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1.
Epidemiol Infect ; 149: e81, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33775266

RESUMO

To assess the relationship between the neutrophil-to-lymphocyte ratio (NLR) and related parameters to the severity of coronavirus disease 2019 (COVID-19) symptoms. Clinical data from 38 COVID-19 patients who were diagnosed, treated and discharged from the Qishan Hospital in Yantai over the period from January to February 2020 were analysed. NLR and procalcitonin (PCT) were determined in the first and fourth weeks after their admission, along with the clinical characteristics and laboratory test results of these patients. Based on results as obtained on the first and fourth weeks after admission, five indices consisting of NLR, white blood cells, neutrophils, lymphocytes (LY) and monocytes (MON) were selected to generate receiver operating characteristic curves, while optimal cutoff values, sensitivities and specificities were obtained according to the Yuden index. Statistically significant differences in neutrophils, LY and the NLR were present in the severe vs. moderate COVID-19 group from the first to the fourth week of their hospitalisation. The cut-off value of NLR for predicting the severity of COVID-19 was 4.425, with a sensitivity of 0.855 and a specificity of 0.979. A statistically significant positive correlation was present between PCT and NLR in the severe group as determined within the first week of admission. NLR can serve as a predictor of COVID-19 disease severity as patients' progress from the first to the fourth week of their hospitalisation. The statistically significant positive correlation between levels of NLR and PCT in severe patients indicated that increases in NLR were accompanied with gradual increases in PCT.


Assuntos
/virologia , Linfócitos/fisiologia , Neutrófilos/fisiologia , Pró-Calcitonina/sangue , Adulto , Idoso , China , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença
2.
Commun Biol ; 4(1): 290, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674719

RESUMO

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.


Assuntos
/imunologia , Degranulação Celular , Interferons/fisiologia , Neutrófilos/fisiologia , Idoso , Animais , Antígenos CD36/fisiologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/metabolismo , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/fisiologia
3.
Exp Parasitol ; 223: 108080, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33548219

RESUMO

Schistosome parasites are complex trematode blood flukes responsible for the disease schistosomiasis; a global health concern prevalent in many tropical and sub-tropical countries. While established transcriptomic databases are accessed ad hoc to facilitate studies characterising specific genes or gene families, a more comprehensive systematic updating of gene annotation and survey of the literature to aid in annotation and context is rarely addressed. We have reanalysed an online transcriptomic dataset originally published in 2009, where seven life cycle stages of Schistosoma japonicum were examined. Using the online pathway analysis tool Reactome, we have revisited key data from the original study. A key focus of this study was to improve the interpretation of the gene expression profile of the developmental lung-stage schistosomula, since it is one of the principle targets for worm elimination. Highly enriched transcripts, associated with lung schistosomula, were related to a number of important biological pathways including host immune evasion, energy metabolism and parasitic development. Revisiting large transcriptomic databases should be considered in the context of substantial new literature. This approach could aid in the improved understanding of the molecular basis of parasite biology. This may lead to the identification of new targets for diagnosis and therapies for schistosomes, and other helminths.


Assuntos
Estágios do Ciclo de Vida , Pneumopatias Parasitárias/parasitologia , Pulmão/parasitologia , Schistosoma japonicum/crescimento & desenvolvimento , Esquistossomose Japônica/parasitologia , Transcriptoma/fisiologia , Análise de Variância , Animais , Degranulação Celular/fisiologia , Conjuntos de Dados como Assunto , Proteínas Facilitadoras de Transporte de Glucose/fisiologia , Interações Hospedeiro-Parasita , Pneumopatias Parasitárias/imunologia , Neutrófilos/fisiologia , Fator 1 de Elongação de Peptídeos/fisiologia , Schistosoma japonicum/genética , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia
4.
PLoS Negl Trop Dis ; 15(1): e0009019, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33411735

RESUMO

Coronavirus Disease 2019 (COVID-19), a disease caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has only recently emerged, while Mycobacterium leprae, the etiological agent of leprosy, has endured for more than 2,000 years. As soon as the initial reports of COVID-19 became public, several entities, including the Brazilian Leprosy Society, warned about the possible impact of COVID-19 on leprosy patients. It has been verified that COVID-19 carriers can be either asymptomatic or present varying degrees of severe respiratory failure in association with cytokine storm and death, among other diseases. Severe COVID-19 patients show increased numbers of neutrophils and serum neutrophil extracellular trap (NET) markers, in addition to alterations in the neutrophil-to-lymphocyte ratio (NLR). The absence of antiviral drugs and the speed of COVID-19 transmission have had a major impact on public health systems worldwide, leading to the almost total collapse of many national and local healthcare services. Leprosy, an infectious neurological and dermatological illness, is widely considered to be the most frequent cause of physical disabilities globally. The chronic clinical course of the disease may be interrupted by acute inflammatory episodes, named leprosy reactions. These serious immunological complications, characterized by cytokine storms, are responsible for amplifying peripheral nerve damage. From 30% to 40% of all multibacillary leprosy (MB) patients experience erythema nodosum leprosum (ENL), a neutrophilic immune-mediated condition. ENL patients often present these same COVID-19-like symptoms, including high levels of serum NET markers, altered NLR, and neutrophilia. Moreover, the consequences of a M. leprae-SARS-CoV-2 coinfection have yet to be fully investigated. The goal of the present viewpoint is to describe some of the similarities that may be found between COVID-19 and leprosy disease in the context of neutrophilic biology.


Assuntos
/imunologia , Hanseníase/imunologia , Neutrófilos/fisiologia , /complicações , Humanos , Hanseníase/complicações
5.
Ecotoxicol Environ Saf ; 211: 111900, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33440266

RESUMO

Gold nanoparticles (AuNPs) are extensively utilized in biomedical fields. However, their potential interaction with host cells has not been comprehensively elucidated. In this study, we demonstrated a size-dependent effect of AuNPs to synergize with bacterial lipopolysaccharide (LPS) in promoting neutrophil extracellular traps (NETs) release in human peripheral neutrophils. Mechanistically, LPS was more efficient to contact with 10 nm AuNPs and promote their uptake in neutrophils compared to 40 and 100 nm AuNPs, leading to a synergistic upregulation of class A scavenger receptor (SRA) which mediated AuNPs uptake and triggered activation of extracellular regulated protein kinase (ERK) and p38. Blocking SRA or inhibiting ERK and p38 activation remarkably abrogated the effect of AuNPs and LPS to induce NETs formation. Further experiments demonstrated that AuNPs and LPS augmented the production of cytosolic reactive oxygen species (ROS) in p38 and ERK dependent manner, through upregulating and activating NADPH oxidase 2 (NOX2). Accordingly, scavenging of ROS or inhibiting the NOX2 dampened NETs release induced by combined AuNPs and LPS treatment. AuNPs and LPS also synergized to upregulate reactive oxygen species modulator 1 (ROMO1) via activating ERK, thereby increasing mitochondrial ROS generation and promoting the release of NETs. In summary, we provide new evidences about the synergy of AuNPs and LPS to augment cellular responses in neutrophils, which implicates the need to consider the amplifying effect by pathogenic stimuli when utilizing nanomaterials in infectious or inflammatory conditions.


Assuntos
Nanopartículas Metálicas/química , Neutrófilos/fisiologia , Armadilhas Extracelulares/efeitos dos fármacos , Ouro/metabolismo , Humanos , Lipopolissacarídeos , Proteínas de Membrana , Proteínas Mitocondriais/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Depuradores/metabolismo
6.
Med Microbiol Immunol ; 209(6): 669-680, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32880037

RESUMO

The ability of bacteria to aggregate and form biofilms impairs phagocytosis by polymorphonuclear leukocytes (PMNs). The aim of this study was to examine if the size of aggregates is critical for successful phagocytosis and how bacterial biofilms evade phagocytosis. We investigated the live interaction between PMNs and Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Staphylococcus epidermidis using confocal scanning laser microscopy. Aggregate size significantly affected phagocytosis outcome and larger aggregates were less likely to be phagocytized. Aggregates of S. epidermidis were also less likely to be phagocytized than equally-sized aggregates of the other three species. We found that only aggregates of approx. 5 µm diameter or smaller were consistently phagocytosed. We demonstrate that planktonic and aggregated cells of all four species significantly reduced the viability of PMNs after 4 h of incubation. Our results indicate that larger bacterial aggregates are less likely to be phagocytosed by PMNs and we propose that, if the aggregates become too large, circulating PMNs may not be able to phagocytose them quickly enough, which may lead to chronic infection.


Assuntos
Biofilmes , Escherichia coli/fisiologia , Neutrófilos/fisiologia , Fagocitose , Pseudomonas aeruginosa/fisiologia , Staphylococcus aureus/fisiologia , Staphylococcus epidermidis/fisiologia , Escherichia coli/ultraestrutura , Humanos , Pseudomonas aeruginosa/ultraestrutura , Pele/microbiologia , Staphylococcus aureus/ultraestrutura , Staphylococcus epidermidis/ultraestrutura
8.
Surg Clin North Am ; 100(4): 757-776, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32681875

RESUMO

This review of the literature concerning bacteria, antibiotics and tissue repair shows there are extensive data supporting microbial interference with wound healing once bacterial burden exceeds 104 CFU per unit of measure, The mechanism of bacterial interference lies largely in prolonging the inflammatory phase of tissue repair. Reducing the microbial bioburden allows tissue repair to continue. Systemic and topical antimicrobials appear critical to reducing the bioburden and facilitating repair. The current controversy over the use of antimicrobials in patients with chronically infected wounds, in particular, revolves around the definition of infection. The reliance on classic clinical signs of inflammation to support antimicrobial use in these patients is tenuous due to the lack of correlation of these signs with the microbial burden known to impair tissue repair.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Cicatrização/fisiologia , Infecção dos Ferimentos/tratamento farmacológico , Infecções Bacterianas/fisiopatologia , Carga Bacteriana/fisiologia , Biofilmes , Hipóxia Celular/fisiologia , Humanos , Neutrófilos/fisiologia , Infecção dos Ferimentos/fisiopatologia
9.
Medicina (B Aires) ; 80 Suppl 3: 31-36, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32658845

RESUMO

In December 2019, a new coronavirus was identified as the cause of an outbreak of pneumonia and respiratory distress in Wuhan, China. It was declared pandemic in March 2020. It is important to know predictors of poor outcomes in order to optimize the strategies of care in newly diagnosed patients. The neutrophil to lymphocyte ratio (NLR) constitutes a novel prognostic marker for oncologic, cardiovascular and infectious diseases. We aimed to assess its prognostic value in COVID-19. We evaluated a retrospective cohort of 131 patients with COVID-19 from March to May 2020. We analyzed the association of an NLR = 3 with severe COVID-19, baseline characteristics of the population and the mortality rate. The median age was 52 years, and 54% were men. 21 patients presented criteria of severe disease, 9 of them required mechanical ventilation. NLR = 3 was found in 81% (18/21) of severe patients and in 33% (36/110) of mild patients (OR = 8.74. 95% CI 2.74-27.86; p < 0.001). Age and hypertension were associated with severe disease. A mortality rate of 7% (9) was obtained. Seven of the 9 patients who died presented NLR = 3, with a significant association between mortality and NLR = 3 (p = 0.03). NLR could be used in conjunction with other predictors, as an early prognostic marker in COVID-19 given its accessibility and low cost.


Assuntos
Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Linfócitos/fisiologia , Neutrófilos/fisiologia , Pandemias , Pneumonia Viral/diagnóstico , Fatores Etários , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
10.
J Dairy Sci ; 103(7): 6200-6208, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32418683

RESUMO

Our objectives were to assess the effects of a diet with a negative dietary cation-anion difference (DCAD) before calving on phagocytosis (Pc) and oxidative burst (OB) function of circulating neutrophils, and to determine the associations of serum ionized (iCa) and total calcium (tCa) concentrations with Pc and OB in transition dairy cows. We hypothesized that multiparous cows fed a negative DCAD diet prepartum would have greater iCa and tCa, and thus improved Pc and OB. From 3 wk before expected parturition until calving, 38 healthy multiparous cows from 3 farms were assigned to negative DCAD treatment (TRT; -100 mEq/kg of diet dry matter; n = 21) or a control (CON; 95 mEq/kg of dry matter; n = 17) diet. Each farm was on one treatment or the other at a time, but all farms contributed cows to both groups. Urine pH was measured weekly and in TRT was 6.1 ± 0.8 with 80% of 50 samples <7 and 74% ≤ 6.5. Phagocytosis, OB, iCa, and tCa were measured at d -7, 1, and 4 relative to calving. Median fluorescence intensity for Pc (MFIP) and OB (MFIOB), and the shift of percentage of cells active for Pc (PPc) and OB (POB) were measured in isolated, stimulated neutrophils via flow cytometry. Outcomes were assessed with mixed linear regression models accounting for repeated measures. There were no differences between treatments in the 4 neutrophil function outcomes. Although MFIOB varied over time, there were no interactions of treatment with time for any outcome. Serum ionized and tCa did not differ between TRT and CON. The least squares means ± standard deviation for iCa were: d -7, 1.23 ± 0.12 vs. 1.21 ± 0.12; d 1, 1.07 ± 0.12 vs. 1.02 ± 0.12; d 4, 1.16 ± 0.12 vs. 1.17 ± 0.12 mmol/L for TRT and CON, respectively; and for tCa: d -7 2.39 ± 0.25 vs 2.44 ± 0.31; d 1, 2.01 ± 0.25 vs 1.97 ± 0.31; d 4, 2.33 ± 0.25 vs 2.32 ± 0.31 mmol/L, respectively. The proportion of blood samples with tCa <2.15mmol/L at d -7, 1 and 4 was 5, 76, and 13%, respectively, with no differences between TRT and CON. Correlations of iCa or tCa with each of the 4 polymorphonuclear leukocyte (PMN) function outcomes were weak (r < |0.3|). We did not observe the hypothesized differences in aspects of innate immunity in clinically healthy multiparous cows fed a negative DCAD. We underline that cows that experienced clinical disease were excluded from this study, which is important for interpretation of the results.


Assuntos
Ração Animal/análise , Cálcio/sangue , Bovinos , Dieta/veterinária , Neutrófilos/fisiologia , Período Periparto , Animais , Cálcio na Dieta , Feminino , Lactação , Minerais , Neutrófilos/efeitos dos fármacos , Parto , Gravidez , Explosão Respiratória/efeitos dos fármacos
11.
J Pediatr ; 221: 181-187.e1, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32446478

RESUMO

OBJECTIVE: To study leukocyte-endothelium interaction, a measure of the initial phase of atheromatosis, in children with overweight or obesity. STUDY DESIGN: A prospective study was conducted in 77 children aged 7-16 years; 47 were children with overweight/obesity and 30 were normal weight. Polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells were isolated from venous blood samples and the interaction of leukocytes over a monolayer of human umbilical vein endothelial cells was analyzed using flow chamber microscopy. The variables studied included leukocyte rolling velocity, rolling flux, and adhesion to endothelial cells. These were compared between children with overweight/obesity and control children. Correlation between the measures of leukocyte-endothelium interaction and anthropometric and biochemical variables was evaluated. RESULTS: In comparison with normal weight children, the PMNs and peripheral blood mononuclear cells of the overweight/obesity group showed a reduction in rolling velocity (P = .000 and P = .001, respectively) and an increase in rolling flux (P = .001 and P = .004), and adhesion (P = .003 and P = .002). The homeostasis model of insulin resistance was correlated inversely with rolling velocity and positively with rolling flux in PMNs. C-reactive protein was correlated positively with rolling flux and adhesion in both types of leucocytes. Fat mass index was correlated with all measures of leukocyte-endothelial interaction and proved to be the main predictor of leukocyte adhesion in the multiple regression analysis (P = .001 for PMNs and P = .006 for peripheral blood mononuclear cells). CONCLUSIONS: Excess fat mass in children is related to the activation of the leukocyte-endothelium interaction, potentially contributing to the development of atherosclerosis.


Assuntos
Células Endoteliais/fisiologia , Leucócitos Mononucleares/fisiologia , Obesidade Pediátrica/fisiopatologia , Adolescente , Proteína C-Reativa/análise , Estudos de Casos e Controles , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Criança , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Neutrófilos/fisiologia , Estudos Prospectivos
12.
Nat Commun ; 11(1): 2385, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404937

RESUMO

Upon tissue injury or microbial invasion, a large number of neutrophils converge from blood to the sites of injury or infection in a short time. The migration through a limited number of paths through tissues and capillary networks seems efficient and 'traffic jams' are generally avoided. However, the mechanisms that guide efficient trafficking of large numbers of neutrophils through capillary networks are not well understood. Here we show that pairs of neutrophils arriving closely one after another at capillary bifurcations migrate to alternating branches in vivo and in vitro. Perturbation of chemoattractant gradients and the increased hydraulic resistance induced by the first neutrophil in one branch biases the migration of the following neutrophil towards the other branch. These mechanisms guide neutrophils to efficiently navigate through capillary networks and outline the effect of inter-neutrophil interactions during migration on overall lymphocyte trafficking patterns in confined environments.


Assuntos
Movimento Celular/fisiologia , Fatores Quimiotáticos/metabolismo , Quimiotaxia/fisiologia , Técnicas Analíticas Microfluídicas/métodos , Neutrófilos/fisiologia , Algoritmos , Células Cultivadas , Humanos , Modelos Biológicos , Neutrófilos/citologia , Transdução de Sinais/fisiologia
14.
Int Immunopharmacol ; 84: 106504, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32304994

RESUMO

AIM: To accumulate evidence that indicated the key role played by virus-triggered inflammation in the 2019-novel coronavirus disease (COVID-19) which emerged in Wuhan City and rapidly spread throughout China. METHODS: Age, neutrophil(NEU)-to-lymphocyte (LYM) ratio (NLR), lymphocyte-to-monocyte (MON) ratio, platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of 93 patients with laboratory confirmed COVID-19 were investigated and compared. The receiver operating characteristic curve was applied to determine the thresholds for five bio-markers, and their prognostic values were assessed via the Kaplan-Meier curve and multivariate COX regression models. RESULTS: The median age was 46.4 years old, and 37cases were females. A total of 27.8% of patients had been to Wuhan, and 73.1% had contacted with people from Wuhan. Fever (83.8%) and cough (70.9%) were the two most common symptoms. Elevated NLR and age were significantly associated with illness severity. The binary logistic analysis identified elevated NLR (hazard risk [HR] 2.46, 95% confidence interval [CI] 1.98-4.57) and age (HR 2.52, 95% CI 1.65-4.83) as independent factors for poor clinical outcome of COVID-19. NLR exhibited the largest area under the curve at 0.841, with the highest specificity (63.6%) and sensitivity (88%). CONCLUSIONS: Elevated age and NLR can be considered independent biomarkers for indicating poor clinical outcomes.


Assuntos
Betacoronavirus , Plaquetas/fisiologia , Infecções por Coronavirus/diagnóstico , Linfócitos/fisiologia , Monócitos/fisiologia , Neutrófilos/fisiologia , Pneumonia Viral/diagnóstico , Adulto , Proteína C-Reativa/análise , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Epidemias , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Prognóstico , Curva ROC
16.
Nat Commun ; 11(1): 1126, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111847

RESUMO

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.


Assuntos
Quimiotaxia de Leucócito , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/terapia , Neutrófilos/fisiologia , Fototerapia , Animais , Membrana Externa Bacteriana/química , Membrana Externa Bacteriana/imunologia , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/química , Cisplatino/farmacocinética , Liberação Controlada de Fármacos , Vesículas Extracelulares/química , Vesículas Extracelulares/imunologia , Imunoterapia Adotiva , Inflamação/etiologia , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ativação de Neutrófilo , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Padrões Moleculares Associados a Patógenos/imunologia , Fototerapia/efeitos adversos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Pharmacol Sci ; 143(1): 17-22, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32122774

RESUMO

Thrombomodulin (TM) is an integral membrane protein expressed on the surface of vascular endothelial cells that suppresses blood coagulation. Recent studies have shown that TM exhibits anti-inflammatory effects by inhibiting leukocyte recruitment. However, the actual modes of action of TM in vivo remain unclear. Here, we describe the pharmacological effects of recombinant human soluble TM (TM alfa) on leukocyte dynamics in living mice using intravital imaging techniques. Under control conditions, neutrophils exhibited three distinct types of adhesion behavior in vessels: 1) "non-adhesion", in which cells flowed without vessel adhesion; 2) "rolling adhesion", in which cells transiently interacted with the endothelium; and 3) "tight binding", in which cells bound strongly to the endothelial cells. Compared to control conditions, local lipopolysaccharide stimulation resulted in an increased frequency of rolling adhesion that was not homogeneously distributed on vessel walls but occurred at specific endothelial sites. Under inflammatory conditions, TM alfa, particularly the D1 domain which is a lectin-like region of TM, significantly decreased the frequency of rolling adhesion, but did not influence the number of tight bindings. This was the first study to demonstrate that TM alfa exerts anti-inflammatory effects by inhibiting rolling adhesion of neutrophils to vascular endothelial cells in living mice.


Assuntos
Anti-Inflamatórios , Adesão Celular , Neutrófilos/fisiologia , Trombomodulina/fisiologia , Animais , Endotélio Vascular/citologia , Masculino , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Proteínas Recombinantes/farmacologia
18.
Biomater Sci ; 8(8): 2289-2299, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32163073

RESUMO

Biomaterial implantation triggers an immune response initially predominated by neutrophils, which activate an inflammatory cascade by producing cytokines, enzymes, immune cell recruitment chemokines, and DNA fiber networks called neutrophil extracellular traps (NETs). While the role of neutrophils has been studied extensively in infection, little is known of their role in the response to biomaterials, in this case titanium (Ti) implants. Furthermore, while implant surface modifications have been shown to attenuate pro-inflammatory polarization in other immune cells, their effects on neutrophil behavior is unknown. The aim of this study was to characterize the neutrophil response to Ti surface topography and hydrophilicity and understand how the products of biomaterial-induced neutrophil activation alters macrophage polarization. Murine neutrophils were isolated by density gradient centrifugation and plated on smooth, rough, and rough hydrophilic (rough-hydro) Ti surfaces. Neutrophils on rough-hydro Ti decreased pro-inflammatory cytokine and enzyme production as well as decreased NET formation compared to neutrophils on smooth and rough Ti. Conditioned media (CM) from neutrophils on smooth Ti enhanced pro-inflammatory macrophage polarization compared to CM from neutrophils on rough or rough-hydro Ti; pretreatment of neutrophils with a pharmacological NETosis inhibitor impaired this macrophage stimulation. Finally, co-culture of neutrophils and macrophages on Ti surfaces induced pro-inflammatory macrophage polarization compared to macrophages alone on surfaces, but this effect was ablated when neutrophils were pretreated with the NETosis inhibitor. These findings demonstrate that neutrophils are sensitive to changes in biomaterial surface properties and exhibit differential activation in response to Ti surface cues. Additionally, inhibition of NETosis enhanced anti-inflammatory macrophage polarization, suggesting NETosis as a possible therapeutic target for enhancing implant integration.


Assuntos
Neutrófilos/fisiologia , Titânio/química , Animais , Materiais Biocompatíveis , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Armadilhas Extracelulares , Interações Hidrofóbicas e Hidrofílicas , Inflamação , Macrófagos/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Propriedades de Superfície
19.
Pathog Dis ; 78(2)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32196074

RESUMO

Extracellular DNA (eDNA) plays an important role in both the aggregation of bacteria and in the interaction of the resulting biofilms with polymorphonuclear leukocytes (PMNs) during an inflammatory response. Here, transmission electron and confocal scanning laser microscopy were used to examine the interaction between biofilms of Pseudomonas aeruginosa and PMNs in a murine implant model and in lung tissue from chronically infected cystic fibrosis patients. PNA FISH, DNA staining, labeling of PMN DNA with a thymidine analogue and immunohistochemistry were applied to localize bacteria, eDNA, PMN-derived eDNA, PMN-derived histone H3 (H3), neutrophil elastase (NE) and citrullinated H3 (citH3). Host-derived eDNA was observed surrounding bacterial biofilms but not within the biofilms. H3 localized to the lining of biofilms while NE was found throughout biofilms. CitH3, a marker for neutrophil extracellular traps (NETs) was detected only sporadically indicating that most host-derived eDNA in vivo was not a result of NETosis. Together these observations show that, in these in vivo biofilm infections with P. aeruginosa, the majority of eDNA is found external to the biofilm and derives from the host.


Assuntos
Biofilmes , DNA Bacteriano/metabolismo , Armadilhas Extracelulares/metabolismo , Animais , Histonas/metabolismo , Humanos , Camundongos , Neutrófilos/fisiologia , Neutrófilos/ultraestrutura , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/fisiologia
20.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053993

RESUMO

Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation.


Assuntos
Degranulação Celular , Neutrófilos/citologia , Neutrófilos/imunologia , Animais , Hipóxia Celular , Armadilhas Extracelulares/imunologia , Humanos , Hipóxia/imunologia , Imunidade Inata , Infecções/imunologia , Inflamação/imunologia , Ativação de Neutrófilo , Neutrófilos/fisiologia , Vesículas Secretórias/imunologia
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