RESUMO
The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.
Assuntos
Inflamação/etiologia , Lipídeos/imunologia , Animais , Anti-Inflamatórios/imunologia , Apoptose , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Modelos Imunológicos , NF-kappa B/imunologia , Fagocitose , Transdução de SinaisRESUMO
Paracetamol is a widely used analgesic and antipyretic with weak anti-inflammatory properties. Experimental evidence suggests that inhibition of prostaglandin biosynthesis contributes to its pharmacological actions. Three cyclooxygenase (COX) isoenzymes are involved in prostaglandin biosynthesis, COX-1, COX-2 and a recently discovered splice-variant of COX-1, COX-3. Our aim was to identify the relative roles for these enzymes in the antinociceptive action of paracetamol in mice. We compared the antinociceptive action of paracetamol with the non-selective non-steroid anti-inflammatory drug, diclofenac and studied paracetamol antinociception in COX-1 and COX-2 knockout mice. Paracetamol (100-400 mg/kg) inhibited both acetic acid- and iloprost-induced writhing responses. In contrast, diclofenac (10-100 mg/kg) inhibited only acetic acid-induced writhing. Only diclofenac reduced peripheral prostaglandin biosynthesis whereas both drugs reduced central prostaglandin production. Prostaglandin E(2) (PGE(2)) concentrations were reduced in different brain regions by administration of paracetamol. COX-1, COX-2 and COX-3 enzyme proteins were expressed in the same brain regions. The effects of paracetamol on writhing responses and on brain PGE(2) levels were reduced in COX-1, but not COX-2, knockout mice. The selective COX-3 inhibitors, aminopyrine and antipyrine also reduced writhing responses and brain PGE(2) biosynthesis. These results suggest that the antinociceptive action of paracetamol may be mediated by inhibition of COX-3.
Assuntos
Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , 6-Cetoprostaglandina F1 alfa/biossíntese , Aminopirina/farmacologia , Animais , Antipirina/farmacologia , Comportamento Animal/efeitos dos fármacos , Western Blotting , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase/farmacologia , Diclofenaco/farmacologia , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandina-Endoperóxido Sintases/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
Acute inflammation can be considered in terms of a series of checkpoints where each phase of cellular influx, persistence, and clearance is controlled by endogenous stop and go signals. It is becoming increasingly apparent that in addition to initiating the inflammatory response, eicosanoids may also mediate resolution. This suggests there are two phases of arachidonic acid release: one at onset for the generation of proinflammatory eicosanoids and one at resolution for the synthesis of proresolving eicosanoids. What is unclear is the identity of the phospholipase (PLA2) isoforms involved in this biphasic release of arachidonic acid. We show here that type VI iPLA2 drives the onset of acute pleurisy through the synthesis of PGE2, LTB4, PAF, and IL-1beta. However, during resolution there is a switch to a sequential induction of first sPLA2 (types IIa and V) that mediates the release of PAF and lipoxin A4, which, in turn, are responsible for the subsequent induction of type IV cPLA2 that mediates the release of arachidonic acid for the synthesis of proresolving prostaglandins. This study is the first of its kind to address the respective roles of PLA2 isoforms in acute resolving inflammation and to identify type VI iPLA2 as a potentially selective target for the treatment of inflammatory diseases.
Assuntos
Fosfolipases A/fisiologia , Pleurisia/enzimologia , Doença Aguda , Animais , Ácido Araquidônico/fisiologia , Carragenina/toxicidade , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Convalescença , Corticosterona/sangue , Ciclo-Oxigenase 2 , Progressão da Doença , Indução Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fosfolipases A2 do Grupo II , Fosfolipases A2 do Grupo IV , Fosfolipases A2 do Grupo V , Fosfolipases A2 do Grupo VI , Interleucina-1/biossíntese , Interleucina-1/genética , Isoenzimas/fisiologia , Leucotrieno B4/biossíntese , Leucotrieno B4/genética , Lipoxinas/biossíntese , Lipoxinas/genética , Lipoxinas/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Fosfolipases A2 , Fator de Ativação de Plaquetas/biossíntese , Fator de Ativação de Plaquetas/genética , Fator de Ativação de Plaquetas/fisiologia , Pleurisia/sangue , Pleurisia/induzido quimicamente , Pleurisia/fisiopatologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Ratos , Ratos WistarRESUMO
Failure of acute inflammation to resolve leads to persistence of the inflammatory response and may contribute to the development of chronic inflammation. Thus, an understanding of inflammatory resolution will provide insight into the etiology of chronic inflammation. In an acute pleurisy, polymorphonuclear leukocytes (PMNs) were found to predominate at the onset of the lesion but decreased in number by undergoing apoptosis, the principal mechanism by which PMNs died in this model. PMNs were progressively replaced by monocytes, which differentiated into macrophages. As with PMNs, macrophages also underwent programmed cell death leading to an abatement of the inflammatory response and eventual resolution. It was found that apoptosis of both these inflammatory cell types was mediated by pro-resolving cyclooxygenase 2-derived 15deoxyDelta12-14PGJ2, which is uniquely expressed during active resolution. Although PMN programmed cell death is well understood, the observation that macrophages apoptose during resolution of acute inflammation is less well described. These results provide insight into the mechanisms that switch off acute inflammation and prevent complications of wound healing and potentially the development of immune-mediated chronic inflammation.
Assuntos
Apoptose , Isoenzimas/fisiologia , Macrófagos/imunologia , Neutrófilos/imunologia , Pleurisia/enzimologia , Pleurisia/imunologia , Prostaglandina D2/análogos & derivados , Prostaglandina-Endoperóxido Sintases/fisiologia , Doença Aguda , Animais , Ciclo-Oxigenase 2 , Inflamação/enzimologia , Isoenzimas/metabolismo , Contagem de Leucócitos , Modelos Imunológicos , Pleurisia/patologia , Prostaglandina D2/biossíntese , Prostaglandina-Endoperóxido Sintases/metabolismo , RatosRESUMO
It is widely accepted that whilst exhibiting clinically useful anti-inflammatory and analgesic activity, the application of non-steroidal anti-inflammatory drugs (NSAIDs) does not affect the underlying pathogenesis of articular diseases such as rheumatoid arthritis. The demonstration of a role for COX-2 in the resolution of inflammation may partly underly the lack of disease modifying activity seen with NSAIDs in long term use in these inflammatory joint diseases. This has led to the suggestion that the anti-arthritic efficacy of these agents may be improved by altering prescribing practice such that they are not given during periods of disease remission, which may be difficult to achieve in the clinic. Alternatively, they may benefit from concomitant administration of chondroprotective agents, such as diacetylrhein, which may protect against the deleterious effects of traditional NSAIDs on cartilage degradation and, further, inhibit additional pathways such as cytokine elaboration which are important in joint destruction.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide/imunologia , Cartilagem Articular/imunologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Antraquinonas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Doença Crônica , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Humanos , Isoenzimas/uso terapêutico , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/uso terapêutico , Prostaglandinas/metabolismo , Falha de TratamentoAssuntos
Adenocarcinoma/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/farmacologia , Dinoprostona/biossíntese , Modelos Animais de Doenças , Camundongos , Antígeno Nuclear de Célula em Proliferação/análise , Células Tumorais CultivadasRESUMO
Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.
Assuntos
Apoptose/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/fisiopatologia , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carragenina/efeitos adversos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Flavonoides/farmacologia , Citometria de Fluxo , Inflamação/etiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pleurisia/etiologia , Pleurisia/imunologia , Ratos , Ratos Endogâmicos Lew , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína bcl-X/efeitos dos fármacosRESUMO
Cyclooxygenase-2 may play a role in resolution of carrageenan-induced pleurisy in rats by generating anti-inflammatory prostanoids. Here, we show exudate prostaglandin F2alpha concentrations rise during resolution of this model. These were reduced by the selective cyclooxygenase-2 inhibitor NS-398, which exacerbated inflammation. Concomitant treatment with NS-398 and the synthetic FP receptor agonist fluprostenol reversed this exacerbation. This suggests prostaglandin F2alpha produced by cyclooxygenase-2 contributes to resolution of this inflammatory reaction.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Dinoprosta/biossíntese , Inflamação/metabolismo , Análise de Variância , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/toxicidade , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Nitrobenzenos/farmacologia , Nitrobenzenos/toxicidade , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico , Pleurisia/metabolismo , Prostaglandinas F Sintéticas/farmacologia , Ratos , Ratos Wistar , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonamidas/farmacologia , Sulfonamidas/toxicidadeRESUMO
Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57/BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2 degrees C below normal) with a dose of 300 mg/kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E(2) concentrations in the brain. In cyclooxygenase (COX)-2(-/-) mice, acetaminophen (300 mg/kg) produced hypothermia accompanied by a reduction in brain PGE(2) levels, whereas in COX-1(-/-) mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1(-/-) mice had approximately 70% lower levels of PGE(2) than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE(2) levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE(2) that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.