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BACKGROUND Heart failure in women increases around the time of menopause when high-fat diets may result in obesity. The heart produces brain natriuretic peptide (BNP), also known as B-type natriuretic peptide. This aims of this study were to assess cardiac hypertrophy and BNP levels in ovariectomized rats fed a high-fat diet. MATERIAL AND METHODS Forty-eight female Wistar rats were divided into four groups: sham-operated rats fed a control diet (SC) (n=12); ovariectomized rats fed a control diet (OC) (n=12); sham-operated rats fed a high-fat diet (SF) (n=12); and ovariectomized rats fed a high-fat diet (OF) (n=12). Body weight and blood pressure were measured weekly for 24 weeks. Rats were then euthanized, and plasma samples and heart tissue were studied for gene expression, hydroxyproline levels, and histological examination. RESULTS A high-fat diet and ovariectomy (group OF) increased the weight body and the systolic blood pressure after three months and five months, respectively. Cardiomyocyte hypertrophy was associated with increased expression of ventricular BNP, decreased natriuretic peptide receptor (NPR)-A and increased levels of hydroxyproline and transforming growth factor (TGF)-β. The plasma levels of BNP and estradiol were inversely correlated; expression of estrogen receptor (ER)β and ERα were reduced. CONCLUSIONS The findings of this study showed that, in the ovariectomized rats fed a high-fat diet, the BNP-NPR-A receptor complex was involved in cardiac remodeling. BNP may be a marker of cardiac hypertrophy in this animal model.

Stryphnodendronspecies, popularly named “barbatimão,” are traditionally used in Brazil as anti-inflammatory agents. This study aimed to investigate the effect of barbatimão and 11 other species on the production of tumor necrosis factor-alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated THP-1 cells, as well as their anti-arthritis activity. The extracts ofStryphnodendron adstringens,Stryphnodendron obovatum,Campomanesia lineatifolia, andTerminalia glabrescenspromoted a concentration-dependent inhibition of TNF-α. Mice injected with LPS in the knee joint were treatedper oswith fractions from the selected extracts. Both the organic (SAO) and the aqueous (SAA) fractions ofS. adstringenspromoted a dose-dependent reduction of leukocyte migration and neutrophil accumulation into the joint, but none of them reduced CXCL1 concentration in the periarticular tissue. In contrast, treatment withC. lineatifoliaandT. glabrescensfractions did not ameliorate the inflammatory parameters. Analyses of SAO by Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) led to the identification of gallic acid along with 11 prodelphinidins, characterized as monomers and dimers of the B-type. Our findings contribute to some extent to corroborating the traditional use ofS. adstringensas an anti-inflammatory agent. This activity is probably related to a decrease of leukocyte migration into the inflammatory site. Polyphenols like gallic acid and prodelphinidins, identified in the active fraction, may contribute to the observed activity.

Acetaminophen (APAP) poisoning is one of the leading causes of acute hepatic failure and liver transplantation is often the only lifesaving alternative. During the course of hepatocyte necrosis, an intense accumulation of neutrophils is often observed within the liver microenvironment. Despite the classic idea that neutrophil accumulation in tissues causes collateral tissue damage, there is a growing body of evidence showing that neutrophils can also orchestrate the resolution of inflammation. In this work, drug-induced liver injury was induced by oral administration of APAP and pharmacological intervention was made 12 h after this challenge. Liver injury and repair kinetics were evaluated by a novel combination of enzyme quantifications, ELISA, specific antagonists of neutrophil enzymes and confocal intravital microscopy. We have demonstrated that neutrophil infiltration is not only involved in injury amplification, but also in liver tissue repair after APAP-induced liver injury. In fact, while neutrophil depletion led to reduced hepatic necrosis during APAP poisoning, injury recovery was also delayed in neutropenic mice. The mechanisms underlying the neutrophil reparative role involved rapid degranulation and matrix metalloproteinases (MMPs) activity. Our data highlights the crucial role of neutrophils, in particular for MMPs, in the resolution phase of APAP-induced inflammatory response. ispartof: CELLS vol:7 issue:12 ispartof: location:Switzerland status: published

Ischemia-reperfusion injury (IRI) is the main cause of morbidity and mortality due to graft rejection after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. This hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion phase, and is characterized by a large neutrophil recruitment to the liver. Production of cytokines, chemokines, and danger signals results in activation of resident hepatocytes, leukocytes, and Kupffer cells. The role of neutrophils as the main amplifiers of liver injury in IRI has been recognized in many publications. Several studies have shown that elimination of excessive neutrophils or inhibition of their function leads to reduction of liver injury and inflammation. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. In addition, the molecules necessary for this type of migration are poorly defined, as the liver presents an atypical sinusoidal vasculature in which the classical leukocyte migration paradigm only partially applies. This review summarizes recent advances in neutrophil-mediated liver damage, and its application to liver IRI. Basic mechanisms of activation of neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of danger signals, adhesion molecules, chemokines, glycosaminoglycans (GAGs), and metalloproteinases is explored. The precise definition of the molecular events that govern the recruitment of neutrophils and their movement into inflamed tissue may offer new therapeutic alternatives for hepatic injury by IRI and other inflammatory diseases of the liver. ispartof: Laboratory Investigation vol:98 issue:1 pages:51-62 ispartof: location:United States status: published

Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.

Background: Ischemia-reperfusion (IR) is a major contributor to graft rejection after liver transplantation. During IR injury, an intense inflammatory process occurs in the liver. Neutrophils are considered central players in the events that lead to liver injury. CXC chemokines mediate hepatic inflammation following reperfusion. However, few studies have demonstrated in real-time the behavior of recruited neutrophils. We used confocal intravital microscopy (IVM) to image neutrophil migration in the liver and to analyze in real-time parameters of neutrophil recruitment in the inflamed tissue in animals treated or not with reparixin, an allosteric antagonist of CXCR1/2 receptors. Material and Methods: WT and LysM-eGFP mice treated with reparixin or saline were subjected to 60 minutes of ischemia followed by different times of reperfusion. Mice received Sytox orange intravenously to show necrotic DNA in IVM. The effect of reparixin on parameters of local and systemic reperfusion-induced injury were also investigated. Results: Ischemia-reperfusion induced liver injury and inflammation, as evidenced by high levels of alanine aminotransferase (ALT) and myeloperoxidase (MPO) activity, chemokine and cytokine production and histological outcome. Treatment with reparixin significantly decreased neutrophil influx. Moreover, reparixin effectively suppressed the increase in serum concentrations of TNFα, IL-6 and CCL3, and the reperfusion-associated tissue damage. The number of neutrophils in the liver increased between 6h and 24h of reperfusion, whereas the distance traveled, velocity, neutrophil size and shape, and cluster formation reached a maximum 6h after reperfusion and then decreased gradually. In vivo imaging revealed that reparixin significantly decreased neutrophil infiltration and movement and displacement of recruited cells. Moreover, neutrophils had smaller size and less elongated shape in treated mice. Conclusions: Imaging of the liver by IVM was successfully implemented to describe neutrophil behavior in vivo during liver injury by IR. Treatment with reparixin decreased not only the recruitment of neutrophils in tissues but also their activation state and capacity to migrate within the liver. CXCR1/2 antagonists may be a promising therapy for patients undergoing liver transplantation. Keywords: Hepatic IR, chemokines, CXCR2, neutrophil-mediated liver injury.

The present study was designed to develop an animal model of hypertension and cardiac hypertrophy associated with obesity in female rats. Furthermore, we studied the involvement of the natriuretic peptide system in the mechanisms of these conditions. Obesity was induced in Wistar rats by a high fat diet and ovariectomy. The rats were divided into four groups: ovariectomized or sham-operated with high-fat diet and ovariectomized or sham-operated with control diet. After 24weeks of diet, rats were killed, and their tissues were removed. Cardiac atrial natriuretic peptide (ANP), clearance receptor (NPr-C) gene expression was determined by PCR. ANP concentrations were measured in plasma. Ovariectomized fat-fed rats (OF) showed increased body weight, visceral fat depot and blood pressure and decreased sodium excretion compared to other groups. Also, these rats showed higher heart-to-body weight and cell diameters of ventricular cardiomyocytes and lower cardiac ANP mRNA and plasma ANP than the control group. The adipocyte and renal NPr-C mRNA of OF rats were higher than the control group. These data showed that combined ovariectomy and high fat diet elicited obesity, hypertension and cardiac hypertrophy. These results suggest that the impairment of the natriuretic peptide system may be one of the mechanisms involved not only in development of hypertension but also in cardiac hypertrophy associated with obesity in ovariectomized rats.

FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais A encefalopatia hepática (EH) é uma complicação neurológica que ocorre em consequência à doença hepática. Pacientes que sofrem com EH podem apresentar sintomas neuropsiquiátricos, neuromusculares e comportamentais, o que causa grande impacto na qualidade de vida e capacidade laborativa. Atualmente, o único tratamento definitivo para a falência hepática é o transplante, evidenciando assim a necessidade de desvendar a fisiopatologia e os mecanismos envolvidos na doença, a fim de encontrar novos focos terapêuticos e medidas suportivas até que o transplante esteja disponível. Modelos experimentais de EH em roedores têm sido amplamente utilizados. Acredita-se que estes modelos forneçam informzações relevantes para a compreensão dos mecanismos envolvidos na patogênese da doença, bem como possibilitem o desenvolvimento de novos alvos terapêuticos. Estudos que avaliam as sequelas neurológicas após o desenvolvimento da EH assim como sua associação com dados teciduais, perfis inflamatório e neuroquímico em fases mais tardias da doença são escassos. Por meio da utilização de camundongos C57BL/6, fêmeas, entre oite e doze semanas de idade, foram investigadas as alterações comportamentais e patológicas associadas às respostas inflamatória e neuroprotetora na EH induzida por falência hepática por injeção intraperitoneal de tioacetamida (TAA). Os camundongos foram divididos em grupos TAA e grupo controle, sendo esses últimos, submetidos à injeção intraperitoneal de salina. Os animais do grupo TAA apresentaram dano hepático associado a maior atividade dos neutrófilos e macrófagos. Além disso, os animais induzidos demonstraram através da aplicação de testes, comportamento semelhante à ansiedade e à depressão e alterações morfológicas dos astrócitos e da micróglia. Este mesmo grupo apresentou redução significativa da expressão das citocinas pró-inflamatórias interferon- (IFN-) e interleucina-6 (IL-6) no hipocampo e do fator neurotrófico derivado do cérebro (BNDF) no córtex cerebral, quando comparado com os animais do grupo controle. Nossos resultados sugerem que disfunções das respostas inflamatória e neuroprotetora estejam associadas à formação dos déficits comportamentais na EH murina. Hepatic encephalopathy (HE) is a neurological complication observed in hepatic failure. HE patients may present neuropsychiatric, neuromuscular, and behavioral disorders, which may impair quality of life and work capability. Currently, the only definitive treatment for hepatic failure is transplantation, which highlights the need for complete understanding of the pathophysiology and mechanisms involved in the disease, in order to establish new therapeutic targets and supportive measures until transplantation is available. Experimental models of HE in rodents have been widely used. It is believed that these models provide relevant information for understanding the mechanisms involved in the pathogenesis of the disease, as well as the development of new therapeutic targets. Studies evaluating neurological sequelae after the development of hepatic encephalopathy as well as its association with tissue data, inflammatory and neurochemical profiles in later stages of the disease are scarce. Using C57BL/6 female mice, between eight and twelve weeks age, we investigated behavioral and pathological changes association with inflammatory and neuroprotective responses during HE that follows hepatic failure induced by intraperitoneal injection of thioacetamide (TAA). Mice were divided into TAA and control groups, the latter being submitted to intraperitoneal injection of saline. TAA animals presented liver damage associated with increased activity of neutrophils and macrophages. In addition, induced animals demonstrated in the applied tests, anxiety-like and depression-like behavior and morphological changes of astrocytes and microglia. This same group showed a significant reduction in expression of proinflammatory cytokines interferon- (IFN-) and interleukin-6 (IL-6) in the hippocampus and the brain-derived neurotrophic factor (BNDF) in the cerebral cortex when compared to the control animals. Our results suggest that inflammatory and neuroprotective responses disorders are associated with behavioral deficits in murine hepatic encephalopathy.