Early postnatal ibuprofen and indomethacin effects in suckling and weanling rat kidneys.

The use of indomethacin in preterm newborn infants with symptomatic patent ductus arteriosus is associated with compromised renal function. Ibuprofen has been shown to be as effective as indomethacin with fewer renal side effects. We examined the hypothesis that early postnatal ibuprofen has less adverse effects on neonatal rat renal prostanoids, COX-2 expression, and angiotensin II than indomethacin. Newborn rats received IP injections of human therapeutic doses of ibuprofen or indomethacin on the first 3 days of life. Control rats were treated with equivalent volume saline. Kidneys were assessed in suckling and weanling rats for prostanoids, COX-2 expression, and angiotensin II. In suckling rats, indomethacin suppressed PGE(2) and COX-2 expression, and increased PGF(2alpha), whereas ibuprofen increased COX-2 and angiotensin II. Although both NSAIDs suppressed 6-ketoPGF(1alpha) and TxB(2) levels in suckling rats, the effect was sustained in weanling rats with indomethacin. Our findings demonstrate that indomethacin exhibits more potent suppressive effects on renal COX-2 and vasodilator prostanoids which are important regulators of renal development and function. These long-term, sustained effects may explain in part, why indomethacin exerts more severe adverse renal effects than ibuprofen, when administered during early postnatal life.

Vaginal versus oral indomethacin in a rabbit model for non-infection-mediated preterm birth: an alternate tocolytic approach.

OBJECTIVE: We examined the hypotheses that vaginal indomethacin is more effective for prolonging gestation, and mediates its tocolytic actions via changes in cervical matrix metalloproteinase (MMP) activity, compared to oral. STUDY DESIGN: Pregnant rabbits induced with mifepristone received oral or vaginal indomethacin; or oral or vaginal vehicle once daily for 2 days. Premature delivery, fetal ductus arteriosus, and cervical MMP activity were assessed. RESULTS: Vaginal indomethacin delayed delivery >72 hours in 100% of the rabbits, extending gestation to 28.2 +/- 0.5 (P < .01) versus 26.4 +/- 0.3, 25.8 +/- 0.5, and 26.5 +/- 0.3 days, for vaginal placebo, oral indomethacin, and oral vehicle, respectively. Fetal ductus arteriosus was patent in all groups. Vaginal indomethacin decreased MMP-1, -8, and -9 activities and increased TIMP-1 levels in the cervix. CONCLUSION: Vaginal indomethacin is more effective than oral for prolonging gestation in the rabbit. Its tocolytic effects may be mediated, in part, by alterations in cervical MMP activity.

Effect of maternal administration of selective cyclooxygenase (COX)-2 inhibitors on renal size, growth factors, proteinases, and COX-2 secretion in the fetal rabbit.

BACKGROUND: Selective cyclooxygenase (COX)-2 inhibitors are currently being considered for management of preterm labor. COX-2 is an important regulator of fetal renal growth and function. Its inhibition may lead to congenital oligonephropathy. OBJECTIVES: We investigated whether maternal administration of a selective COX-2 inhibitor would adversely affect fetal renal growth. METHODS: Three groups of timed pregnant rabbits at 13 days gestation were examined. Group 1 received oral celecoxib (30 mg/kg/day) from 13 to 20 days gestation (Cel-A); group 2 received celecoxib from 13 to 28 days gestation (Cel-B), and group 3 received equivalent volumes of the vehicle from 13 to 28 days gestation. The fetuses were delivered by cesarean section at 29 days gestation. The kidneys were weighed and analyzed for vascular endothelial growth factor (VEGF) and its soluble receptors, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, COX-2, and total cellular protein levels. Sections from the cortex and medulla were assessed histologically. RESULTS: Fetal kidney size was unaffected. VEGF levels were elevated in the Cel-B group. Soluble VEGF receptors, MMP-2, TIMP-1 and COX-2 levels remained unchanged. MMP-9 levels were suppressed in both treated groups, which resulted in significantly lower MMP-9/TIMP-1 ratios. Although TIMP-2 secretion was enhanced in the Cel-B group, MMP-2/TIMP-2 ratios were unaffected. No significant histological changes were detected. CONCLUSIONS: We conclude that maternal administration of therapeutic doses of celecoxib does not adversely affect fetal renal growth. MMP-9 is increased in various nephropathies, but may also have protective effects therefore its suppression by COX-2 inhibitors needs further study.

Increased lung matrix metalloproteinase-9 levels in extremely premature baboons with bronchopulmonary dysplasia.

Matrix metalloproteinases (MMPs) regulate the formation of normal lung architecture. Extremely premature infants exposed to hyperoxia and mechanical ventilation often develop lung inflammation and injury. We hypothesized that an imbalance between MMPs and their tissue inhibitors plays a key role. Our hypothesis was tested to: 1) examine the ontogeny of lung MMPs and tissue inhibitors of metalloproteinases (TIMPs); and 2) determine the effects of hyperoxia and mechanical ventilation on lung MMPs and TIMPs in premature newborn baboons developing chronic lung disease/bronchopulmonary dysplasia (CLD/BPD). Lung specimens were obtained from five groups of gestational controls (GCs) sacrificed at 125, 140, 160, 175, and 185 (term) days of gestation, one fetal baboon model of CLD/BPD delivered at 125 days, and two at 140 days of gestation. Paraffin-embedded lung tissue sections were examined for pathological changes, and frozen lung specimens were analyzed for MMPs-1, -2, -8, and -9; TIMPs-1 and -2; and messenger RNA expression of type I collagen. In GCs, MMP-1 and -9 were elevated in the last trimester, whereas MMP-2 and -8 levels were decreased. Significant changes in lung architecture were noted in the BPD models. MMP-1 was increased in the 125-day model, but decreased in both 140-day models. MMP-8 and collagen mRNA levels were decreased, while MMP-9 and MMP-9 to TIMP-1 ratios were increased in all BPD models. We conclude that an imbalance between MMP-9 and TIMP-1 leading to excessive MMP-9 activity contributes to lung inflammation and edema in CLD/BPD.

Response of fetal prostanoids, nitric oxide, and ductus arteriosus to the short- and long-term antenatal administration of celecoxib, a selective cyclo-oxygenase-2 inhibitor, in the pregnant rabbit.

OBJECTIVE: The purpose of this study was to test the hypothesis that the maternal administration of therapeutic doses of celecoxib would not affect ductus arteriosus patency or alter renal and hepatic prostanoids in the fetal rabbit. STUDY DESIGN: Pregnant rabbits received celecoxib from 13 to 20 days (celecoxib-A), from 13-28 days (celecoxib-B), or vehicle from 13 to 28 days by gavage. Fetal serum and lung tissue were analyzed for nitric oxide oxidation products. Fetal plasma, liver, and kidney were analyzed for prostaglandin levels. RESULTS: The ductus arteriosus was patent in both treatment groups. Celecoxib induced elevations of plasma prostaglandin E(2) production. In celecoxib-B liver and kidney, the 6-keto-prostaglandin F(1alpha) and prostaglandin F(2alpha) levels were increased, and the prostaglandin E(2) and thromboxane B(2) levels were decreased substantially. CONCLUSION: This preliminary evaluation demonstrates that the maternal administration of celecoxib does not influence fetal ductus arteriosus patency adversely in rabbits.