RESUMO
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a serious public health issue. Its evolution involves an acute stage, characterized by no specific symptoms, and the chronic stage during most individuals are asymptomatic, but about 30-40% of them become symptomatic presenting the cardiac or digestive disease. Host immune response mechanisms involved in symptomatic or asymptomatic chronic disease are not fully understood. The pro-inflammatory cytokines are crucial in host resistance. However, a fine control of this inflammatory process, by action of anti-inflammatory cytokines, is necessary to avoid tissue injury. This control was found to be responsible for no clinical manifestations in asymptomatic individuals. Toll-like receptors (TLRs) are extremely important in defining the cytokine profile released in response to a micro-organism. We found that patients with the cardiac form predominantly released the pro-inflammatory cytokines: IFN-γ, TNF-α and IL-17 with the involvement of both, TLR2 and TLR4. In contrast, patients with asymptomatic disease release predominantly the anti-inflammatory cytokines IL-10 and TGF-ß, but also with TLR2 and TLR4 participation. The mechanisms by which stimulation of the same TLRs results in release of different pattern of cytokines, depending on the patients group that is being evaluated, are discussed.
Assuntos
Doenças Assintomáticas , Cardiomiopatia Chagásica/imunologia , Leucócitos Mononucleares/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Trypanosoma cruzi/imunologia , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Diagnóstico Diferencial , Progressão da Doença , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Tempo de Reação/imunologiaRESUMO
In paracoccidioidomycosis, a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb), studies have focused on the role of neutrophils that are involved in primary response to the fungus. Neutrophil functions are regulated by pro- and anti-inflammatory cytokines. The molecular mechanisms involved in this process are not fully understood, but there are strong evidences about the involvement of toll-like receptors (TLR). We aimed at evaluating TLR2 and TLR4 expression on human neutrophils activated with GM-CSF, IL-15, TNF-alpha or IFN-gamma and challenged with a virulent strain of P. brasiliensis (Pb18). Moreover, we asked if these receptors have a role on fungicidal activity, H(2)O(2) and IL-6, IL-8, TNF-alpha and IL-10 production by activated and challenged cells. All cytokines increased TLR2 and TLR4 expression. Pb18 also increased TLR2 expression inducing an additional effect to that of cytokines. On the contrary, it inhibited TLR4 expression. All cytokines increased neutrophil fungicidal activity and H(2)O(2) production, but this process was not associated with TLR2 or TLR4. Neutrophils activation with GM-CSF and TNF-alpha resulted in a significative increase in IL-8 production, while IL-15 and IFN-gamma have no effect. Pb18 alone also increased IL-8 production. None of the cytokines activated neutrophils for IL-10 release. This cytokine was only detected after Pb18 challenge. Interestingly, IL-8 and IL-10 production involved TLR2 and mainly TLR4 modulation. Our data suggest that Pb18 uses TLR4 to gain access to human neutrophils. This interaction results in IL-8 and IL-10 production that may be considered as a pathogenic mechanism in paracoccidioidomycosis.
Assuntos
Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Paracoccidioidomicose/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Adulto , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-8/biossíntese , Interleucina-8/imunologia , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Paracoccidioides/imunologia , Receptor 2 Toll-Like/biossíntese , Receptor 4 Toll-Like/biossíntese , Adulto JovemRESUMO
BACKGROUND: The purpose of this investigation was to examine the effect of isoflurane, remifentanil, and preconditioning in renal ischemia/reperfusion injury (IRI). METHODS: All 52 male Wistar rats were anesthetized with isoflurane, intubated and mechanically ventilated. The animals were randomly divided into: S group (sham; n = 11) that underwent only right nephrectomy; as well as the I group of right nephrectomy and ischemia for 45 minutes by clamping of left renal artery. (n = 11); the IP (n = 9), the R (n = 10), and the RP (n = 11) groups. In addition, the R and RP animals received remifentanil (2 microg.kg(-1).min(-1)) during the entire experiment. The IP and RP group underwent ischemic preconditioning (IPC = three cycles of 5 minutes). Serum creatinine values were determined before and after IRI, as well as 24 hours later. In addition to an Histological study, cells from the left kidney were evaluated for apoptosis by flow cytometry (FCM). RESULTS: The Creatinine value of 0.8 +/- 0.2 mg/dl in the S group was significantly lower at 24 hours than the I 3.9 +/- 1.5 mg/dl; IP 2.6 +/- 1.7 mg/dl; R 3.3 +/- 2.8 mg/dl; or RP 1.8 +/- 0.5 mg/dl groups. The RP group value was significantly lower than those of the I, IP, and R groups (p < 0.05). The S group showed less proximal tubular cell damage than the I, IP, R, and RP groups (p < 0.05). The percentages of apoptotic cells (FITC(+)/PI(-)) were: S group = 11.6 +/- 6.5; I = 16.7 +/- 7.3; IP = 37.0 +/- 28.4; R = 11.7 +/- 6.6, and RP = 8.8 +/- 1.5. The difference between the IP vs RP group was significant. Similar percentages of necrotic cells (FITC(+)/PI(+)) and intact cells (FITC(-)/PI(-)) were observed among the groups. CONCLUSIONS: Ischemic preconditioning showed no protective effect in the isoflurane group (IP) but when isoflurane was administered associated with remifentanil (RP), there was a beneficial effect on the kidney, as demonstrated by flow cytometry and serum creatinine values.