-alpha, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE(2) treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE(2) also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE(2) is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Collagen; Disease Models, Animal; Infusions, Subcutaneous; Interleukin-1beta; Lung; Lung Injury; Male; Mice; Peroxidase; Pneumonia; Protective Agents; Pulmonary Edema; Pulmonary Fibrosis; Time Factors; Tumor Necrosis Factor-alpha; Tyrosine

Nonsteroidal anti-inflammatory drugs (NSAIDs) are antitumorigenic in humans as well as in animal models of intestinal neoplasia, such as the adenomatous polyposis coli (Min/+) (Apc(Min/+)) mouse. NSAIDs inhibit cyclooxygenase (COX) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which NSAIDs exert their antitumorigenic effects. However, mounting evidence suggests the existence of COX-independent mechanisms. In the present study, we attempted to clarify this issue by treating Apc(Min/+) mice bearing established tumors with NSAIDs (piroxicam and sulindac, 0.5 and 0.6 mg/mouse/day, respectively) for 6 days and concomitantly bypassing COX inhibition by treatment with the E prostaglandin (EP) receptor agonists 16,16-dimethyl-prostaglandin E(2) (PGE(2)) and 17-phenyl-trinor-PGE(2) (10 microg each, three times daily) administered via gavage and/or i.p. routes. Treatment with piroxicam and sulindac resulted in 95% and 52% fewer tumors, respectively, and a higher ratio of apoptosis:mitosis in tumors from sulindac-treated mice as compared with controls. These effects were attenuated by concomitant EP receptor agonist treatment, suggesting PGE(2) is important in the maintenance of tumor integrity. Immunological sequestration of PGE(2) with an anti-PGE(2) monoclonal antibody likewise resulted in 33% fewer tumors in Apc(Min/+) mice relative to untreated controls, additionally substantiating a role for PGE(2) in tumorigenesis. The EP receptor subtype EP1 mediates the effects of PGE(2) by increasing intracellular calcium levels ([Ca(2+)](i)), whereas antagonism of EP1 has been shown to attenuate tumorigenesis in Apc(Min/+) mice. We demonstrate that [Ca(2+)](i) is significantly elevated in tumors of Apc(Min/+) mice relative to the adjacent normal-appearing mucosa. Furthermore, treatment with piroxicam results in significantly lower [Ca(2+)](i) in tumors, and this effect is attenuated by concomitant treatment with the EP1/EP3 receptor agonist 17-phenyl-trinor-PGE(2). Overall, our results suggest that NSAIDs exert their antitumorigenic effects, in part, via interference with PGE(2) biosynthesis, and these effects may be mediated through changes in intracellular calcium levels.

Topics: 16,16-Dimethylprostaglandin E2; Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Apoptosis; Calcium; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Drug Interactions; Intestine, Small; Male; Mice; Mice, Inbred C57BL; Mitosis; Piroxicam; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Sulindac

The amelioration of secretory diarrhea has been reported after the administration of zaldaride maleate (ZAL), a selective calmodulin inhibitor, to male rodents. In this study, the antidiarrheal effect of ZAL in female rats was compared with that in male rats. In female and male rats, ZAL significantly ameliorated 16,16-dimethyl prostaglandin E2-induced diarrhea at doses of 1 and 3 mg/kg (p.o.), respectively, with ID50 values of 0.7 mg/kg (p.o.) in the females and 10.3 mg/kg (p.o.) in males. In castor oil-induced diarrhea, ZAL also significantly reduced the incidence of diarrhea in female and male rats at doses of 10 and 30 mg/kg (p.o.), respectively. When the same dose of ZAL was given orally to female and male rats, the maximum plasma level of this compound was approximately 3 times higher in female rats than in male rats. In contrast, after intravenous administration of the same dose of ZAL to female and male rats, the total clearance of this compound was similar. In an Ussing chamber experiment, the inhibitory action of ZAL on vasoactive intestinal polypeptide-induced ion secretion in the colon showed no difference between female and male rats. In conclusion, the antidiarrheal effect of ZAL in female rats is more potent than that in males, and could be due to the difference in plasma levels of this compound between female and male rats after oral administration.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antidiarrheals; Benzimidazoles; Castor Oil; Colon; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Sprague-Dawley; Secretory Rate; Sex Characteristics

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.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Carnosine; Chloramines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Gastric Mucosa; Male; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sucralfate; Zinc; Zinc Compounds

Perfusion of the main pancreatic duct in cats with a dilute solution of bile salts increases ductal permeability. Subsequent perfusion of a permeable duct with activated pancreatic enzymes results in acute edematous pancreatitis. Simultaneous infusion of 16-16 dimethyl-PgE2 converts edematous pancreatitis to acute hemorrhagic pancreatitis (AHP). AHP may be associated with a reduction in pancreatic blood flow; it is certainly associated with increases in microvascular permeability. Low dose dopamine is a splanchnic vasodilator and may also reduce pancreatic microvascular permeability through beta agonist effects. In these studies, we investigated the effect of dopamine in an established feline model of biliary AHP. We also studied its effect on blood flow in both normal pancreas and after induction of AHP. We found that dopamine significantly reduced the degree of pancreatic inflammation, even when administered up to 12 h after onset of biliary AHP. However, the drug had no significant effect on blood flow either in normal pancreas or in the gland affected by hemorrhagic pancreatitis. We concluded that the effect of dopamine was most likely due to its ability to reduce pancreatic microvascular permeability.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Biliary Tract Diseases; Capillary Permeability; Cats; Disease Models, Animal; Dopamine; Infusions, Intravenous; Pancreas; Pancreatitis; Regional Blood Flow

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.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Fatty Acids, Monounsaturated; Injections, Intraperitoneal; Lipid Metabolism; Lipids; Liver; Liver Diseases; Liver Glycogen; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Reye Syndrome

We studied the conversion of acute edematous pancreatitis (AEP) to acute hemorrhagic pancreatitis (AHP) in an experimental model in cats. In the model, 16,16 dimethyl PgE2 effects this conversion by increasing microvascular permeability. First, we induced AEP in cats and then gave PgE2 at increasing intervals after the induction of AEP to see how long an interval would still allow conversion. In 6 groups of cats, PgE2 was administered for 2 h, starting at 2, 4, 6, 8, 10, or 12 h after the creation of AEP. Twelve h later, the cats were sacrificed and the pancreases were graded for inflammation and hemorrhage. Significant pancreatic hemorrhage did not occur when the PgE2 was administered at 12 h compared to 2 h. Next, we determined that PgE2 still retained its ability to increase pancreatic vascular permeability when administered 12 h after the creation of AEP. This was done by perfusing a marker molecule through the MPD (fluorescein isothiocyanate labeled dextran: FITC-D, mol wt 20,000) and then finding it in portal venous blood (PVB). The presence of FITC-D in PVB signified increased vascular permeability, since normally none was present. We concluded that conversion of AEP to AHP was possible during the first 12 h after induction of AEP. Lack of conversion at 12 h was not caused by a lack of vascular reactivity at that time.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Capillary Permeability; Cats; Disease Models, Animal; Edema; Gastrointestinal Hemorrhage; Pancreatic Juice; Pancreatitis; Time Factors

Acute edematous pancreatitis was produced in rats by subcutaneous administration of caerulein. Pancreas weight, pancreas histology and plasma amylase were used as endpoints to quantitate the severity of the syndrome. A caerulein dose of 10 micrograms/kg.hour produced the most severe pancreatitis, whereas at 5 micrograms/kg.hour the values were half-maximal. The pancreatic lesions were characterized by edema, formation of cytoplasmic vacuoles, leukocytic infiltration, necrosis, and with time (12-hour caerulein infusion) dilated acini. Cholecystokinin octapeptide also produced pancreatitis when given at ten times the dose required for caerulein (50 micrograms/kg.hour instead of 5 micrograms/kg.hour). Carbachol did not induce pancreatitis. Two prostaglandins, 16,16-dimethyl prostaglandin E2 injected subcutaneously and prostaglandin E2 infused subcutaneously, dose dependently prevented caerulein-induced pancreatitis (pancreatic edema, leukocytic infiltration, and necrosis) and reduced the number and size of intracellular vacuoles. The ED50 were 15 to 25 micrograms/kg for 16,16-dimethyl prostaglandin E2 and 90 micrograms/kg.hour for prostaglandin E2. Neither prostaglandin, given at doses inhibiting the development of pancreatitis, prevented the retardation of gastric emptying caused by caerulein, a finding suggesting that the prostaglandins may act specifically on the effect of caerulein on the pancreas but not on caerulein receptors in gastric smooth muscle. Indomethacin, an inhibitor of prostaglandin synthesis, and methscopolamine bromide, an anticholinergic agent, had no effect on caerulein-induced pancreatitis. We concluded that prostaglandins of the E type prevent the development of caerulein-induced pancreatitis. The mechanism by which prostaglandins protect the pancreas may involve stabilization of lysosomes within the acinar cells and inhibition of intracellular activation of pancreatic digestive enzymes.

Topics: 16,16-Dimethylprostaglandin E2; Amylases; Animals; Carbachol; Ceruletide; Cholecystokinin; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Indomethacin; Infusions, Parenteral; Organ Size; Pancreas; Pancreatitis; Prostaglandins E, Synthetic; Rats

Burn injuries have been shown to impair immune function. One of the hypotheses for the etiology of the immunosuppression is that burn injuries result in an elevation of prostaglandin E (PGE) levels which then impair leukocyte function. We evaluated the effect of PGE levels on immune function in multiple animal models utilizing T cell subset levels for our immunologic measurements. Elevations in PGE levels were achieved by administering 16,16-dimethyl-prostaglandin E (dPGE) and reductions by administering indomethacin. The animal models included burned rats, burned-septic rats, and nonburned rats. Neither indomethacin nor dPGE administration resulted in alterations of any of the T cell subset populations in our models.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Burns; Disease Models, Animal; Indomethacin; Leukocyte Count; Male; Prostaglandins E, Synthetic; Pseudomonas Infections; Rats; Rats, Inbred Lew; Spleen; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Wound Infection

The present study investigates whether prostaglandins "cytoprotect" the gastric mucosa against hemorrhage-induced stress ulceration by assessing the influence of 16,16-dimethyl prostaglandin E2 (16,16-dm PGE2) on gross and microscopic lesion formation, intramucosal tissue pH, H+ back-diffusion, and mucosal blood flow in rat gastric mucosa exposed to luminal acid (100 mM HCl) during hemorrhagic shock (13 ml/kg for 20 min). Intramucosal tissue pH was measured using pH-sensitive antimony microelectrodes, and mucosal blood flow was measured by the radiolabeled microsphere technique. 16,16-dm PGE2 (5 micrograms/ml topically) significantly protected the gastric mucosa against gross (lesion index 2.25 +/- 0.34 vs 0.87 +/- 0.21) and microscopic (lesion index 2.12 +/- 0.20 vs 0.87 +/- 0.09) damage during the shock. This protection was associated with a significantly lesser acidification of the mucosa during the shock (intramural tissue pH 6.67 +/- 0.08 vs 6.03 +/- 0.17). In order to elucidate whether the lesser intramucosal acidification was due to diminished entry of H+ (H+ back diffusion) into or better disposal of H+ from the mucosa, the influences of 16,16-dm PGE2 on transmucosal H+ fluxes and mucosal blood flow were determined. It appeared that 16,16-dm PGE2 had no influence on the rate of H+ back-diffusion, but it significantly enhanced mucosal blood flow both in the corpus (0.23 +/- 0.04 vs 0.14 +/- 0.03 ml/min/g) and in the antrum (0.24 +/- 0.03 vs. 0.14 +/- 0.03 ml/min/g) during the shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Animals; Disease Models, Animal; Hydrogen-Ion Concentration; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Shock, Hemorrhagic; Stomach Ulcer; Stress, Physiological

To determine whether a serum parameter of collagen metabolism, serum procollagen type III peptide, correlated with hepatic collagen in a model of diet-induced fibrosis, rats were fed a control or cirrhogenic diet for 6 months and treated with either subcutaneous vehicle or the hepatoprotective prostaglandin 16,16-dimethyl prostaglandin E2 (100 micrograms per kg) twice daily. Pair-fed rats from each group were killed after 2, 4 or 6 months. The value of serum procollagen type III peptide to body weight integrated over time (Kt) correlated linearly with hepatic hydroxyproline content (r = 0.97) at killing time t. Good correlations were also seen between Kt and histopathological assessment of aniline blue-stainable collagen (r = 0.93) and between the histopathology and hydroxyproline content (r = 0.97). Rats receiving 16,16-dimethyl prostaglandin E2 had lower values of all three parameters compared to rats receiving vehicle, confirming the previously demonstrated hepatoprotective effect of 16,16-dimethyl prostaglandin E2. The excellent correlation between Kt and the two other traditional parameters of hepatic collagen suggest that sequential measurements of serum procollagen type III peptide can be used to predict alterations in liver collagen deposition in rats.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Body Weight; Collagen; Deficiency Diseases; Disease Models, Animal; Hydroxyproline; Liver; Liver Cirrhosis, Experimental; Male; Peptide Fragments; Predictive Value of Tests; Procollagen; Rats; Rats, Inbred Strains; Time Factors

Stress ulceration can be prevented clinically by prophylaxis with antacids or sucralfate, while hyperosmolar glucose and prostaglandins have prevented gastric mucosal injury in experimental models. We compared these four agents' effectiveness in gastric mucosal protection as well as their interaction with the pathophysiology of hemorrhagic shock. Gastric mucosal injury was produced in a canine model with the insults important in clinical situations: intragastric acid, intragastric bile, and gastric mucosal ischemia. Hypotension was maintained at a constant level for 3 hr, during which one of the prophylactic treatments or vehicle (H2O) was given hourly intragastrically. The stomachs were harvested for quantification of gastric mucosal injury after return of shed blood. The percentage of gastric area damaged was significantly decreased to 1.0 +/- 0.7% by antacids but was increased to 43.5 +/- 4.9% by 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2), in comparison to vehicle treatment which caused 28.4 +/- 4.7% lesioned mucosa. Additionally, hemodynamic function differed between treatment groups after 1 hr of shock. Irrespective of treatment group, parameters reflecting volume status and hemodynamic function correlated significantly with the amount of gastric mucosal injury measured in individual animals. Intragastric treatments did not variably affect systemic pH or systemic glucose, and neither of these parameters was related to gastric mucosal injury. In conclusion, antacids effectively prevent stress ulceration in canine hemorrhagic shock, while the worsening of gastric mucosal injury and hemodynamic function we observed with 16,16-dmPGE2 treatment indicates that this agent could be hazardous in hypotensive patients.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antacids; Disease Models, Animal; Dogs; Glucose Solution, Hypertonic; Hydrogen-Ion Concentration; Peptic Ulcer; Regional Blood Flow; Shock, Hemorrhagic; Stomach; Stress, Physiological; Sucralfate

In a model of acute pancreatitis which requires that pancreatic enzymes leak from a permeable duct, we studied the role of intravenous enterokinase (195,000 daltons) in pancreatic enzyme activation. Anesthetized cats were given intravenous 16,16-dimethyl prostaglandin E2 to increase pancreatic blood flow and microvascular permeability. In some animals the permeability of the pancreatic duct was increased by perfusion of the duct with glycodeoxycholic acid (7.5 mM). Endogenous enzyme secretion was stimulated by IV CCK and secretin. Some cats also received enterokinase intravenously. Those animals that received PGE2, glycodeoxycholate, and enterokinase all developed pancreatitis. When any of these agents were not given the pancreases appeared normal. These findings were consistent with the hypothesis that intravenous enterokinase leaked from small pancreatic blood vessels into the pancreatic parenchyma and/or ducts where activation of pancreatic enzymes occurred. The development of pancreatitis appeared to require an increase in both microvascular and ductal permeability.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Capillary Permeability; Cats; Disease Models, Animal; Enteropeptidase; Glycodeoxycholic Acid; Pancreas; Pancreatic Ducts; Pancreatitis; Particle Size; Permeability

Pharmacological attempts to alter the course of experimental pancreatitis in the opossum were made using synthetic 16, 16-dimethyl prostaglandin E2 (16, 16-dm PGE2). Anatomically, the opossum has an elongated ampulla resulting in a supraduodenal pancreatic duct-common bile duct junction allowing for bile reflux pancreatitis to be produced by ligating the distal common bile duct. Preliminary evaluation demonstrated that at 72 hours common bile duct ligation distal to the pancreatic duct orifice produced pancreatitis comparable in severity to that produced by a Pfeffer loop. When the oppossum distal common bile duct was ligated, serum amylase concentrations progressively increased from control values of 182 +/- 43 to 742 +/- 62 Somogyi units/dl at 5 hours. Administration of 0.2 microgram-kg-1-min-1 16, 16-dm PGE2 significantly decreased the hyperamylasemia associated with bile reflux pancreatitis and, in addition, decreased the pancreatic gland weights when compared to control values. Subsequent evaluation of the administration of 75 micrograms-kg-1 16, 16-dm PGE2 every 12 hours for 72 hours to opossums with distal common bile duct ligation demonstrated no significant differences in serum amylase concentrations when compared to control values. Histologic evaluation of the pancreas glands at 72 hours demonstrated increased glandular integrity when the pancreas glands from the opossums receiving 16,16-dm PGE2 were compared to the glands subjected to distal common bile duct ligation alone. This report identifies several favorable characteristics in the course of experimental pancreatitis associated with the administration of a synthesis PGE analog at the onset of the inflammatory process.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Amylases; Animals; Bile Reflux; Biliary Tract Diseases; Disease Models, Animal; Female; Male; Opossums; Pancreatitis; Prostaglandins E, Synthetic

The gastric mucosa of animals and man can be damaged by noxious agents and protected by prostaglandins. We developed a Heidenhain pouch dog model which allows the study of multiple doses of the protective or noxious agent. Mucosal damage in the pouch caused by instillation of 160 mM aspirin suspended in 150 mM HCl for two 15-min periods was determined by measuring hemoglobin concentration in isotonic mannitol washes. Hemoglobin levels 24 h after the administration of the acid-aspirin suspension were significantly higher than basal levels. Pretreatment with oral doses of 0.3-3 micrograms/kg 16,16-dimethyl PGE2 at 24 and 18 h and 30 min before the acid-aspirin suspension decreased hemoglobin concentrations in the washes (p less than 0.001).

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Disease Models, Animal; Dogs; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Male; Prostaglandins E, Synthetic; Stomach; Stomach Diseases

Topics: 16,16-Dimethylprostaglandin E2; Animals; Atropine; Carbachol; Disease Models, Animal; Drug Interactions; Gastric Emptying; Gastrointestinal Motility; Guinea Pigs; Hydroxydopamines; Intestinal Obstruction; Male; Prostaglandins E, Synthetic; Rats; Sympathetic Nervous System