morphine and Inflammation

Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard. The condition has been attributed to the passage of fetal colonic content (meconium), intraamniotic bleeding with the presence of heme catabolic products, or both. The frequency of green-stained amniotic fluid increases as a function of gestational age, reaching approximately 27% in post-term gestation. Green-stained amniotic fluid during labor has been associated with fetal acidemia (umbilical artery pH <7.00), neonatal respiratory distress, and seizures as well as cerebral palsy. Hypoxia is widely considered a mechanism responsible for fetal defecation and meconium-stained amniotic fluid; however, most fetuses with meconium-stained amniotic fluid do not have fetal acidemia. Intraamniotic infection/inflammation has emerged as an important factor in meconium-stained amniotic fluid in term and preterm gestations, as patients with these conditions have a higher rate of clinical chorioamnionitis and neonatal sepsis. The precise mechanisms linking intraamniotic inflammation to green-stained amniotic fluid have not been determined, but the effects of oxidative stress in heme catabolism have been implicated. Two randomized clinical trials suggest that antibiotic administration decreases the rate of clinical chorioamnionitis in patients with meconium-stained amniotic fluid. A serious complication of meconium-stained amniotic fluid is meconium aspiration syndrome. This condition develops in 5% of cases presenting with meconium-stained amniotic fluid and is a severe complication typical of term newborns. Meconium aspiration syndrome is attributed to the mechanical and chemical effects of aspirated meconium coupled with local and systemic fetal inflammation. Routine naso/oropharyngeal suctioning and tracheal intubation in cases of meconium-stained amniotic fluid have not been shown to be beneficial and are no longer recommended in obstetrical practice. A systematic review of randomized controlled trials suggested that amnioinfusion may decrease the rate of meconium aspiration syndrome. Histologic examination of the fetal membranes for meconium has been invoked in medical legal litigation to time the occurrence of fetal injury. However, inferences have been largely based on the results of in vitro experiments, and extrapolation of such findings to the clinical setting warrants caution. Fetal defecatio

Topics: Amniotic Fluid; Chorioamnionitis; Female; Heme; Humans; Infant, Newborn; Inflammation; Meconium; Meconium Aspiration Syndrome; Pregnancy; Pregnancy Complications

This review summarizes neonatal meconium aspiration syndrome in light of meconium-induced inflammation and inflammatory surfactant inactivation, related to both endogenous and therapeutic exogenous surfactant. The wide effect of meconium on surfactant properties is divided into three points. Direct effect of meconium on surfactant properties refers mainly to fragmentation of dipalmitoylphosphatidylcholine and other surfactant phospholipids together with cleavage of surfactant proteins. Initiation of inflammatory response due to activation of receptors by yet unspecified compounds involves complement and Toll-like receptor activation. A possible role of lung collectins, surfactant proteins A and D, which can exert both pro- and anti-inflammatory reactions, is discussed. Initiation of inflammatory response by specified compounds in meconium reflects inflammatory functioning of cytokines, bile acids, and phospholipases contained in meconium. Unifying sketch of many interconnections in all these actions aims at providing integrated picture of inflammatory surfactant inactivation.

Topics: Humans; Infant, Newborn; Inflammation; Meconium; Surface-Active Agents

Does meconium cause meconium aspiration syndrome (MAS) or is meconium discharge only a marker of fetal hypoxia? This dispute has lasted for centuries, but since the 1960s, detrimental effects of meconium itself on the lungs have been demonstrated in animal experiments. In clinical MAS, persistent pulmonary hypertension of the newborn is the leading cause of death in MAS. Regarding the complex chemical composition of meconium, it is difficult to identify a single agent responsible for the pathophysiology. However, considering that meconium is stored in the intestines, partly unexposed to the immune system, aspirated meconium could be recognized as ‘danger', representing damaged self. The common denominator in the pathophysiology could therefore be activation of innate immunity. Thus, a bulk of evidence implies that meconium is a potent activator of inflammatory mediators, including cytokines, complement, prostaglandins and reactive oxygen species. We hypothesize that the two main recognition systems of innate immunity, the Toll-like receptors and the complement system, recognize meconium as ‘danger', which leads not only to lung dysfunction but also to a systemic inflammatory response. This might have therapeutic implications in the future.

Topics: Animals; Complement Activation; Cytokines; Humans; Immunity, Innate; Infant, Newborn; Inflammation; Lung; Meconium; Meconium Aspiration Syndrome; Toll-Like Receptors

Over the past 5 years, increasing understanding about the pathophysiology of meconium-stained amniotic fluid (MSAF) and the meconium aspiration syndrome (MAS) has occurred. Many new therapies are being used in an attempt to prevent MAS and to treat the disorder. The authors review the current status of knowledge concerning the MSAF and MAS and management of these entities.

Topics: Amniotic Fluid; Chorioamnionitis; Female; Humans; Infant, Newborn; Inflammation; Intensive Care, Neonatal; Meconium; Meconium Aspiration Syndrome; Pregnancy; Pregnancy Outcome; Respiratory Distress Syndrome, Newborn

Topics: Chorioamnionitis; Chorionic Villi; Cytomegalovirus Infections; Female; Humans; Inflammation; Meconium; Obstetric Labor, Premature; Placenta; Placenta Diseases; Placental Circulation; Pregnancy; Pregnancy Complications, Infectious; Syphilis

A study was conducted to investigate whether aspiration of amniotic fluid is associated with a deleterious effect on absorption of colostral immunoglobulins or on blood gas and acid-base values of healthy newborn calves. Fourteen calves purchased from commercial sources were transported to a research facility immediately after birth and fed colostrum with known concentrations of immunoglobulins. Blood samples for gas analyses were collected within 5 hours of birth, 24 hours later, and prior to euthanasia. Between 3 and 5 days of age, calves were euthanatized by an overdose of barbiturates. Eleven calves had evidence of bronchoaspiration of amniotic fluid, as determined by presence of meconium, squamous epithelium, or keratin in histologic sections of fixed lung or by cytologic analysis of bronchoalveolar lavage fluid. Blood gas tensions and pH were within reference ranges in 11 of 14 calves. Aspiration of amniotic fluid could not be linked to any specific changes in blood gas tensions, acid-base status, or absorption of colostral immunoglobulins. Presence of keratin and meconium in the lungs often was accompanied by mild exudative alveolitis and focal atelectasis. It was concluded that aspiration of small amounts of amniotic fluid with or without meconium is common in calves and is not associated with hypoxemia, respiratory acidosis, or failure of passive transfer.

Topics: Acid-Base Equilibrium; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Cattle; Colostrum; Female; Immunoglobulins; Inflammation; Intestinal Absorption; Lung; Male; Meconium

Preterm birth may result in adverse health outcomes. Very preterm infants typically exhibit postnatal growth restriction, metabolic disturbances, and exaggerated inflammatory responses. We investigated the differences in the meconium microbiota composition between very preterm (<32 weeks), moderately preterm (32-37 weeks), and term (>37 weeks) human neonates by 16S rRNA gene sequencing. Human meconium microbiota transplants to germ-free mice were conducted to investigate whether the meconium microbiota is causally related to the preterm infant phenotype in an experimental model. Our results indicate that very preterm birth is associated with a distinct meconium microbiota composition. Fecal microbiota transplant of very preterm infant meconium results in impaired growth, altered intestinal immune function, and metabolic parameters as compared to term infant meconium transplants in germ-free mice. This finding suggests that measures aiming to minimize the long-term adverse consequences of very preterm birth should be commenced during pregnancy or directly after birth.

Topics: Animals; Cytokines; Fecal Microbiota Transplantation; Female; Gene Expression Regulation; Germ-Free Life; Growth and Development; Hormones; Humans; Infant, Newborn; Infant, Premature; Inflammation; Male; Meconium; Metabolism; Mice; Weight Gain

Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors.. To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model.. Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA.. SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14.. Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

Topics: Animals; Animals, Newborn; Complement Activation; Complement C5; Cytokines; Humans; Inflammation; Lipopolysaccharide Receptors; Meconium; Meconium Aspiration Syndrome; Random Allocation; Swine

Topics: Animals; Humans; Infant, Newborn; Inflammation; Intensive Care, Neonatal; Meconium; Meconium Aspiration Syndrome; Systemic Inflammatory Response Syndrome

Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free radicals compared to controls (P < 0.05). Surfactant therapy, but particularly combined surfactant + budesonide therapy reduced markers of oxidative stress versus untreated animals (P < 0.05). In conclusion, budesonide added into surfactant enhanced effect of therapy on oxidative damage of the lung.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Female; Free Radicals; Inflammation; Lung; Lung Injury; Male; Meconium; Meconium Aspiration Syndrome; Neutrophils; Oxidative Stress; Pulmonary Edema; Pulmonary Surfactants; Rabbits; Trachea

The aim was to measure concentrations of four neutrophil-derived proteins in meconium as biomarkers describing prenatal environment.. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations were measured using ELISA kits in serial meconium portions (n = 81) from 20 healthy neonates.. The highest concentration was for calprotectin (286.5 ± 214.6 µg/g) with a positive correlation (r = 0.75, p < 0.0001) with myeloperoxidase (1.81 ± 1.72 µg/g). For PMN-elastase (1.70 ± 2.69 µg/g) a negative correlation was observed with calprotectin and myeloperoxidase (r = -0.51, p < 0.0001; r = -0.60, p < 0.0001, respectively). Concentration of lactoferrin (45.07 ± 78.53 µg/g) correlated only with that of myeloperoxidese (r = 0.36, p = 0.0009).. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations in meconium are interrelated. These proteins may serve as objective biomarkers describing and/or assessing the intrauterine environment.

Topics: Adult; Biomarkers; Birth Weight; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Inflammation; Lactoferrin; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Male; Meconium; Neutrophils; Peroxidase

Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.

Topics: Analgesics; Animals; CCR5 Receptor Antagonists; Chronic Disease; HEK293 Cells; Humans; Inflammation; Male; Mice; Models, Molecular; Molecular Targeted Therapy; Neuralgia; Receptors, CCR5; Receptors, Opioid, mu

Necrotizing enterocolitis (NEC) leads to significant morbidity and mortality in the neonatal intensive care unit. Although current evidence would suggest that bacteria contribute to the pathogenesis of NEC, no single bacterium has yet been identified.. The aims of this study were to investigate fecal S100A12 concentrations and the intestinal bacterial community in premature infants (24-32 weeks) and investigate any associations between the microbiota and the development of NEC.. Meconium and feces were collected from premature newborn infants (between 24 and 32 weeks gestation) over the first 4 weeks of life. Fecal S100A12 concentrations were assayed by immunoassay, and samples were subject to 16S rDNA analysis using next-generation sequencing techniques.. Fecal samples were collected from four infants that developed NEC and 18 control infants. Prior to developing NEC, fecal S100A12 concentrations were not elevated; however, following NEC diagnosis, concentrations were highly elevated. The fecal bacterial communities of infants with NEC did not differ significantly from control infants. However, potentially pathogenic bacteria were detected in significantly more infants with NEC than in controls (p = 0.0007).. At birth, fecal S100A12 concentrations were not elevated in premature infants subsequently developing NEC in this cohort. Following NEC diagnosis, S100A12 concentrations were highly elevated, suggesting that this potentially could act as a marker of disease progression. Higher detection rates of potentially pathogenic bacteria in NEC infants suggest that a range of potentially pathogenic bacteria may collectively contribute to NEC pathogenesis.

Topics: Bacteria; Case-Control Studies; Enterocolitis, Necrotizing; Feces; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Inflammation; Male; Meconium; Opportunistic Infections; S100A12 Protein

In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed to their poor solubility and metabolic stability. In this Letter, we report on the further optimization of this series, leading to the relatively polar and peripherically acting CB2 agonists 41 and 49. Although both compounds were not active in acute pain models, the less selective compound 41 displayed good, sustained activity in a chronic model of neuropathic pain without the tolerance observed with morphine. In addition, both 41 and 49 delayed the onset of clinical symptoms in an experimental model for Multiple sclerosis.

Topics: Animals; Benzimidazoles; Brain; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Humans; Inflammation; Mice; Models, Chemical; Multiple Sclerosis; Neuralgia; Rats; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; Time Factors

Since inflammation and oxidation play a key role in the pathophysiology of neonatal meconium aspiration syndrome, various anti-inflammatory drugs have been tested in the treatment. This study evaluated whether the phosphodiesterase (PDE) 3 inhibitor olprinone can alleviate meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated rabbits intratracheally received 4 ml/kg of meconium (25 mg/ml) or saline. Thirty minutes after meconium/saline instillation, meconium-instilled animals were treated by intravenous olprinone (0.2 mg/kg) or were left without treatment. All animals were oxygen-ventilated for an additional 5 h. A bronchoalveolar lavage (BAL) of the left lungs was performed and differential leukocyte count in the sediment was estimated. The right lungs were used to determine lung edema by wet/dry weight ratio, as well as to detect oxidative damage to the lungs. In the lung tissue homogenate, total antioxidant status (TAS) was determined. In isolated lung mitochondria, the thiol group content, conjugated dienes, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation products, and activity of cytochrome c oxidase (COX) were estimated. To evaluate the effects of meconium instillation and olprinone treatment on the systemic level, TBARS and TAS were determined in the blood plasma, as well. Meconium instillation increased the relative numbers of neutrophils and eosinophils in the BAL fluid, increased edema formation and concentrations of oxidation markers, and decreased TAS. Treatment with olprinone reduced the numbers of polymorphonuclears in the BAL fluid, decreased the formation of most oxidation markers in the lungs, reduced lung edema and prevented a decrease in TAS in the lung homogenate compared to non-treated animals. In the blood plasma, olprinone decreased TBARS and increased TAS compared to the non-treated group. Conclusion, the selective PDE3 inhibitor olprinone has shown potent antioxidative and anti-inflammatory effects in the meconium-induced oxidative lung injury.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Edema; Humans; Imidazoles; Infant, Newborn; Inflammation; Leukocyte Count; Lung Injury; Meconium; Mitochondria; Oxidative Stress; Phosphodiesterase 3 Inhibitors; Pyridones; Rabbits

Meconium, the first intestinal discharge of the newborn, contains material accumulated during fetal life. Meconium activates complement and CD14 and may induce a systemic inflammatory response. Toll-like receptors are classical pattern-recognition receptors recognizing both exogenous and host-derived ligands. The cyanobacterial product CyP is a potent LPS antagonist binding to the TLR4/MD-2 complex. The aim of the present study was to investigate the role of the CD14/TLR4/MD-2 complex in meconium-induced inflammation.. Whole blood from six donors was preincubated with anti-CD14 or CyP. Meconium was added and the samples were incubated for 4h. Twenty-seven inflammatory mediators were measured in a Bioplex Array Reader. Human embryonic kidney cells transfected with plasmids containing NF-kappaB dependent luciferase reporter, human MD-2, TLR4, TLR2 and/or CD14, were incubated with meconium or LPS for 18 h. Luciferase activity in cytoplasmic extracts was measured using a Luciferase Assay System kit.. Meconium induced formation of a broad panel of inflammatory mediators. CyP and anti-CD14 significantly (p<0.001) inhibited meconium-induced formation of (a) proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IFN-gamma) by 60-80% and 72-94%, respectively, (b) anti-inflammatory cytokines (IL-10, IL-1Ra) by 58-59% and 50-65%, respectively, (c) chemokines (IL-8, MCP-1, MIP-1alpha, MIP-1beta, eotaxin, IP-10) by 43-77% and 57-87%, respectively, and (d) growth factors (G-CSF, GM-CSF, basic FGF, PDGFbb) by 53-71% and 40-78%, respectively, with no statistical significant difference between Cyp and anti-CD14. The inflammatory response could only partly be explained by LPS, suggesting that endogenous components of meconium contribute to the inflammatory response. Meconium activated NF-kappaB dose-dependently in cells expressing TLR4/MD-2 together with CD14, while no effect was seen in cells expressing TLR4/MD-2 alone or in TLR2/CD14 transfected cells.. The results indicate that the CD14-dependent meconium-induced inflammatory reaction is mediated through the TLR4/MD2 complex. These data may have implications for future therapeutic strategies for meconium aspiration syndrome.

Topics: Adult; Anti-Inflammatory Agents; Cell Line; Chemokines; Cyanobacteria; Cytokines; Humans; Infant, Newborn; Inflammation; Inflammation Mediators; Lipopolysaccharide Receptors; Lymphocyte Antigen 96; Meconium; NF-kappa B; Polysaccharides, Bacterial; Toll-Like Receptor 4; Transfection

Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes. We now report that, within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. In humans, the temporal and causal relations between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation but were less often sterile than controls. Moreover, after introduction of bacteria into their lungs, pigs with CF failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Our finding that pigs with CF have a host defense defect against bacteria within hours of birth provides an opportunity to further investigate CF pathogenesis and to test therapeutic and preventive strategies that could be deployed before secondary consequences develop.

Topics: Animals; Animals, Newborn; Cystic Fibrosis; Disease Models, Animal; Ileus; Inflammation; Lung; Meconium; Mucus; Pancreatic Diseases; Radiography, Thoracic; Survival Analysis; Swine; Time Factors

We previously showed that meconium causes lung cell death by apoptosis and inflammatory cytokine expression. Whether this is due to meconium exposure itself, or meconium related hypoxia remains unclear.. To elucidate the effects of meconium, saline, milk, hypoxia and hyperoxia induced lung injury.. We studied 5 groups of rabbit pups: (I) normal saline; (II) Milk; (III) 10% solution of meconium; (IV) only to 15 minutes of hypoxia (10% O(2)), and (V) 5 minutes of hypoxia (95% O(2)). After exposure lung lavage cells were used for apoptotic cell count and cytokine expression. In vitro response of human A 549 epithelial cells to meconium-and milk exposure was also studied.. There was no difference in cell death between saline and milk groups. However, meconium caused a significant cell loss compared to saline and milk-Inflammatory cytokines increased significantly in meconium group compared to saline or milk group. Although hypoxic and hyperoxic lungs showed increased inflammatory reaction compared to saline-treated lungs, this injury was not significant compared to meconium group. Studies with A549 cells also showed similar results.. We conclude that lung cell injury in meconium aspiration is mainly from meconium itself.

Topics: Animals; Animals, Newborn; Cell Line; Humans; Hypoxia; Infant, Newborn; Inflammation; Lung Injury; Meconium; Meconium Aspiration Syndrome; Milk; Rabbits

Meconium aspiration syndrome has a complex pathophysiology. Meconium activates the complement system and meconium-induced cytokine formation is differentially mediated by complement and CD14. C1-inhibitor (C1-INH) regulates complement and contact-system activation mainly by protease inhibition, but may reduce inflammation by other mechanisms as well.. The aim of the study was to investigate the initial mechanisms of meconium-induced complement activation and to study the effect of C1-INH on the meconium-induced inflammatory reaction.. Human serum from five donors was preincubated with an anti-MBL monoclonal antibody and then incubated with meconium for 30 min at 37 degrees C. Human cord whole blood, anticoagulated with lepirudin, from six donors was preincubated with C1-INH and then incubated with meconium for 30 min and 4h at 37 degrees C. Complement activation products specific for the different pathways were measured by ELISAs: classical pathway C1rs/C1-INH complexes, classical and lectin pathway C4d, alternative pathway C3bBbP, and terminal pathway sC5b-9 complex (TCC). A Bio-Plex Array Reader was used to measure 27 inflammatory mediators.. The anti-MBL monoclonal antibody significantly reduced meconium-induced formation of C4d by 63% (p=0.0159) and TCC by 27% (p=0.0079). C1-INH dose-dependently inhibited meconium-induced formation of C1rs/C1-INH complexes, C4d, C3bBbP, and TCC compared to albumin (p<0.002 for all). C1-INH induced a dose-dependent and substantial inhibition of meconium-induced formation of the proinflammatory cytokines TNFalpha, IL-1 beta, IL-6 and IFN-gamma (p<0.01 for all), the chemokines IL-8, MCP-1, MIP-1 alpha, MIP-1 beta, and eotaxin (p<0.02 for all), the growth factors G-CSF, GM-CSF, basic FGF, and PDGFbb (p<0.05 for all), and the anti-inflammatory cytokine IL-1ra (p<0.001).. Meconium activated the lectin complement pathway as well as the alternative pathway. C1-INH efficiently reduced a broad spectrum of inflammatory mediators even at the lowest concentration. Administration of C1-INH may thus reduce the inflammatory response in MAS.

Topics: Complement Activation; Complement C1; Complement C1 Inhibitor Protein; Complement Pathway, Alternative; Cytokines; Fetal Blood; Humans; Infant, Newborn; Inflammation; Meconium; Meconium Aspiration Syndrome

Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS).. Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied.. Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF.. Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

Topics: Adolescent; Child; Child, Preschool; Crohn Disease; Cystic Fibrosis; Duodenum; Female; Fibroblasts; Ganglion Cysts; Humans; Ileum; Ileus; Infant; Inflammation; Intestinal Atresia; Intestinal Mucosa; Intestinal Pseudo-Obstruction; Lymphocytes; Male; Manometry; Meconium; Muscle Cells; Myenteric Plexus; Retrospective Studies

The pathogenetic cascade of meconium aspiration syndrome (MAS) in newborn infants is complex and still incompletely studied. The variable clinical presentation of MAS is basically connected with variation of the amount and consistency of aspirated meconium and also its distribution within the affected lungs. The contributing role of other factors, like intrauterine fetal compromises, lung maturity at the time of insult as well as direct and indirect effects of meconium and its components on the lung alveolar and vascular integrity and development, remains to be studied in further detail. Better understanding of the lung injury processes in MAS, specifically inflammatory injury and non-inflammatory apoptosis and their interplay, may offer new possibilities to treat the severely affected infants, and needs therefore to be explored. Systemic dispersion of intrapulmonary meconium and its components may further induce inflammatory circulatory changes and injurious effects in distant organs, but the mechanisms and clinical significance of these systemic complications are still poorly known. It is thus evident that lung injury processes and potent long-term consequences in various extrapulmonary organs, specifically the brain, as well as development of new approaches to their treatment and prevention form great challenges for future research of MAS.

Topics: Humans; Infant, Newborn; Inflammation; Lung; Meconium; Meconium Aspiration Syndrome

Topics: Humans; Infant, Newborn; Inflammation; Lung; Meconium; Meconium Aspiration Syndrome

Despite the good survival rate of fetuses with gastroschisis, the length and cost of hospitalization for surgically repaired gastroschisis are high. In gastroschisis, prolonged exposure of the intestine to amniotic fluid (AF) containing intestinal waste products results in intestinal damage, including intestinal wall thickening and fibrous peel formation. The deleterious effects of AF on gastroschisis can be prevented by lowering the concentration of intestinal waste products. We describe the treatment of a case of fetal gastroschisis by repeated AF exchange and infusion. Following repeated, successful transabdominal AF exchange and infusion, the concentrations of various intestinal waste products were decreased. AF exchange and infusion may prevent intestinal damage and improve postnatal outcome in gastroschisis by diluting the AF, probably by lowering the concentrations of intestinal waste products.

Topics: Adult; Amniocentesis; Amniotic Fluid; Female; Fetal Diseases; Gastroschisis; Humans; Infant, Newborn; Inflammation; Meconium; Pregnancy; Prenatal Care; Ultrasonography, Prenatal

Topics: Humans; Infant, Newborn; Inflammation; Lung; Meconium; Meconium Aspiration Syndrome

Meconium-stained amniotic fluid (MSAF) is thought to be a sign of fetal hypoxia, which causes activation of coagulation and inhibition of fibrinolysis. Inflammation is also seen in MSAF. On the other hand, thrombin activatable fibrinolysis inhibitor (TAFI) is an inhibitor of fibrinolysis and a regulator of vascular inflammation. For this reason, in this study we aimed to evaluate the relation between hypoxia, fibrinolysis, and inflammation by determining the levels of TAFI activity (TAFIa) in MSAF where inflammation was also thought to have a role in the pathogenesis.. The MSAF group consisted of 22 neonates; 20 neonates served as the control group. Plasma TAFIa levels were evaluated in all neonates in the first six hours of life.. TAFIa levels were significantly higher in the MSAF group when compared with the control group and the levels correlated negatively with cord blood pH levels.. Increased TAFIa levels in neonates with MSAF might be due to hypoxia. Inflammation observed in MSAF may also play an additional role in increased TAFIa expression. Although no clinical complication that can be attributed to this increase was seen, one should be alert to the complications of depressed fibrinolysis that might be observed in these neonates.

Topics: Amniotic Fluid; Carboxypeptidase B2; Female; Fetal Blood; Gestational Age; Humans; Hydrogen-Ion Concentration; Hypoxia; Infant, Newborn; Inflammation; Male; Meconium

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.

Topics: Animals; Biological Availability; Disease Models, Animal; Glycine; Hydroquinones; Hyperalgesia; Inflammation; Pain; Rats; Stereoisomerism; Structure-Activity Relationship

Topics: Amniotic Fluid; Animals; Disease Models, Animal; Gastroschisis; Inflammation; Intestinal Diseases; Meconium; Rats

Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconium-induced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60-70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response.

Topics: Antibodies, Monoclonal; CD11b Antigen; Complement Activation; Complement C5a; Complement System Proteins; Dose-Response Relationship, Drug; Flow Cytometry; Hirudins; Humans; Infant, Newborn; Inflammation; L-Selectin; Meconium; Meconium Aspiration Syndrome; Neutrophil Activation; Neutrophils; Oxidative Stress; Protein Binding; Recombinant Proteins; Respiratory Burst; Syndrome

(1) To determine the nature and extent of placental pathologic findings; (2) to associate placental pathologic findings with clinical indicators of infection; (3) to evaluate placental pathology in the context of the guidelines outlined by the College of American Pathologists (CAP).. A retrospective cohort study, through review of maternal and neonatal charts and placental pathology, of 100 sequential pregnancies in which placentas were submitted to pathology. Data were examined using descriptive statistics, and proportional differences were compared using the chi-square test and Fisher's exact test.. Overall, 75% of placentas submitted for pathology review had pathologic abnormalities. Fifty percent had findings consistent with inflammation, 38% had findings consistent with vascular abnormalities, and 18% had findings consistent with meconium. Fetal clinical indicators of infection were associated with placental findings of chorioamnionitis (p < or = 0.01), while maternal clinical indicators were not. Similarly, fetal clinical indicators were associated with placental findings of fetal inflammation (p < or = 0.025), whereas maternal indicators were not associated with placental findings of maternal inflammation. A diagnosis of chorioamnionitis in labour by the attending physician was associated with pathologic findings (p < or = 0.05). A CAP indication was found in 75% of the placentas. There was no difference in incidence of placental pathology between those placentas submitted with and without a CAP indication.. Placental findings of inflammation or infection were associated with fetal clinical indicators of infection, but not with maternal indicators. Placental pathology is very useful in identifying undiagnosed maternal infection or inflammation.

Topics: Adult; Chorioamnionitis; Cohort Studies; Congenital Abnormalities; Female; Fetal Growth Retardation; Fetal Membranes, Premature Rupture; Humans; Infant, Newborn; Inflammation; Meconium; Obstetric Labor Complications; Obstetric Labor, Premature; Placenta; Placenta Diseases; Pregnancy; Pregnancy Complications; Pregnancy, Multiple; Retrospective Studies

Inflammation plays an important role in the pathogenesis of meconium aspiration syndrome, and pneumonitis is one of the major characteristics. We have previously shown that meconium has chemotactic properties because of the presence of IL-8. We hypothesize that IL-8 and other proinflammatory substances in meconium may amplify inflammation in meconium aspiration syndrome, inducing endogenous cytokine production by lung epithelial cells. We measured proinflammatory substances in first-pass meconium from healthy newborns and evaluated the effect of sterile meconium on cytokine production in cultured A549 alveolar epithelial cells in vitro. IL-1beta, IL-6, IL-8, and tumor necrosis factor-alpha were measured by ELISA, and heme was measured spectrophotometrically. After incubation of meconium samples with A549 cells, cytokine concentrations in the supernatant were measured. Meconium samples contained variable amounts of IL-1beta, IL-6, IL-8, tumor necrosis factor-alpha, and heme. On stimulation of A549 cells with meconium, the IL-8 concentration in the culture supernatant significantly increased above baseline measurements, whereas tumor necrosis factor-alpha showed a variable pattern and IL-1beta or IL-6 remained unchanged. There was no quantitative relationship between the concentration of the measured cytokines and heme in meconium and cytokine release by the A549 cells after meconium exposure. Meconium contains proinflammatory substances. All samples induced IL-8 release and some induced tumor necrosis factor-alpha release in cultured A549 epithelial cells. We speculate that proinflammatory substances in meconium can induce lung inflammation in meconium aspiration syndrome in two ways: directly via cytokines and heme present in meconium and indirectly by inducing cytokine release by the epithelial lung cells.

Topics: Adult; Cells, Cultured; Cytokines; Epithelial Cells; Female; Heme; Humans; Infant, Newborn; Inflammation; Interleukin-8; Meconium; Pregnancy; Respiratory Mucosa

Exposure of the peritoneal cavity to meconium causes a marked inflammatory response. The effect of intraperitoneal meconium on intestinal morphology and plasma nitrite and nitrate (NO2(-) + NO3(-)) levels and how this inflammatory process is influenced by hyperbaric oxygen (HBO) treatment were investigated in this study. The purpose was to determine whether HBO treatment could be considered a useful adjunct in the resuscitative treatment of severely ill patients admitted with meconium peritonitis (MP). Rats were divided into three groups. Human meconium (MP group, n=10) and sterile saline (control group, n=10) were injected intraperitoneally for 3 days. The procedure for meconium injection was combined with HBO treatment for the HBO group (n=10). HBO was administered for 7 days. In all groups, peritoneal swap cultures, plasma NO2(-) + NO3(-) levels, intestinal diameters, and macroscopic and microscopic changes in the intestine were determined on the 8th day. Bacterial growth was not detected in the peritoneal swap cultures. There was a significant difference in NO2(-) + NO3(-) levels between the MP and HBO groups ( P<0.05), between the MP and control groups ( P<0.01), and between the HBO and control groups ( P<0.05). Thin fibrinous adhesions in both the MP and HBO groups, and thickened and dilated intestinal loops in the MP group were observed macroscopically. The intestinal diameter in the MP group was significantly greater than in the HBO and control groups. The only microscopic difference was seen in the serosal layer. Compared with the animals in the control and HBO groups, the intestine of the rats in the MP group showed prominent serosal thickening, edema, capillary proliferation and cellular infiltration. The ameliorated inflammatory changes and decreased dilatation of the intestine accompanied by a significant decrease in NO2(-) + NO3(-) levels suggest that as an adjunctive treatment, HBO may have a beneficial effect in the resuscitative treatment of meconium peritonitis.

Topics: Animals; Hyperbaric Oxygenation; Inflammation; Male; Meconium; Models, Animal; Peritonitis; Rats

To understand the pathogenesis of meconium aspiration syndrome, we compared the pulmonary and inflammatory effects of the water and lipid extracts of human meconium instilled into the lungs of newborn piglets. The piglets were artificially ventilated, made hypoxemic, and randomized into three groups. At start of reoxygenation, 3 ml/kg of one of the following mixtures was instilled intratracheally: (1) meconium (n = 12); (2) water extract of meconium (n = 12), and (3) lipid extract of meconium (n = 12). During 8 h of reoxygenation, hemodynamics, pulmonary gas exchange, lung mechanics, and interleukin-8 concentrations in tracheobronchial aspirates were monitored. Oxygenation index (p = 0.04) and mean airway pressure (p = 0.04) increased more in the lipid extract group than in the water extract group. Dynamic compliance and mean arterial blood pressure decreased (p < 0.05) in the meconium and lipid extract groups, but not in the water extract group. At 8 h of reoxygenation, the interleukin-8 concentration in the tracheobronchial aspirates was three times higher in the lipid extract group as compared with the water extract group (110 +/- 102 vs. 37 +/- 27 pg/ml; p = 0.02). In conclusion, pulmonary dysfunction in meconium aspiration syndrome is caused by both the water- and lipid-soluble fractions of meconium, with stronger inflammatory and more detrimental effects promoted by the lipid extract than the water extract.

Topics: Animals; Animals, Newborn; Blood Pressure; Humans; Hypoxia; Infant, Newborn; Inflammation; Interleukin-8; Lipids; Lung; Lung Diseases; Meconium; Meconium Aspiration Syndrome; Oxygen; Pulmonary Gas Exchange; Respiration, Artificial; Solubility; Swine; Tissue Extracts; Vascular Resistance; Water

It is uncertain how often the passage of meconium in utero is a response to some event causing fetal distress as opposed to being simply the physiologic functioning of a maturing intestinal tract. The extent to which meconium may produce injury or inflammation in pulmonary and placental tissues after intrauterine exposure is also unclear. This study was a retrospective review of 123 cases, 79 stillborn and 44 liveborn less than one month of age, autopsied at The Johns Hopkins Hospital, and showing histologic evidence of intrauterine meconium exposure by aspirated meconium or meconium macrophages in placental tissues. Of 55 cases with pulmonary inflammation, 13 (24%) had fetal pneumonia, 5 (9%) had postnatal bronchopneumonia, and 37 (67%) had inflammation secondary to meconium aspiration. There was inflammation of the umbilical cord in 31 (41%) of the 75 cases with available slides, 11 (15%) had funisitis associated with chorioamnionitis and 18 (58%) were secondary to meconium exposure. There were 19 cases with focal injury of cord vessels from meconium, two of which had cord ulceration. Inflammation of the membranes and chorionic plate was present in 24 (33%) of the 72 cases where it could be assessed, and was due to chorioamnionitis in 11 (46%) and to meconium in 13 (54%). In general, meconium-related inflammations was much less severe in the membranes than in the cord. There were 67 (54%) cases with definite or probable evidence of fetal distress. In 38 (48%) stillborns no cause of fetal death in utero was identified and in 18 (41%) liveborns there was no known prenatal problem. The results support the concept that meconium passage in utero may occur either as a response to fetal distress or as a physiologic process. Inflammation in the lung and placental tissues, and vascular injury in the umbilical cord may arise secondary to in utero exposure to meconium.

Topics: Female; Fetal Death; Fetus; Humans; Infant, Newborn; Inflammation; Meconium; Meconium Aspiration Syndrome; Placenta; Placenta Diseases; Pneumonia; Pregnancy; Retrospective Studies; Umbilical Cord; Vascular Diseases

In a study of nonsteroidal antiinflammatory and analgesic agents, a series of 1,3-dihydro-3-(substituted phenyl)imidazo[4,5-b]pyridin-2-ones-and 3-(substituted phenyl)triazolo[4,5-b]pyridines was prepared. Many of the imidazolones were alkylated on the free nitrogen. In a modified Randall-Selitto analgesic assay, the pain thresholds of both the inflamed and normal foot were elevated. This is not commonly observed with nonsteroidal antiinflammatory agents. The most active compounds were 1,3-dihydro-3[3,4-(methylenedioxy)phenyl]imidazo[4,5-b]pyridin-2-one (I-15) and its N-allyl (I-21) and N-isopropyl (I-121) derivatives. In the triazole series the 3-(2-fluoro- and 2,4-difluorophenyl)triazolo[4,5-b]pyridines (T-1 and T-8) were the best. The imidazole compounds were somewhat superior in analgesic activity to codeine and d-propoxyphene without showing any narcotic characteristics. Some of the compounds also possessed activity against carrageenan-induced foot edema in the rat, so these compounds represent a new class of nonnarcotic analgesic antiinflammatories, capable of producing a greater degree of analgesia than that obtainable with other nonsteroidal antiinflammatory agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Inflammation; Mice; Naloxone; Pyridines; Pyridones; Rats; Reaction Time; Structure-Activity Relationship; Substance Withdrawal Syndrome

Topics: Amniotic Fluid; Animals; Bronchi; Cesarean Section; Enterococcus faecalis; Escherichia coli; Extraembryonic Membranes; Exudates and Transudates; Female; Fetal Diseases; Fibrin; Gastric Juice; Gestational Age; Inflammation; Injections; Ink; Klebsiella pneumoniae; Leukocytes; Lung; Meconium; Pneumonia; Pregnancy; Pulmonary Alveoli; Rabbits; Staphylococcus

Topics: Amnion; Extraembryonic Membranes; Female; Humans; Inflammation; Meconium; Microscopy, Electron; Necrosis; Neutrophils; Placenta; Pregnancy; Pregnancy Complications; Rupture