RESUMO
LY392098 is a member of a novel class of biarylpropylsulfonamides that potentiates AMPA receptor-mediated responses both in vitro and in vivo. In this study, the effects of LY392098 were evaluated in two "behavioral despair" models (the forced swim and tail suspension tests) commonly used to identify clinically useful antidepressants. LY392098 reduced immobility in the forced swim test in both rats and mice, with a minimum effective dose of 0.5 mg/kg (i.p.) in both species. LY392098 (0.1-10 mg/kg, i.p.) did not affect motor activity of rats, indicating that the ability of this compound to reduce immobility in the forced swim test is unrelated to a motor stimulant action. LY392098 also reduced immobility in the tail suspension test in a dose-dependent manner, with a minimum effective dose of 5 mg/kg (i.p). A non-competitive AMPA antagonist (LY300168) blocked the activity of LY392098 in the forced swim test, but did not affect imipramine-induced reductions in immobility. Thus, AMPA receptor activation appears to be required for the antidepressant-like effect of LY392098, but not imipramine. These findings indicate that biarylpropylsulfonamides, exemplified by LY392098, may represent a novel class of antidepressants.
Assuntos
Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Receptores de AMPA/fisiologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Antidepressivos Tricíclicos/farmacologia , Comportamento Animal/fisiologia , Benzodiazepinas/administração & dosagem , Imipramina/farmacologia , Imobilização/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.
Assuntos
Aminoácidos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Agonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/agonistas , Aminoácidos/química , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Bicíclicos com Pontes/metabolismo , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , AMP Cíclico/biossíntese , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Ratos , Proteínas Recombinantes/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Convulsões/tratamento farmacológico , EstereoisomerismoRESUMO
Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. Raloxifene was administered orally by gavage at doses of 0, 0.1, 1, or 10 mg/kg/d to female CD rats (25/group) on Gestation Day 6 (GD 6) through Postpartum Day 20 (PD 20). Females were allowed to deliver and maintain their progeny until PD 21. All dead pups and pups culled on PD 1 were given internal and external examinations. One pup/sex/litter was assigned to each of the following assessment groups: 1) the primary pair for the F1 generation study, in which survival, growth, development, behavior, indicators of sexual maturation, and reproductive performance were evaluated; 2) terminal necropsy evaluations at PD 21; 3) terminal necropsy evaluations at 60 d of age; and 4) assessments of immune function at 5 to 6 weeks of age. At termination on PD 21, 60, or approximately 140, a necropsy was performed; crown rump and tibia lengths were measured; pituitary weights were taken; and a portion of the anterior pituitary was retained for growth hormone, luteinizing hormone, and prolactin content determinations (control and 10-mg/kg groups only). The remainder of the pituitary and reproductive tissues were retained for histologic evaluations. Dose-related depressions in maternal body weight and food consumption occurred during gestation. Mean gestation length was increased at 1 and 10 mg/kg. Delayed, extended, and/or disrupted parturition occurred in dams given 10 mg/kg, which resulted in a high incidence of maternal morbidity and/or death, increased numbers of dead pups, and the survival of only 66% of live pups to PD 21. Progeny body weights were not decreased at birth, but were depressed progressively in a dose-related manner during the 3-week lactation period. Negative geotaxis and incisor eruption were apparently accelerated in the 1- and 10-mg/kg groups, but eye opening was delayed at 10 mg/kg. Postweaning activity levels, auditory startle, and passive avoidance performance were not affected in the raloxifene groups. Dose-related decreases in spleen cellularity and thymus weights occurred in both sexes, but immune system function, as measured by splenic natural killer cell activity and antibody response to sheep red blood cells, was not affected. Postweaning body weights and growth parameters, as well as pituitary hormone content, were affected in both an age- and sex-specific manner. Preputial separation was not affected, but vaginal patency occurred ca 2 d earlier than controls in females from the 10-mg/kg group. Estrous cycles of the F1 females were not affected during the first two weeks after vaginal opening, but were disrupted at 12 to 14 weeks of age in the 10-mg/kg group. These females showed poorer mating and fertility indices, and litter size was reduced in the two females that were pregnant. Histologically, reproductive organs were not affected in males at any age or in females at PD 21. At PD 60, vaginal mucification occurred in females from the 0.1- and 1-mg/kg groups. At PD 140, the only finding was a high rate of uterine hypoplasia in the 10-mg/kg group, and this finding occurred in the absence of any concomitant ovarian or vaginal changes. These reproductive and developmental findings are consistent with estrogen antagonist activity of raloxifene.
Assuntos
Antagonistas de Estrogênios/farmacologia , Trabalho de Parto/efeitos dos fármacos , Piperidinas/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Sistema Imunitário/efeitos dos fármacos , Imunoglobulinas/sangue , Hormônios Hipofisários/metabolismo , Gravidez , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal , Cloridrato de Raloxifeno , Ratos , Receptores de Estrogênio/agonistasRESUMO
Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.1, 1, or 10 mg/kg. In Study 1, GD 20 evaluations of maternal reproductive parameters identified dose-related increases in pre- and postimplantation loss, reductions in the numbers of corpora lutea and live conceptuses, and reduced fetal weight. The low fetal weights were consistent with an extent of morphologic development that corresponded to developmental ages up to 8 d younger than GD 20. Study 2 characterized the potential impact of this disrupted and apparently delayed implantation on gestation length, parturition, and progeny viability. Dams were allowed to deliver and rear their offspring through Postpartum Day 21. Gestation lengths were extended up to 1 week, and litter sizes were reduced in a dose-dependent manner. Nevertheless, parturition occurred normally and pup morphology, survival, and physical and behavioral development were unaffected.
Assuntos
Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Antagonistas de Estrogênios/farmacologia , Piperidinas/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estudos de Avaliação como Assunto , Feminino , Viabilidade Fetal/efeitos dos fármacos , Idade Gestacional , Trabalho de Parto/efeitos dos fármacos , Masculino , Gravidez , Cloridrato de Raloxifeno , Ratos , Receptores de Estrogênio/agonistasRESUMO
2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.
Assuntos
Ansiolíticos/síntese química , Anticonvulsivantes/síntese química , Compostos Bicíclicos com Pontes/síntese química , Agonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato/metabolismo , Administração Oral , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Colforsina/farmacologia , AMP Cíclico/metabolismo , Desenho de Fármacos , Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/farmacologia , Camundongos , Modelos Moleculares , RatosRESUMO
The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.
Assuntos
Adenilil Ciclases/metabolismo , Agonistas de Aminoácidos Excitatórios/síntese química , Prolina/análogos & derivados , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Animais Recém-Nascidos , Anticonvulsivantes , Córtex Cerebral/metabolismo , Colforsina/farmacologia , AMP Cíclico/biossíntese , Agonistas de Aminoácidos Excitatórios/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Humanos , Ligação de Hidrogênio , Sistema Límbico/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Prolina/química , Prolina/metabolismo , Prolina/farmacologia , Ratos , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , EstereoisomerismoAssuntos
Cicloleucina/análogos & derivados , Sistema Límbico/efeitos dos fármacos , Neurotoxinas/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Convulsões/fisiopatologia , Aminoácidos Dicarboxílicos/farmacologia , Aminobutiratos/farmacologia , Animais , Cicloleucina/administração & dosagem , Cicloleucina/farmacologia , Relação Dose-Resposta a Droga , Lateralidade Funcional , Sistema Límbico/fisiologia , Sistema Límbico/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos , Microinjeções , Modelos Neurológicos , Fosfosserina/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Convulsões/induzido quimicamente , EstereoisomerismoRESUMO
The behavioral consequences of metabotropic glutamate receptor (mGluR) activation were investigated following intracerebral administration of the mGluR selective agonists (RS)3,5-dihydroxyphenyl-glycine (3,5-DHPG), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), (1R,3S)-1-aminocyclopentane-1,3-dicarboxylate (1R,3S-ACPD), L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP) and (2S,3S,4S)alpha-(carboxycyclopropyl)glycine (L-CCGI) into the thalamus in mice. Injections of 3,5-DHPG, 1S,3R-ACPD and L-CCGI produced dose-dependent increases in limbic seizures with a potency order of 3,5-DHPG = 1S,3R-ACPD > L-CCGI. This effect of 1S,3R-ACPD was stereoselective, since the inactive isomer (1R,3S-ACPD) did not elicit seizure activity. Limbic seizures induced by the phosphoinositide-coupled mGluR subtype selective agonist 3,5-DHPG were attenuated by the mGluR antagonist L-2-amino-3-phosphonopropanoic acid (L-AP3) and dantrolene, inhibitors of mGluR-mediated intracellular calcium mobilization. Interestingly, L-AP4, L-SOP and low doses of L-CCGI also protected against 3,5-DHPG seizures. These data indicate that mGluR agonist-induced limbic seizures in mice are mediated by activation of phosphoinositide-coupled mGluRs. Furthermore, these seizures can be protected against by activation of mGluRs that are negatively-linked to cAMP formation.
Assuntos
Agonistas de Aminoácidos Excitatórios/toxicidade , Sistema Límbico/fisiopatologia , Receptores de Glutamato Metabotrópico/agonistas , Convulsões/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Convulsões/fisiopatologiaRESUMO
The functional role of metabotropic glutamate receptor (mGluR) activation was investigated following intracerebral administration of 1S,3R-ACPD in mice. Injections of 1S,3R-ACPD (50-800 nmol in 5 microliters) into the thalamus produced a dose-dependent increase in limbic seizures. These effects were stereoselective since 1R,3S-ACPD, did not elicit seizure activity. Pharmacologically, limbic seizures were attenuated by the mGluR partial agonist/antagonist L-2-amino-3-phosphonopropionate (L-AP3) and dantrolene, an inhibitor of intracellular calcium mobilization, but not by D-AP3 or ionotropic glutamate receptor antagonists (MK-801 or GYKI-52466). Thus, activation of mGluRs by 1S,3R-ACPD in mice, induces limbic seizures that may involve the mobilization of intracellular calcium stores.
Assuntos
Anticonvulsivantes/farmacologia , Cicloleucina/análogos & derivados , Sistema Límbico/fisiologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Convulsões/induzido quimicamente , Animais , Cicloleucina/administração & dosagem , Cicloleucina/farmacologia , Relação Dose-Resposta a Droga , Hipocampo/anatomia & histologia , Injeções , Masculino , Camundongos , Receptores de Aminoácido/antagonistas & inibidores , Convulsões/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Tálamo/anatomia & histologiaRESUMO
Metabotropic glutamate receptors are a recently described receptor class with emerging importance in synaptic plasticity and brain development. Activation of metabotropic glutamate receptors results in several cellular secondary messenger events that are especially important during postnatal development. This study characterized the effects of D,L-2-amino-3-phosphonopropionate (D,L-AP3), an aspartic acid analog with agonist and antagonist activity at the metabotropic receptor, on the postnatal development of the rat eye and optic nerve. Sprague-Dawley rat pups were treated daily (i.p.) with saline or 500 mg/kg D,L-AP3 on postnatal days (PND) 4-10 or 10-14. After making clinical and ophthalmoscopic examinations, rats were necropsied between 65 and 70 days of age and light microscopic evaluations were made of eyes and optic nerves. Between postnatal days 10-20, all treated rats exhibited motor tremors, circling, and head tilt. Ophthalmoscopic lesions were more severe in rats treated on days 4-10 than days 10-14 and included decreased retinal vasculature, cataracts, and retinal dysplasia, hypoplasia, and detachment. All rats treated on days 4-10 had severe optic nerve atrophy/hypoplasia grossly and severe retinal atrophy, retinal detachment, and cataracts histologically. Seven of eight rats treated on days 10-14 had qualitatively similar but less severe lesions. Overall, rats treated with D,L-AP3 on PND 4-10 had earlier and more severe retinal and optic nerve lesions when compared to rats treated on PND 10-14. These data characterize the morphologic effects in adult rats exposed to D,L-AP3 as neonates and suggest a possible role for the metabotropic receptor in the postnatal development of retina and optic nerve.
Assuntos
Alanina/análogos & derivados , Animais Recém-Nascidos/fisiologia , Oftalmopatias/induzido quimicamente , Doenças do Nervo Óptico/induzido quimicamente , Envelhecimento/fisiologia , Alanina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Olho/patologia , Oftalmopatias/patologia , Masculino , Nervo Óptico/patologia , Doenças do Nervo Óptico/patologia , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/patologiaRESUMO
We previously reported that increased production of prostaglandin E2 by monocytes is a pivotal mechanism in posttrauma immunopathology. Here we characterize monocyte levels of transforming growth factor beta and examine the effects of elevated transforming growth factor beta on prostaglandin E2 release by patients' monocytes. Trauma patients' and normals' monocyte supernates (+/- stimulation with muramyl dipeptide) were acid treated and assayed for transforming growth factor beta using the mink lung-cell bioassay. Alternatively, human transforming growth factor beta was added to patients' and normals' monocytes and prostaglandin E2 production assayed. Significantly elevated transforming growth factor beta levels (median = 181.7 pmol/10(6) monocytes) were detected in immunosuppressed patients' monocytes but not immunocompetent trauma patients' (median = 32.0 pM) or normals' (median = 20.4 pM) monocytes. Adding transforming growth factor beta to monocytes resulted in a significant elevation of prostaglandin E2 levels. Elevated monocyte transforming growth factor beta levels in trauma patients could be both suppressing T-lymphocyte functions and maintaining elevated monocyte prostaglandin E2 synthesis.
Assuntos
Tolerância Imunológica/fisiologia , Monócitos/metabolismo , Fator de Crescimento Transformador beta/biossíntese , Ferimentos e Lesões/imunologia , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adulto , Idoso , Queimaduras/imunologia , Queimaduras/metabolismo , Dinoprostona/biossíntese , Feminino , Humanos , Interferon gama/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Ferimentos e Lesões/metabolismoRESUMO
Appearance of increased proportions of monocytes bearing the 72kd(FcRI) receptor for IgG correlated to aberrant monocyte (MO) functions, depressed immune functions, and poor clinical outcome. The trauma patients' FcRI+ MO subpopulation produced the majority of their elevated IL-6, TNF alpha, TGF beta, and PGE2. IgG stimulation of patients' MO through FcRI not only stimulated TNF alpha, IL-6, and PGE2 levels, but also greatly augmented the levels of these monokines produced after subsequent bacterial challenge. Post-trauma increased IL-6 levels can lead to polyclonal B-cell activation and high levels of circulating, nonspecific IgG as seen in trauma patients. This nonspecific IgG triggers the FcRI on the increased numbers of FcRI+ MO leading to ever-increasing monokine levels. IL-4 was found to downregulate patients' FcRI+ MO production of mediators. The cycle of altered cytokine levels, increased FcRI+ MO numbers, elevated IgG, and augmented triggering of FcRI+ MO may be broken by addition of IL-4.