Endosomal TLR3 signaling in stromal osteoblasts induces prostaglandin E2-mediated inflammatory periodontal bone resorption.

Toll-like receptors (TLRs) are pattern recognition receptors that play a critical role in innate immune diseases. TLR3, which is localized in the endosomal compartments of hematopoietic immune cells, is able to recognize double-stranded RNA (dsRNA) derived from viruses and bacteria and thereby induce innate immune responses. Inflammatory periodontal bone resorption is caused by bacterial infections, which initially is regulated by innate immunity; however, the roles of TLR3 signaling in bone resorption are still not known. We examined the roles of TLR3 signaling in bone resorption using poly(I:C), a synthetic dsRNA analog. In cocultures of mouse bone marrow cells and stromal osteoblasts, poly(I:C) clearly induced osteoclast differentiation. In osteoblasts, poly(I:C) increased PGE2 production and upregulated the mRNA expression of PGE2-related genes, Ptgs2 and Ptges, as well as that of a gene related to osteoclast differentiation, Tnfsf11. In addition, we found that indomethacin (a COX-2 inhibitor) or an antagonist of the PGE2 receptor EP4 attenuated the poly(I:C)-induced PGE2 production and subsequent Tnfsf11 expression. Poly(I:C) also prolonged the survival of the mature osteoclasts associated with the increased mRNA expression of osteoclast marker genes, Nfatc1 and Ctsk. In ex vivo organ cultures of periodontal alveolar bone, poly(I:C) induced bone-resorbing activity in a dose-dependent manner, which was attenuated by the simultaneous administration of either indomethacin or an EP4 antagonist. These data suggest that TLR3 signaling in osteoblasts controls PGE2 production and induces the subsequent differentiation and survival of mature osteoclasts. Endogenous TLR3 in stromal osteoblasts and osteoclasts synergistically induces inflammatory alveolar bone resorption in periodontitis.

Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis.

The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. This study aimed to elucidate the impact of new pyrrolo[3,4-d]pyridazinone derivatives, compounds 7b, 10b, or 13b, on the course of experimental colitis in rats and to assess whether these new compounds may influence Th17/Treg axis. Rats were pretreated with studied compounds intragastrically before intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid used for colitis induction. Body weight loss, disease activity index, colon index, and colon tissue damage were analyzed to evaluate the severity of colitis. The colonic levels of RORγt, STAT3, CCR6, Foxp3, IL-6, IL-10, IL-17, TNF-α, IL-23, and PGE2 were assessed. Pretreatment with compounds 7b and 13b alleviated the severity of colitis and concomitantly counteracted the increased levels of RORγt, STAT3, CCR6, IL-6, IL-17, IL-23, TNF-α, and PGE2. The beneficial effect of compounds 7b and 13b may be due to the decrease in the levels of Th17-specific transcription factors and cytokines. The studied compounds might therefore constitute a promising therapeutic strategy in Th17/Treg imbalance-driven inflammatory conditions such as IBD.

Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice.

Glucocorticoid (GC)-induced avascular osteonecrosis of femoral head (AOFH) is a devastating complication, and no cures are currently available for it. Previous studies have demonstrated that implantation of bone marrow mesenchymal stem cells (BMMSCs) may prevent the progression of pre-collapse AOFH. Based on previous observations, we hypothesized that GCs induce AOFH via the COX-2 (cyclooxygenase-2)-PGE-2 (prostaglandin E2)-HIF-1α (hypoxia-inducible factor-1α) axis, and that modification of BMMSCs may improve the efficacy of their implantation. BMMSCs isolated from wild-type (WT) mice were treated with dexamethasone (Dex) and the results showed that Dex repressed the expression of COX-2. Femoral head samples harvested from both WT and COX-2 knock-out (COX-2-/-) mice were subjected to micro-computed tomography and histological examinations. Compared with their WT littermates, COX-2-/- mice had larger trabecular separations, diminished microvasculature, and reduced HIF-1α expression in their femoral heads. In vitro angiogenesis assays with tube formation and fetal metatarsal sprouting demonstrated that Dex repressed angiogenesis and PGE-2 antagonized its effects. An AOFH model was successfully established in C57BL/6J mice. In vitro experiment showed that BMMSCs infected with Lentivirus encoding HIF-1α (Lenti-HIF-1α) resulted in a robust increase in the production of HIF-1α protein. Implantation of BMMSCs overexpressing HIF-1α into femoral heads of AOFH mice significantly reduced osteonecrotic areas and enhanced bone repair, thus largely preserving the structural integrity of femoral heads. Our studies provide strong rationales for early intervention with core decompression and implantation of modified BMMSCs for GC-induced AOFH, which may spare patients from expensive and difficult surgical procedures.

Long-term prostaglandin E1 therapy in congenital heart defects.

Seventeen neonates received an intravenous infusion of prostaglandin E1 for an average of 39 days (range 8 to 104). Seven (group 1) had transposition of the great arteries with no ventricular septal defect or a small one; eight (group 2) had ductus-dependent pulmonary flow (pulmonary atresia or stenosis in six and tricuspid atresia in two); and two (group 3) had aortic coarctation, one with no ventricular septal defect, the other with ventricular septal defect, isthmus hypoplasia and descending aortic flow supplied mainly by the ductus. An increase in the arterial partial pressure of oxygen (PO2) was seen in groups 1 and 2. Six patients from group 1 and two from group 2 developed heart failure; cortical hyperostosis of long bones was seen in three patients from group 1 and three from group 2; one from group 1 had refractory diarrhea. Other side effects seen at the beginning improved as the rate of infusion diminished. In group 3, the patient with complex coarctation had a decrease in blood pressure in the arms, an increase in pressure in the legs and restoration of renal function; in the patient with no ventricular septal defect, heart failure worsened during therapy. Histologic changes seen in three ductus were attributed to the closing process. When delaying surgery in selected ill infants with heart defects is deemed advantageous, long-term infusions of prostaglandin E1 are feasible.

Toxic effects of intravenous and oral prostaglandin E therapy in patients with liver disease.

BACKGROUND: Prostaglandins are cytoprotective agents that have been shown to benefit patients with a variety of acute and chronic liver diseases. Few data exist on the frequency of adverse effects of prostaglandins in these patients. METHODS: We retrospectively studied 105 patients with liver disease who were treated with either intravenous (i.v.) or oral prostaglandin E (PGE). Forty-four patients with primary nonfunction after liver transplantation and 36 patients with fulminant hepatic failure received i.v. PGE1 for 4.5 +/- 2.6 and 12.6 +/- 10.9 days, respectively. Twenty-five patients with recurrent hepatitis B viral infection after liver transplantation received oral PGE1 for 105 +/- 94 days or PGE2 for 464 +/- 399 days. RESULTS: Twenty-six of 80 patients (33%) receiving i.v. PGE1 developed gastrointestinal and/or cardiovascular side effects and 8% developed arthritis. Twenty-three of 25 patients (92%) who received high-dose oral PGE1 or PGE2 incurred arthritis and/or gastrointestinal adverse effects. Twenty-five patients received prolonged PGE therapy (oral > 60 days; i.v. > 28 days). Of this group, 23 (92%) developed clubbing and cortical hyperostosis resembling hypertrophic osteoarthropathy. All adverse effects were dose related and resolved with reduction or cessation of therapy. CONCLUSION: PGE therapy resulted in a wide spectrum of multisystem adverse effects which were reversible with reduction or cessation of therapy. Although the administration of PGE was safe and generally well tolerated, close medical supervision is necessary to avoid serious side effects.

Prolonged prostaglandin E1 infusion: histologic effects on the patent ductus arteriosus.

An infant with Ebstein's malformation of the tricuspid valve and severe pulmonic stenosis underwent a 39-day course of prostaglandin E1 infusion, and a histologic study of the ductus arteriosus was undertaken after autopsy. There were marked alterations in the ductal and juxtaductal structures following this prolonged infusion of prostaglandin E1. The internal elastic lamella of the ductus was disrupted in many areas. The media showed widespread areas of disruption with cavity formation. The adventitia adjacent to the junction of the ductus with the pulmonary artery was thickened and infiltrated with mononuclear cells. The nerve trunks in the adventitia were markedly infiltrated with mononuclear cells and showed cavitation as well as considerable surrounding edema. Mucopolysaccharides were increased throughout the ductus. These changes produced increased fragility of the ductal and juxtaductal structures, thus increasing the likelihood of spontaneous aneurysms and rupture, or of tearing or rupture at the aortic and pulmonary junctions at the time of surgical closure of the ductus. Unusual fragility of the ductus, pulmonary artery, and aorta has been observed during ligation of the ductus following prostaglandin E infusions lasting seven and ten days. Additionally, another patient who had received prostaglandin E infusion for six days demonstrated aneurysmal fullness to the ductus arteriosus at autopsy. The histologic findings and intraoperative experience in this study suggest that there may be a real danger of spontaneous or surgically related rupture of the ductus arteriosus after prolonged infusion of prostaglandins.

Prostaglandin E1 therapy. Is it associated with a higher incidence of wound infection in the cyanotic neonate?

Prostaglandin (PGE1) may be used to maintain ductal patency in the infant with cyanotic congenital heart disease, but the risk of infection may be increased. Between October, 1976 and December, 1982, 38 neonates with complex cyanotic congenital heart disease required operations creating systemic-to-pulmonary artery shunts. Of 13 patients who did not receive PGE1 therapy, none developed a wound infection. Of 25 patients who did receive PGE1 therapy, four (16 percent) developed a significant wound infection. The two patient groups were similar when compared by age and weight at operation, by severity of heart disease and by the presence of other congenital anomalies. Pathogenic Staphylococcus epidermidis was recovered from all infected wounds, all of which responded favorably over a period of two to four weeks with a short course of antibiotics and wound debridement.

Retinal hemorrhages in the newborn following labor induced by oxytocin or dinoprostone.

We examined the fundi of 100 newborns following labor induced by intravenous oxytocin or by oral dinoprostone. Retinal hemorrhage was observed in 40% of neonates in the dinoprostone treatment group, as compared with 28% in the oxytocin treatment group. The accumulation of prostaglandins in the fetal circulation may be responsible for the hemorrhages, which clear spontaneously once the noxious agent is metabolized. Other organ systems must be carefully examined in the neonate to detect other possible untoward effects.

Detrimental effect of high-dose prostaglandin E1 in the treatment of ischemic ulcers.

Eight patients with ischemic lower extremity ulcers were entered into a randomized, controlled trial of intravenous prostaglandin E1 (PGE1) versus placebo. All ulcers had been stable or increasing in size for at least 3 weeks prior to the study. Each patient had rest pain assessment, Doppler pressure measurements, and ulcer measurements before and after infusion. Four patients received PGE1 and four received placebo. There were no significant preinfusion differences between groups. Rest pain remained stable or improved in all patients. In the placebo group the mean absolute ankle pressure decreased 5 +/- 14 mm Hg, but the mean ankle/arm pressure ratio increased 0.03 +/- 0.06. In the PGE1 group the mean absolute ankle pressure decreased 16 +/- 16 mm Hg and the mean ankle/arm pressure ratio decreased 0.05 +/- 0.06. Neither difference is statistically significant. Patients who received placebo had no change or decrease in ulcer size, but all patients who received PGE1 had an increase in ulcer size (P = 0.05, Wilcoxon rank sum test). One of the four placebo patients required extremity amputation during follow-up of 10.5 +/- 3.5 months. All four patients in the PGE1 group required amputation within 3.3 +/- 2.6 months. Despite theoretic benefits, intravenous PGE1 may be detrimental in the treatment of ischemic ulcers.

Prostaglandin E2 induction of labor for fetal demise.

Intrauterine fetal demise is a source of anxiety to both patient and physician. Heretofore, the standard treatment was either careful observation until the patient went into labor or attempt at induction of labor with oxytocin. Unfortunately, oxytocin stimulation has not proven to be uniformly successful for this problem. Prostaglandin E2 suppositories have been shown to be effective in inducing uterine evacuation after intrauterine fetal demise. In the opinion of the authors, this approach will in the future replace the sometimes dangerous and emotionally laden convention of watchful delayed therapy.

A maternal death associated with prostaglandin E2.

A maternal death following prostaglandin E2 (PGE2) administration is reported. It is suggested that prostaglandin may not be safer than other methods of uterine evacuation for late abortion and fetal death.

Cervical ripening with prostaglandin E2 vaginal suppositories.

A prospective, randomized, double-blind, placebo-controlled study was undertaken to evaluate the safety and efficacy of a 3-mg prostaglandin E2 (PGE2) vaginal suppository for the initiation of cervical ripening before the induction of labor. All patients were required to have an initial Bishop score of 4 or les. The 3-mg PGE2 vaginal suppository was found to be an effective method of both cervical ripening and labor induction. Its use resulted in a highly significant improvement in the mean Bishop score compared with the placebo group (2.67 versus 0.55 points, P less than .00005). Its use also resulted in a significant reduction in the number of failed inductions (5 versus 23%, P less than .0005). Moreover, 68% of the patients treated with PGE2 labored after initial suppository placement, and 42% of these patients never required oxytocin augmentation of labor. However, there were three instances of uterine hyperstimulation/hypertonus following placement of the 3-mg PGE2 suppository, suggesting that perhaps a lower dose of PGE2 would improve its safety as a ripening agent without affecting its efficacy.

Treatment of postpartum uterine atony with prostaglandin E2 vaginal suppositories.

When severe postpartum hemorrhage secondary to uterine atony is unresponsive to medical management, including oxytocic drugs and/or ergonovine and its derivatives, surgical intervention becomes necessary. This case of postpartum uterine atony, with several features suggesting persistent myometrial dysfunction which did not respond to usual medical measures, responded to treatment with intravaginal prostaglandin E2 (PGE2) suppositories. Prostaglandin E2 vaginal suppositories may be useful in the treatment of persistent postpartum uterine atony.

Guidelines for the elective induction of labor with oral Prostaglandin E2.

Fifty multiparous patients at 37 weeks or more of gestation with a vertex presentation and a Bishop score of 7 or more had labor induced with oral Prostaglandin E2 tablets. All responded and delivered vaginally. The induction to delivery time averaged 4 hours and 44 minutes. The average number of tablets required was 3.64. Four women experienced nausea and an additional 4 women had some vomiting. Two patients showed hypertonus and 11 had frequent contractions. Many progressed rapidly after they began active labor. There was no evidence of fetal distress. Guidelines are suggested for the use of oral Prostaglandin E2 tablets to adequately control the labor process and prevent hypercontractility.

Association of extrauterine fetal death with failure of prostaglandin E2 suppositories.

The use of prostaglandin E2 vaginal suppositories is an effective method of uterine evacuation for patients with intrauterine fetal demise. Advanced extrauterine gestation, because of its rarity, is usually not a primary consideration for patients presenting with fetal death. This report presents 4 such cases and strongly suggests that, when this drug is used for the treatment of fetal death, failure to induce contractions and to effect uterine evacuation within a reasonable time should prompt the consideration of extrauterine pregnancy.

Second-trimester abortion by intramuscular 15-methyl-prostaglandin F2 alpha or intravaginal prostaglandin E2 suppositories: a randomized trial.

OBJECTIVE: To compare intramuscular (IM) prostaglandin 15 methyl-F2 alpha (15M-PGF2 alpha) with prostaglandin E2 (PGE2) vaginal suppositories for second-trimester abortion in terms of efficacy and side effects. METHODS: Fifty-one women were randomized to receive either 15M-PGF2 alpha IM injections or PGE2 intravaginal suppositories for second-trimester abortion. Efficacy and side effects of the two agents were analyzed by two-tailed t tests, chi 2 analysis with Fisher exact test, and survival analysis. RESULTS: The mean times to rupture of membranes, delivery of fetus, and delivery of placenta were significantly less for women receiving PGE2 vaginal suppositories. The cumulative abortion rate after 24 hours for the PGE2 group was 96%, compared with 69% for the 15M-PGF2 alpha group. Although there were few differences in side effects, the 15M-PGF2 alpha group had significantly fewer headaches, fevers, and chills. CONCLUSION: Intravaginal PGE2 is superior to IM 15M-PGF2 alpha for second-trimester abortion.

Management of uterine hyperstimulation after prostaglandin E2 administration.

Recent literature suggests that intravaginal or intracervical application of prostaglandin E2 gel may be an effective agent for cervical ripening. One potentially disastrous reported side effect is uterine hyperstimulation. This case report represents the first description of the successful management of uterine hyperstimulation with intravenous ritodrine therapy after the intravaginal administration of prostaglandin E2.

Cervical ripening and labor induction with intracervical triacetin base prostaglandin E2 gel: a placebo-controlled study.

A double-blind, randomized, placebo-controlled study was undertaken to evaluate the efficacy of a single-dose, shelf-stable preparation of prostaglandin E2 gel (PGE2) when used intracervically in patients with low Bishop scores. Two different preparations (0.5 and 0.25 mg) of PGE2 were used and a total of 45 patients were studied. Both preparations of PGE2 demonstrated a statistically significant increase in the spontaneous labor rate as compared with the placebo gel. Bishop scores were altered in all patients not proceeding to labor spontaneously, but the changes were most significant in the low- and high-dose groups. No significant deleterious affects were noted. The efficacy and safety of this new, sterile, and stable preparation makes it suitable for clinical use.

Preinduction cervical ripening with prostaglandin E2 intracervical gel.

A double-blind, placebo-controlled, dose-ranging study was undertaken to evaluate the efficacy of two doses of intracervical prostaglandin E2 gel in patients with unfavorable Bishop scores. Mean change in Bishop score, success of softening, time to labor, and time to delivery were all significantly different in the two treatment groups as compared with the placebo group. Twenty-three of 30 treated patients had uterine contractions lasting greater than four hours and eight patients delivered during the observation period. Moreover, one case of uterine hyperactivity and five cases of severe fetal heart rate decelerations were noted in the treatment groups. Although efficacious for cervical ripening, caution is warranted when using this technique in patients at risk for placental insufficiency.

The effect of prostaglandin E1 in patients undergoing clinical cardiopulmonary bypass.

The effect of prostaglandin E1 (PGE1) on protection of platelets during cardiopulmonary bypass (CPB) was evaluated in 9 patients, who were compared with an identical control group of 10 patients undergoing coronary artery bypass grafting. To evaluate the hemodynamic side-effects, PGE1 (0.05 micrograms/kg/min) was infused prior to CPB, resulting in a 26% drop in mean systemic arterial pressure. With this dose, no inhibition of the adenosine diphosphate-induced aggregation could be measured in the pulmonary artery sample. During CPB, the same infusion dose resulted in a severe drop in systemic arterial pressure below 50 mm Hg in 7 of the 9 patients. In 5 of these patients, volume load and phenylephrine infusion could not compensate for the pressure drop, and PGE1 had to be reduced to 0.02 micrograms/kg/min. Platelet aggregation was reduced significantly in the PGE1-treated group compared with the control group, but not completely inhibited during CPB. However, in the postbypass period no platelet preservation was seen in the PGE1 group. In both groups, platelet number and function were equally low. No differences were measured in blood loss or blood transfusion requirements. Except for hypotension, no side-effects of the PGE1 treatment were seen. It is concluded that the hypotension caused by minimal doses of PGE1 during CPB precluded using higher doses, which might have had a greater effect on platelet inhibition. These hypotensive side-effects should be reduced or eliminated before PGE1 can be expected to have the same protective effect on platelet damage that has been demonstrated in animal experiments.