Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

Platelet activating factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important factor in tumor outcomes. Platelet activating factor acts by specific binding to its receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating factor receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages suppressor phenotype. In experimental models, blocking of platelet activating factor receptor reduced tumor growth and increased animal survival. During chemotherapy and radiotherapy, tumor cells that survive treatment undergo accelerated proliferation, a phenomenon known as tumor cell repopulation. Work from our group and others showed that these treatments induce overproduction of platelet activating factor-like molecules and increase expression of its receptor in tumor cells. In this scenario, antagonists of platelet activating factor markedly reduced tumor repopulation. Here, we note that combining chemo- and radiotherapy with platelet activating factor antagonists could be a promising strategy for cancer treatment.

Efeito de inibidores da sintase de óxido nítrico na dor inflamatória e influxo celular da artrite induzida por zymosan em ratos / Effect of nitric oxide synthse in articular inflammatory pain and cellular influx of zymosan-induced arthritis in rats

Objetivo: Investigar o papel do óxido nítrico (NO) no influxo celular (IC) e a incapacitação articular (IA) na artrite por zymosan (AZy). Métodos: Ratos Wistar receberam injeção de Zy (1mg) no joelho direito. Grupos-controles receberam salina. A IA foi avaliada pelo Teste de incapacitação articular para ratos. Após sacrifício, o IC e a liberação de PGE2 foram avaliados no lavado articular. Avaliou-se o edema pela diferença peso úmido/peso seco do tecido articular. Grupos foram tratados i.p. com L-NAME - inibidor de sintases de NO (NOS) (LN=30-300mg/kg) ou aminoguanidina (AG=30-30mg/kg) - inibidor seletivo de iNOS - 30 min antes ou 2 h após o Zy. Resultados: O pré-tratamento com L-NAME ou AG inibiu de forma dose-dependente a IA e o IC, mas não o edema ou a liberação de PGE2, sendo máximo para LN ou AG (100mg/kg). L-arginina (1g/kg) co-injetada com LN (100mg/kg) reverteu a inibição da IA e do IC. D-NAME (100mg/kg) não teve efeito. Co-injeção de naloxona (antagonista opióide) reverteu o efeito de LN e AG sobre a IA. A pressão arterial média elevou-se (p<0,01) após LN (100mg/kg), mas não com AG (100mg/kg). LN e AG (100mg/kg) dados 2 h após Zy não tiveram efeito. Azul de metileno (inibidor de GMPc), e não hemoglobina (scavenger de NO), reduziu IA e IC (p<0,01). Nitroprussiato de sódio (doador de NO) dado 2h após ZY, reduziu a IA, mas não o IC (p<0,01). Conclusões: A antinocicepção na AZy por inibição da iNOS só ocorre como pré-tratamento, por efeito antiinflamatório via GMPc, independentemente de NO exógeno ou de PGE2, associada à liberação de opióides endógenos. Um doador de NO produz analgesia de AZy. Enfim, o trabalho demonstra efeito analgésico de um doador de NO em um modelo de periartrite, abrindo a perspectiva do uso dessas substâncias em humanos

A new murine model of persistent lung eosinophilic inflammation

We summarize here the main characteristics of a novel model of pulmonary hypersensitivity. Mice were immunized with a subcutaneous implant of a fragment of heat solidified chicken egg white and 14 days later challenged with ovalbumin given either by aerosol or by intratracheal instillation. This procedure induces a persistent eosinophilic lung inflammation, a marked bone marrow eosinophilia, and Th2-type isotypic profile with histopathological findings that resemble human asthma. Further, this model is simple to perform, reproducible in different strains of mice, does not require adjuvants nor multiple boosters. Based on these characteristics we propose it as a suitable murine model of allergic eosinophilic lung inflammation.

Fisiopatologia da lesao pulmonar na pancreatite aguda / Physiopathology of pancreatitis lung injury

Sinais clinicos de lesao pulmonar desenvolvem-se em ate 50 a 70 por cento dos pacientes com pancreatite aguda. A despeito disto, a fisiopatologia da lesao pulmonar na pancreatite aguda nao esta totalmente compreendida ate o momento. O edema pulmonar e a principal complicacao respiratoria da pancreatite aguda. A permeabilidade aumentada das membranas endotelial pulmonar e epitelial alveolar sao as causas do edema pulmonar. Varios fatores tem sido apontados como causadores do edema pulmonar: liberacao de enzimas pancreaticas proteoliticas, radicais livres de oxigenio, fosfolipase A, acidos graxos livres, fator de necrose tumoral, fator ativador lactario, metabolitos do acido aracdonico e microembolizacao pulmonar. A compreensao da fisiopatologia da lesao pulmonar faculta ao medico uma melhor abordagem terapeutica dos pacientes com pancreatite aguda. O objetivo deste trabalho e expor as teorias que explicam a lesao pulmonar da pancreatite aguda

Lesão pulmonar na pancreatite aguda. Influência da redução do conteúdo enzimático do pâncreas / Lung injury in acute pancreatitis. Influence of pancreatic enzymes reduction

A previous report has show that cerulein in physiological doses reduces the rate mortality of pancreatitis by decreasing the enzyme content of the pancreas. Clinically detectable signs of lung injury develop in up to 50-70 percent of patients with acute pancreatitis. The aim of the present study was to assess the effect of acute reduction of pancreatic enzyme content on the pancreatitis pulmonary injury. Experimental haemorrhagic pancreatitis was induced by intraductal injection of 5 per cent sodium taurocholate in two groups of Wistar rats: group I (pancreatitis) and group II (pancreatitis after decreasing pancreatic enzyme content). Dye Evans blue was used to evaluate the lung injury. The degree of histologically observed lesions were similar in both groups, but the pulmonary lesion was smaller in group II than group I (p < 0.05). In conclusion: 1) pancreatitis' pulmonary lesion may be related with pancreatic enzymes that reach the blood stream and 2) the reduction of the pancreatic enzyme content has a beneficial effect on acute pancreatitis and reduces its pulmonary injury.

Mechanisms of tissue injury induced by immune-complexes

Tissue injury induced by immune-complexes (IC) contributes to the pathogenesis of several diseases. The mechanisms by which IC induce lesions are, however, poorly understood. We review here some studies on the role of lipid mediators, eicosanoids and platelet activating factor (PAF), in the development of these lesions. In experimental models of IC-induced pneumonitis and arthritis, vascular and articular lesions were detected. The hemorrhagic lesions in the lungs were shown to be mediated by leukotriene B4 (LTB4) and nitric oxide (NO). PAF was also involved but only when the release of LTB4 was dependent on PAF as shown in the rat pneumonitis model. In the mouse model, LTB4 release was not dependent on PAF and in this situation PAF was no longer essential for the development of the hemorrhagic lesions. Similar results were observed in the IC-induced arthritis model where the articular cartilage lesions were shown to be mediated by LTB4 and NO but by PAF. In these models TNF was also generated and its release was stimulated by PAF. The role of this cytokine in the development of the lesions is, however not clear. Interesting interactions between these mediators were also observed, such as PAF inducing release of LTB4 and of TNF. Based on our data and on recent literature we proposed a hypothesis to explain the mechanisms involved in the development of tissue injury induced by IC.

Antigen-induced arthritis in rabbits: a suitable experimental model for the study of arachidonic acid metabolites in articular inflammatory processes

O presente estudo investigou a presença de substâncias de reaçäo lenta da anafilaxia (SRS-A) no líquido sinovial de coelhos com artrite induzida por antígeno utilizando ensaio biológico em ileo isolado de cobaio suspenso em câmara oxigenada contendo atropina, mepiramina e metisergide. Considerou-se SRS-A presente quando a infusäo do líquido sinovial promovia uma contraçäo com pelo menos três minutos de duraçäo que era abolida pela adiçäo de FPL-5512 ao meios. Todos os líquidos sinoviais de joelhos injetados com o antígeno de animais sacrificados até oito horas a partir do início da artrite apresentaram atividade de SRS-A. Nenhum líquido de articulaçöes experimentais com mais de oito horas de artrite, assim como em nenhuma das articulaçöes controles foi detectada a presença dessas substâncias. Esses resultados tornam o modelo experimental em questäo apropriado para o estudo da participaçäo das leucotrienes na fisiopatologia dos processos inflamatórios articulares assim como para o ensaio e desenvolvimento de novas drogas anti-inflamatórias