Immunoinflammatory mediators in the pathogenesis of diabetes mellitus / Mediadores imunoinflamatórios na patogênese do diabetes mellitus

ABSTRACT Characterized as a metabolic syndrome with multiple consequences for the lives of patients, diabetes mellitus is also classified as a chronic non-communicable disease of great scope in the world. It is a complex disease, with different points of view, including the relation between inflammatory process, obesity and insulin resistance due to the performance of the various immunoinflammatory mediators - called adipokines - on glycemic homeostasis. Recent studies have precisely addressed this aspect for the development of drugs that assist in the protection of pancreatic ß cells from the damages arising from oxidative stress and inflammatory process, in order to control the hyperglycemic picture, which is characteristic of diabetes mellitus.

RESUMO Caracterizado como uma síndrome metabólica de múltiplas consequências para a vida de seus portadores, o diabetes mellitus é também classificado como uma doença crônica não transmissível de grande abrangência no mundo. Trata-se de uma doença complexa, com diversos pontos de vista, dentre eles a relação entre processo inflamatório, obesidade e resistência à ação da insulina, devido à atuação dos diversos mediadores imunoinflamatórios, chamados de adipocinas, sobre a homeostase glicêmica. Recentes estudos têm abordado justamente este aspecto para o desenvolvimento de fármacos que auxiliem na proteção das células ß pancreáticas dos danos advindos do estresse oxidativo e processo inflamatório, de modo a controlar o quadro hiperglicêmico característico do diabetes mellitus.

Propionibacterium acnes-killed attenuates the inflammatory response and protects mice from sepsis by modulating inflammatory factors

BACKGROUND: Sepsis is a systemic inflammation associated with infection caused by pathogenic micro-organisms with high mortality rates. OBJECTIVE: In this study, we investigated the protective effect of Propionibacterium acnes-killed against polymicrobial sepsis induced by cecal ligation and puncture. METHODS: The mice were treated by intramuscular route in 1, 3, 5, and 7 days before the cecal ligation and puncture induction. The control group animals received vehicle (saline solution 0.9%) and the animals of the treated group received the P. acnes-killed (0.4 mg/animal). After anesthesia, midline laparotomy was performed with exposure of cecum followed by ligature and one transverse perforation of the same, with a 18 G needle, for induction of lethal sepsis. After surgery, the cecum of the animals was replaced into the peritoneal cavity, and it was closed with a 4.0 nylon suture. The survival of animals subjected to lethal sepsis was evaluated after cecal ligation and puncture induction. Six hours after the induction of sepsis, neutrophil migration, the number of bacteria, TNF-α, MCP-1, IL-6, and IL-10 were performed in the peritoneal lavage. RESULTS: Prophylactic treatment with P. acnes-killed increased the survival of the animals, followed by a significant decrease in the TNF-α, IL-10, and MCP-1 levels, 6 h after cecal ligation and puncture. Furthermore, P. acnes-killed administration reduced the number of bacteria in the peritoneal cavity with increased migration of leukocytes, especially neutrophils. CONCLUSION: P. acnes-killed promoted increased survival rate of animals with sepsis, in part attributed to its immunomodulatory properties against pathogenic microorganisms, as well as better control of infection by reducing bacterial counts.

Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.

Bilirubin protects grafts against nonspecific inflammation-induced injury in syngeneic intraportal islet transplantation

Nonspecific inflammatory response is the major cause for failure of islet grafts at the early phase of intraportal islet transplantation (IPIT). Bilirubin, a natural product of heme catabolism, has displayed anti-oxidative and anti-inflammatory activities. The present study has demonstrated that bilirubin protected islet grafts by inhibiting nonspecific inflammatory response in a syngeneic rat model of IPIT. The inflammation-induced cell injury was mimicked by exposing cultured rat insulinoma INS-1 cells to cytokines (IL-1beta, TNF-alpha and IFN-gamma) in in vitro assays. At appropriate lower concentrations, bilirubin significantly attenuated the reduced cell viability and enhanced cell apoptosis induced by cytokines, and protected the insulin secretory function of INS-1 cells. Diabetic inbred male Lewis rats induced by streptozotocin underwent IPIT at different islet equivalents (IEQs) (optimal dose of 1000, and suboptimal doses of 750 or 500), and bilirubin was administered to the recipients every 12 h, starting from one day before transplantation until 5 days after transplantation. Administration of bilirubin improved glucose control and enhanced glucose tolerance in diabetic recipients, and reduced the serum levels of inflammatory mediators including IL-1beta, TNF-alpha, soluble intercellular adhesion molecule 1, monocyte chemoattractant protein-1 and NO, and inhibited the infiltration of Kupffer cells into the islet grafts, and restored insulin-producing ability of transplanted islets.

High mobility group box 1 as a mediator of endotoxin administration after hemorrhagic shock-primed lung injury

High mobility group box 1 (HMGB1) was discovered as a novel late-acting cytokine that contributes to acute lung injury (ALI). However, the contribution of HMGB1 to two-hit-induced ALI has not been investigated. To examine the participation of HMGB1 in the pathogenesis of ALI caused by the two-hit hypothesis, endotoxin was injected intratracheally in a hemorrhagic shock-primed ALI mouse model. Concentrations of HMGB1 in the lung of the shock group were markedly increased at 16 h (1.63 ± 0.05, compared to the control group: 1.02 ± 0.03; P < 0.05), with the highest concentration being observed at 24 h. In the sham/lipopolysaccharide group, lung HMGB1 concentrations were found to be markedly increased at 24 h (1.98 ± 0.08, compared to the control group: 1.07 ± 0.03; P < 0.05). Administration of lipopolysaccharide to the hemorrhagic shock group resulted in a notable HMGB1 increase by 4 h, with a further increase by 16 h. Intratracheal lipopolysaccharide injection after hemorrhagic shock resulted in the highest lung leak at 16 h (2.68 ± 0.08, compared to the control group: 1.05 ± 0.04; P < 0.05). Compared to the hemorrhagic shock/lipopolysaccharide mice, blockade of HMGB1 at the same time as lipopolysaccharide injection prevented significantly pulmonary tumor necrosis factor-alpha, interleukin-1beta and myeloperoxidase. Lung leak was also markedly reduced at 16 h; blockade of HMGB1 24 h after lipopolysaccharide injection failed to alter lung leak or myeloperoxidase at 48 h. Our observations suggest that HMGB1 plays a key role as a late mediator when lipopolysaccharide is injected after hemorrhagic shock-primed ALI and the kinetics of its release differs from that of one-hit ALI. The therapeutic window to suppress HMGB1 activity should not be delayed to 24 h after the disease onset.

Corpúsculos e mediadores lipídicos na resposta inflamatória a saliva de Lutzomiya longipalpis durante a infecção com Leishmania chagasi / Corpuscles and lipid mediators in the inflammatory response to the saliva of Lutzomyia longipalpis during infection with Leishmania chagasi

Lutzomyia longipalpis é o principal transmissor da Leishmania chagasi, agente etiológico da leishmaniose visceral (LV), a forma mais letal da doença. A saliva de L. longipalpis possui moléculas capazes de modular as repostas hemostática, inflamatória e imunológica do hospedeiro, favorecendo o estabelecimento da infecção. Entretanto, poucos trabalhos têm abordado o papel da saliva de L. longipalpis na indução de mediadores lipídicos e sua implicação nos momentos iniciais da infecção por Leishmania. Neste trabalho, investigamos o papel do sonicado de glândula salivar (SGS) de Lutzomyia longipalpis na indução da formação de corpúsculos lipídicos (CL) e produção de mediadores lipídicos durante os estágios iniciais da infecção por Leishmania chagasi. O SGS foi capaz de induzir in vitro a formação de CLs e a produção de PGE2 em macrófagos murinos. Durante a infecção de camundongos C57BL/6 por L. chagasi, a presença de saliva de L. longipalpis aumentou a formação de CLs em macrófagos após 3 horas de estímulo, o que esteve correlacionado com o aumento do influxo de células para o sítio inflamatório, principalmente neutrófilos. A infecção de L. chagasi em presença do SGS de L. longipalpis induziu a produção de LTB4 e PGE2 em leucócitos peritoneais ex vivo. Após 3 horas, macrófagos e neutrófilos infectados, bem como a interação entre essas células foram observadas. O percentual de macrófagos infectados e o número de parasitas por macrófago esteve reduzido durante a infecção em presença de SGS. O conjunto dos nossos resultados indica que a saliva do vetor desempenha um papel importante na modulação da inflamação durante os estágios iniciais da infecção por L. chagas i e abre novas perspectivas para o entendimento da imunopatogênese da leishmaniose visceral.

Celastrol inhibits production of nitric oxideandproinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells

Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia play an important role in human neurodegenerative disorders. Here, we investigated whether celastrol, which has been used as a potent anti-inflammatory and anti-oxidative agent in Chinese medicine, attenuates excessive production of NO and proinflammatory cytokines such as TNF-alpha and IL-1beta in LPS-stimulated BV-2 cells, a mouse microglial cell line. We report here that the LPS-elicited excessive production of NO, TNF-alpha, and IL-1beta in BV-2 cells was largely inhibited in the presence of celastrol, and the attenuation of inducible iNOS and these cytokines resulted from the reduced expression of mRNAs of iNOS and these cytokines, respectively. The molecular mechanisms that underlie celastrol-mediated attenuation were the inhibition of LPS-induced phosphorylation of MAPK/ERK1/2 and the DNA binding activity of NF-kappaB in BV-2 cells. The results indicate that celastrol effectively attenuated NO and proinflammatory cytokine production via the inhibition of ERK1/2 phosphorylation and NF-kappaB activation in LPS-activated microglia. Thus, celastrol may be an effective therapeutic candidate for use in the treatment of neurodegenerative human brain disorders.

Prostanoids modulate inflammation and alloimmune responses during graft rejection

Acute rejection of a transplanted organ is characterized by intense inflammation within the graft. Yet, for many years transplant researchers have overlooked the role of classic mediators of inflammation such as prostaglandins and thromboxane (prostanoids) in alloimmune responses. It has been demonstrated that local production of prostanoids within the allograft is increased during an episode of acute rejection and that these molecules are able to interfere with graft function by modulating vascular tone, capillary permeability, and platelet aggregation. Experimental data also suggest that prostanoids may participate in alloimmune responses by directly modulating T lymphocyte and antigen-presenting cell function. In the present paper, we provide a brief overview of the alloimmune response, of prostanoid biology, and discuss the available evidence for the role of prostaglandin E2 and thromboxane A2 in graft rejection.

Macrophage elastase (MMP-12): a pro-inflammatory mediator?

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.

Inflammatory mediators in nasal lavage among school-age children from urban and rural areas in São Paulo, Brazil

CONTEXTO: Alguns estudos demonstram que o processo inflamatório nas vias aéreas nasais poderia refletir ou mesmo afetar as vias aéreas inferiores. Decidimos avaliar indiretamente o estado inflamatório das vias aéreas nasais de dois grupos de escolares com diferente sensibilização aos aeroalérgenos mais comuns. OBJETIVO: Comparar a atividade inflamatória nas vias aéreas nasais, através da determinação de mediadores inflamatórios no lavado nasal em duas populações distintas de crianças em idade escolar. TIPO DE ESTUDO: Estudo transversal. LOCAL: O estudo foi realizado em duas escolas públicas de ensino fundamental, uma em zona urbana e outra em zona rural, no Estado de São Paulo. MÉTODOS: Foram constituídos dois grupos de 40 escolares que apresentam diferentes taxas de sensibilização a aeroalérgenos comuns. Amostras do lavado nasal foram colhidas para determinação de proteína catiônica eosinofílica (ECP) e triptase. Testes não-paramétricos foram usados na análise estatística. RESULTADOS: Níveis significativamente maiores de proteína catiônica eosinofílica foram encontrados nos estudantes da área urbana (p < 0,05). Não houve diferença estatística nos níveis de triptase entre os dois grupos. Observou-se ainda que, na área urbana, as crianças sensibilizadas aos aeroalérgenos apresentaram maiores concentrações de proteína catiônica eosinofílica, o que não foi observado nas crianças da zona rural. DISCUSSAO: A ausência de atividade de mastócitos e a degranulação aumentada de eosinófilos revelaram uma inflamação crônica nas vias aéreas das crianças estudadas. A maior atividade de eosinófilos na zona urbana, coincidindo com a maior sensibilização aos aeroalérgenos, sugere que deve haver algum fator a mais na área urbana que modula a resposta das vias aéreas influenciando a ativação das células inflamatórias locais. CONCLUSAO: Nossos achados não mostraram diferenças nos níveis de triptase no lavado nasal entre os dois grupos estudados. Por outro lado, as crianças da area urbana apresentaram maiores concentrações de proteína catiônica eosinofílica do que aquelas da zona rural. Observamos ainda que, na area urbana, as crianças sensibilizadas por aeroalérgenos apresentaram maiores concentrações de proteína catiônica eosinofílica do que aquelas não sensibilizadas, enquanto esta diferença não foi observada nas crianças da area rural.

Continuous renal replacement therapies in ICU patients with septic shock: impact on inflammatory mediators removal

Continuous renal replacement therapies are widely used for patients with acute renal failure specially in critically ill patients in ICU. It has been suggested that hemofiltration may also eliminate toxic mediators thought to be important in the pathophysiology of sepsis. The present study examined whether hemofiltration can eliminate inflammatory mediators in patients with sepsis. A total of 28 consecutive patients with septic shock, as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. All patients had renal affection. Patients were randomly assigned to receive hemofiltration in addition to usual ICU care [n = 17] [group 1], or to usual care plus hemodiafiltration [n =11 [group 2]. We measured the plasma concentrations of complement fraction C3a, IL-6 and TNF -a at baseline, 2 hours and 24 hours after these procedures. C3a showed a fall in concentration between baseline and 2 hrs, which not reached statistical significance during hemofiltration [from median 495.5 to 363 ng/ml, P =.48] and statistical significance during hemodiafiltration [from median 524 to 379.7 ng/ml, P = <0.05]. Furthermore, during HF C3a showed a significant fall in concentration during the interval between 2 hrs and 24hrs [from median, 363 to 274.6 ng/mL, p<0.05], HDF [from median, 379.7 to 215.8 ng/mL, p<0.05]. TNF showed a fall in concentration between baseline and 2 hrs, which reached statistical significance during hemofiltration [from median 397.9 to 332.8 pg/ml, P =0.035] and statistical significance during hemodiaflltration [from median 430.7 to 347.2 pg/ml, P 0.02]. However, during HF TNF showed a non significant change in concentration during the interval between baseline and 24hrs [from median, 397.9 to 410.4 pg/mL, p = 0.6], HDF [from median, 430.7 to 405.6 pg/mL, p = 0.5]. IL-6 showed a fall in concentration between baseline and 2 hrs, which reached statistical significance during hemofiltratio in [from median 1051 to 843.6 pg/ml, P =0.03] and statistical significant during hemodiaflltration [from median 1111.3 to 859 pg/ml, P 0.025]. However, during HFJL-6 showed a non significant change in concentration during the interval between baseline and 24hrs [from median, 1051 to 905 pg/ml, p = 0.13], HDF [from median, 1111.3 to 901.9pg/mL, p = 0.07]. No correlation were detected between inflammatory mediators removal and changing the size of hemofilter [surface area 0.7 and 1.35 square meter] p>0.05. or changing hemofiltration rate [from 1 to 2 liters/hour]. p>0.05. In conclusion, short-term hemofiltration with a highly biocompatible membrane in patients with septic multiple organ dysfunction syndrome and renal failure may even eliminate some of the mediators from septic plasma like C 3a. Filtration of the classic cytokines IL-6 and TNF-a is presumably of minor importance, but clearance of the first few hours may occur so we cannot advocate the use of continuous therapies as a treatment in sepsis for removal of inflammatory mediators only, but in presence of renal affection, these slow renal replacement therapies results in fewer cardiovascular side effects than intermittent techniques, Furthermore, continuous hemofiltration allows better control of fluid balance and simultaneous continuation of total parenteral nutrition in addition to reduction of anaphylatoxin concentrations which could be of clinical importance, since beneficial therapeutic effects in sepsis have been correlated with a fall of anaphylatoxin concentrations

Oxido nítrico exhalado como marcador de inflamación en niños con asma / The exhaled nitric oxide is a inflammatory response

El óxido nítrico es un gas reactivo que se produce de manera endógena por enzimas óxido nítrico sintetasa. Existe una gran producción de óxido nítrico inducida por la isoforma de la enzima óxido nítrico sintetasa, que da como resultado la formación de productos citotóxicos, que son importantes mediadores de los mecanismo de defensa y de la respuesta inflamatoria normal. El óxido nítrico puede detectarse en el aire exhalado en humanos, sus concentraciones están incrementadas en pacientes con asma, y después de la exposición a alergenos. La medición del óxido nítrico exhalado se efectúa por métodos sencillos, no invasivos, para valorar el grado de inflamación de la vía aérea y la respuesta al tratamiento con esteroides en pacientes pediátricos

Superantigenos: una particular interaccion entre microorganismos y el sistema inmune / Superantigens: a particular interaction between microorganisms and the immune system

El descubrimiento de los superatígenos (SAgs) aportó nuevos conceptos en el estudio de las interacciones entre los microorganismos y el sistema inmune. Se trata de moléculas que, asociadas a las de Clase II del Complejo Mayor de Histocompatibilidad (CMH), se unen al dominio variable de la cadena Beta Vbeta) del receptor de antígenos Ags) de los linfocitos T alphaBeta (TCRalphaBeta) que les confiere la especialidad de familia. Así, los SAgs son capaces de activar a un alto número de linfocitos T y de células portadoras de las moléculas de Classe II del CMH, generando una masiva liberación de linfoquinas y mediadores inflamatorios que ha sido relaciona con sus efectos tóxicos. Los SAgs endógenos están codificados por los provirus de tumores murinos (Mtv) que se hallan integrados al genoma de los ratones. Los exógenos son producidos por bacterias y virus, siendo los mejor caracterizados los relacionados con las intoxicaciones alimentarias. Aun no se han hallado datos concluyentes en cuanto a la existencia de SAgs de parásitos y se requieren estudos más detallados para establecer su presencia y posible efecto en las infecciones parasitarias.