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1.
Front Immunol ; 11: 574862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042157

RESUMO

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mastócitos/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Edema Pulmonar/imunologia , Trombose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Influenza Humana/virologia , Interleucina-4/imunologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Edema Pulmonar/patologia , Edema Pulmonar/virologia , Trombose/patologia , Trombose/virologia
2.
Psychiatr Danub ; 32(Suppl 1): 93-104, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32890371

RESUMO

Mechanisms of cortical psychoses are approached by complementing big data-driven genetics and imaging with a putatively subverted neurovascular "reverse plumbing" by arteries. The "cortical spread" of grey matter loss in schizophrenia and the mid-pericallosal "congestion" in fMRI of periodic catatonia - treatable electromagnetically along arteries - are interpreted in terms of the fastest interstitial outflow through the Cerebral IntraMural Reverse Arterial Flow-engine (CIMURAF, Treviranus 2018-19) draining "waste" via arterio-adventitial lymphatics to the neck. Such repetitively sliding segments of CIMURAF are wrung downstream by muscles likely steered by the neurovascular pterygopalatine ganglion. At the pericallosal artery, along its ideal long straight segment, this likely happens diverging from the mid-callosum towards the front and the back. In the case of a convergent inversion a mid-callosal clash will result, which is observable in psychoses as a mid-callosal high-flow-spot simultaneously with hyper-perfusions of branches and "backwatering" of pial vessels with reactive waste - till date interpreted psycho-mathematically. CIMURAF might also accelerate the perivascular intrusion of MCs by flushing autocrine signals (of which electro-magnetism moves the dipoles) through a putative periadventitial counter-current. Psychoses plausible occur through tryptase-mediated attacks operated by mast cells against oligodendrocytes' cytoskeleton (Medic 2009) and probably via complement-4 (Schizophrenia WG, 2014) against neurons. Usually MCs are essential long-lived "orchestrators" of homeostases and immune or barrier defences interacting with nerves, immunocytes, organs, and routes. MCs after somatic programming as to "destination & destiny" (Treviranus 2017a, 6.2., 2018) rapidly intrude also into the brain's parenchyma, first within the lymphatics and then putatively by crossing-over to extraluminal arterial routes. MCs transverse the BBBs, while macrophages only trespass in "disease" (Faraco et al. 2017). Both can be "subverted" by a list of microbes (and putatively blown up by COVID-19 within walls). Enuresis and MCs' reactions to clozapine add to the interactive support from (epi-)genetics and imaging.


Assuntos
Mastócitos/imunologia , Transtornos Psicóticos/imunologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Infecções por Coronavirus , Gânglios , Humanos , Mastócitos/patologia , Pandemias , Pneumonia Viral
3.
Life Sci ; 258: 118230, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777303

RESUMO

Here we evaluate the role of mast cells in infection with influenza A/H5N1 virus in immunized mice. CBA mice were immunized intramuscularly with formalin-inactivated A/Vietnam/1194/2004 (H5N1)NIBRG-14 (H5N1). Serum samples were obtained on days 7, 12, 14, 21 after immunization. At day 14, the mice were infected intranasally with the A/Indonesia/5/2005 (H5N1)IDCDC-RG2 (H5N1) influenza virus with half of the animals receiving a mixture of the antihistamines. 67% of the vaccinated mice were protected from the lethality compared to 43% in the PBS-immunized group. Administration of antihistamines increased survival up to 85%-95%. Immunohistochemical examination using CD117 staining of the lungs demonstrated a larger quantity of activated mast cells after infection of immunized mice compared to mock-immunized mice. This was correlated to increased histamine level in the lungs and blood. Our experimental results suggest the involvement of mast cells and the histamine they produce in the pathogenesis of influenza infection in case of incomplete formation of the immune response to vaccination and mismatch of the vaccine and infection influenza viruses.


Assuntos
Degranulação Celular/fisiologia , Liberação de Histamina/fisiologia , Virus da Influenza A Subtipo H5N1 , Mastócitos/fisiologia , Mastócitos/virologia , Infecções por Orthomyxoviridae/metabolismo , Animais , Embrião de Galinha , Chlorocebus aethiops , Mastócitos/patologia , Camundongos , Infecções por Orthomyxoviridae/patologia , Células Vero
4.
PLoS One ; 15(6): e0234001, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511268

RESUMO

The cuprizone induced animal model of demyelination is characterized by demyelination in many regions of the brain with high levels of demyelination in the corpus callosum as well as changes in neuronal function by 4-6 weeks of exposure. The model is used as a tool to study demyelination and subsequent degeneration as well as therapeutic interventions on these effects. Historically, the cuprizone model has been shown to contain no alterations to blood-brain barrier integrity, a key feature in many diseases that affect the central nervous system. Cuprizone is generally administered for 4-6 weeks to obtain maximal demyelination and degeneration. However, emerging evidence has shown that the effects of cuprizone on the brain may occur earlier than measurable gross demyelination. This study sought to investigate changes to blood-brain barrier permeability early in cuprizone administration. Results showed an increase in blood-brain barrier permeability and changes in tight junction protein expression as early as 3 days after beginning cuprizone treatment. These changes preceded glial morphological activation and demyelination known to occur during cuprizone administration. Increases in mast cell presence and activity were measured alongside the increased permeability implicating mast cells as a potential source for the blood-brain barrier disruption. These results provide further evidence of blood-brain barrier alterations in the cuprizone model and a target of therapeutic intervention in the prevention of cuprizone-induced pathology. Understanding how mast cells become activated under cuprizone and if they contribute to blood-brain barrier alterations may give further insight into how and when the blood-brain barrier is affected in CNS diseases. In summary, cuprizone administration causes an increase in blood-brain barrier permeability and this permeability coincides with mast cell activation.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Mastócitos/efeitos dos fármacos , Animais , Barreira Hematoencefálica/metabolismo , Cuprizona/administração & dosagem , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Junções Íntimas/metabolismo
5.
J Allergy Clin Immunol ; 146(2): 300-306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561389

RESUMO

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Gerenciamento Clínico , Mastocitose Cutânea/tratamento farmacológico , Mastocitose Sistêmica/tratamento farmacológico , Pandemias , Pneumonia Viral/epidemiologia , Betacoronavirus/imunologia , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Difosfonatos/uso terapêutico , Prova Pericial , Glucocorticoides/efeitos adversos , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Mastocitose Cutânea/diagnóstico , Mastocitose Cutânea/epidemiologia , Mastocitose Cutânea/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/epidemiologia , Mastocitose Sistêmica/patologia , Agonistas Mieloablativos/efeitos adversos , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Medicina de Precisão/métodos , Fatores de Risco , Vitamina D/uso terapêutico
6.
Am J Pathol ; 190(8): 1763-1773, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32450152

RESUMO

Within the human lung, mast cells typically reside adjacent to the conducting airway and assume a mucosal phenotype (MCT). In rare pathologic conditions, connective tissue phenotype mast cells (MCTCs) can be found in the lung parenchyma. MCTCs accumulate in the lungs of infants with severe bronchopulmonary dysplasia, a chronic lung disease associated with preterm birth, which is characterized by pulmonary vascular dysmorphia. The human mast cell line (LUVA) was used to model MCTCs or MCTs. The ability of MCTCs to affect vascular organization during fetal lung development was tested in mouse lung explant cultures. The effect of MCTCs on in vitro tube formation and barrier function was studied using primary fetal human pulmonary microvascular endothelial cells. The mechanistic role of MCTC proteases was tested using inhibitors. MCTCLUVA but not MCTLUVA was associated with vascular dysmorphia in lung explants. In vitro, the addition of MCTCLUVA potentiated fetal human pulmonary microvascular endothelial cell interactions, inhibited tube stability, and disrupted endothelial cell junctions. Protease inhibitors ameliorated the ability of MCTCLUVA to alter endothelial cell angiogenic activities in vitro and ex vivo. These data indicate that MCTCs may directly contribute to disrupted angiogenesis in bronchopulmonary dysplasia. A better understanding of factors that regulate mast cell subtype and their different effector functions is essential.


Assuntos
Displasia Broncopulmonar/patologia , Células Endoteliais/patologia , Pulmão/patologia , Mastócitos/patologia , Neovascularização Fisiológica/fisiologia , Animais , Linhagem Celular , Células Cultivadas , Humanos , Camundongos
7.
BMC Surg ; 20(1): 111, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448270

RESUMO

BACKGROUND: Laparoscopy induces adhesion due to ischemia-reperfusion injury. However, the detail pathomechanism is poorly understood. This study aimed to investigate the impact of laparoscopy on mast cell and mesothelium morphological changes in the rat. METHODS: Forty-nine males of Sprague-Dawley Rattus norvegicus were divided into four groups: a) control and b) intervention groups P1, P2, and P3 that underwent 60 min laparoscopic using carbon dioxide (CO2) insufflation at 8, 10, and 12 mmHg groups, respectively. Serum hydrogen peroxide (H2O2), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and oxidative stress index (OSI) levels were determined 24 h after laparoscopy. Histopathological analyses of mast cell infiltration and degranulation and mesothelium thickness in the liver, greater omentum, mesenterium, small intestine, and peritoneum were performed 7 days after the procedure. RESULTS: H2O2, MDA, and OSI levels were significantly increased in the intervention groups compared with the control (p<0.05), while the SOD and CAT levels were decreased in the intervention groups compared with the control (p<0.05). Mast cell infiltration and degranulation were higher in the intervention groups than in control (p<0.05), while the mesothelium thickness was significantly lower in the laparoscopic groups than in control (p<0.05). Interestingly, the decrease in mesothelium thickness was strongly associated with the increase in mast cell infiltration and degranulation (p<0.01). CONCLUSIONS: Our study shows that laparoscopy in rats increases mast cell infiltration and degranulation, which also results in and correlates with a decrease in mesothelial thickness.


Assuntos
Degranulação Celular/fisiologia , Laparoscopia/efeitos adversos , Mastócitos/patologia , Traumatismo por Reperfusão/etiologia , Animais , Epitélio/patologia , Peróxido de Hidrogênio/sangue , Intestino Delgado/patologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
8.
PLoS Pathog ; 16(5): e1008579, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32421753

RESUMO

Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.


Assuntos
Células Precursoras Eritroides/imunologia , Eritropoese/imunologia , Mastócitos/imunologia , Mastocitose/imunologia , Trichinella spiralis/imunologia , Triquinelose/imunologia , Animais , Anidrase Carbônica I/genética , Anidrase Carbônica I/imunologia , Células Precursoras Eritroides/parasitologia , Células Precursoras Eritroides/patologia , Feminino , Mastócitos/parasitologia , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Camundongos , Camundongos Transgênicos , Triquinelose/genética , Triquinelose/patologia
9.
PLoS One ; 15(4): e0231101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302339

RESUMO

Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ß-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ß-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.


Assuntos
Alérgenos/metabolismo , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Infecções Estreptocócicas/tratamento farmacológico , Alérgenos/imunologia , Animais , Basófilos/imunologia , Basófilos/microbiologia , Basófilos/patologia , Degranulação Celular/imunologia , Sobrevivência Celular/imunologia , Dinitrofenóis/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/patologia , Imunoglobulina E/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Mastócitos/imunologia , Mastócitos/microbiologia , Mastócitos/patologia , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Albumina Sérica Humana/imunologia , Albumina Sérica Humana/metabolismo , Infecções Estreptocócicas/imunologia , Streptococcus oralis/imunologia , Streptococcus oralis/patogenicidade , Açúcares/metabolismo
10.
Surg Today ; 50(9): 1091-1098, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32239305

RESUMO

PURPOSE: A novel pharmacological mechanism of valproate was analyzed using a hamster model of adhesion. METHODS: Valproate or placebo was administered just after cecal injury and adhesion severity scores and histological were analyzed. RESULTS: The adhesion severity scores in the placebo- and valproate-treated groups were 2.67 ± 0.42 and 1.0 ± 0.37, respectively, with a significant difference between the groups. A significant increase in mast cell numbers was observed in the placebo-treated group vs. the sham-operated group; however, the mast cell number in the adhesive lesion was significantly lower in the valproate-treated group than in the placebo-treated group. The number of cells positive for chymase, an enzyme in mast cells, in the adhesive lesion was significantly higher in the placebo-treated group, but its increase was attenuated significantly by treatment with valproate. The myeloperoxidase gene expression level in the cecum was significantly higher in the placebo-treated group than in the sham-operated group, but there was no significant difference in the myeloperoxidase gene expression level between the sham-operated and valproate-treated groups in. In an in vitro experiment, valproate inhibited purified human and hamster chymases dose-dependently. CONCLUSION: The chymase inhibitory effect of valproate may contribute to prevent adhesion formation after abdominal injury.


Assuntos
Ceco/lesões , Mastócitos/patologia , Doenças Peritoneais/patologia , Doenças Peritoneais/prevenção & controle , Aderências Teciduais/patologia , Aderências Teciduais/prevenção & controle , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologia , Animais , Ceco/metabolismo , Contagem de Células , Células Cultivadas , Quimases/metabolismo , Cricetinae , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mastócitos/enzimologia , Doenças Peritoneais/etiologia , Peroxidase/genética , Peroxidase/metabolismo , Índice de Gravidade de Doença , Aderências Teciduais/etiologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-32159365

RESUMO

Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased ß-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.


Assuntos
Degranulação Celular/efeitos dos fármacos , Doxorrubicina , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Terapia por Exercício , Mastócitos/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiotoxicidade , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
12.
Einstein (Sao Paulo) ; 18: eAO5105, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32159607

RESUMO

OBJECTIVE: To evaluate the density of anti-galectin-3-immunostained cells, collagen percentage, mast cell density and presence of pathological processes in intestinal muscle biopsies of patients. METHODS: Thirty-five patients who underwent intestinal biopsy were selected from 1997 to 2015. Patients were divided into three groups: chagasic patients with mucosal lesion (n=13), chagasic patients with intact mucosa (n=12) and non-chagasic patients with no mucosal lesion (n=10). Histological processing of the biopsied fragments and immunohistochemistry for galectin-3 were performed. Additional sections were stained with hematoxylin and eosin to evaluate the general pathological processes, picrosirius for evaluation of collagen and toluidine blue to evaluate the mast cell density. RESULTS: Patients of mucosal lesion group had a significantly higher frequency of ganglionitis and myositis when compared to the chagasic patients with intact mucosa and non-chagasic group. The density of anti-galectin-3-immunostained cells was significantly higher in the chagasic patients with intact mucosa group when compared to the non-chagasic group. The group of chagasic patients with intact mucosa presented a higher percentage of collagen in relation to the patients with mucosal lesion and to the non-chagasic group, with a significant difference. There was no significant difference in mast cell density among the three groups. CONCLUSION: The higher density of anti-galectin-3-immunostained cells in patients in the chagasic patients with intact mucosa group suggested the need for greater attention in clinical evaluation of these patients, since this protein is associated with neoplastic transformation and progression.


Assuntos
Anticorpos Monoclonais/análise , Doença de Chagas/patologia , Colonoscopia/métodos , Galectina 3/análise , Mucosa Intestinal/patologia , Megacolo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia , Estudos de Casos e Controles , Contagem de Células , Colágeno/análise , Feminino , Fibrose , Galectina 3/imunologia , Humanos , Imuno-Histoquímica , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Miosite/patologia , Estudos Retrospectivos , Estatísticas não Paramétricas
14.
Cancer Res ; 80(11): 2311-2324, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179512

RESUMO

Tumor growth and development is determined by both cancer cell-autonomous and microenvironmental mechanisms, including the contribution of infiltrating immune cells. Because the role of mast cells (MC) in this process is poorly characterized and even controversial, we investigated their part in breast cancer. Crossing C57BL/6 MMTV-PyMT mice, which spontaneously develop mammary carcinomas, with MC-deficient C57BL/6-KitW-sh/W-sh (Wsh) mice, showed that MCs promote tumor growth and prevent the development of basal CK5-positive areas in favor of a luminal gene program. When cocultured with breast cancer cells in vitro, MCs hindered activation of cMET, a master regulator of the basal program, and simultaneously promoted expression and activation of estrogen receptor (ESR1/ER) and its target genes (PGR, KRT8/CK8, BCL2), which are all luminal markers. Moreover, MCs reduced ERBB2/HER2 levels, whose inhibition further increased ESR1 expression. In vivo and in silico analysis of patients with breast cancer revealed a direct correlation between MC density and ESR1 expression. In mice engrafted with HER2-positive breast cancer tumors, coinjection of MCs increased tumor engraftment and outgrowth, supporting the link between MCs and increased risk of relapse in patients with breast cancer. Together, our findings support the notion that MCs influence the phenotype of breast cancer cells by stimulating a luminal phenotype and ultimately modifying the outcome of the disease. SIGNIFICANCE: Mast cells impact breast cancer outcome by directly affecting the phenotype of tumor cells through stimulation of the estrogen receptor pathway.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Mastócitos/patologia , Receptores Estrogênicos/metabolismo , Animais , Neoplasias da Mama/genética , Comunicação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo
15.
Am J Gastroenterol ; 115(2): 224-233, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31913192

RESUMO

OBJECTIVES: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs. METHODS: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical remission (CR) patients were identified, with absence of endoscopic abnormalities and symptoms. RESULTS: MC/hpf were increased in HI-EoE compared with control (17 ± 11 vs 8 ± 6, P < 0.0). Patients with persistent endoscopic abnormalities had increased total (20 ± 12 vs 13 ± 10, P = 0.001) and degranulated (8 ± 6 vs 5 ± 4, P = 0.002) MC/hpf, with no difference in eosinophils. MC/hpf predicted furrowing (odds ratio = 1.06, P = 0.01) and rings (odds ratio = 1.05, P = 0.03) after controlling for treatment type, proton-pump inhibitor, eosinophils, and duration of therapy. Patients with persistent basal zone hyperplasia and dilated intercellular spaces had increased MC/hpf. Eosinophils were weakly correlated with MC/hpf in the mid (r = 0.30, P < 0.001) and distal (r = 0.29, P < 0.001) esophagus. Clinical remission patients had lower MC/hpf compared with patients with persistent symptoms and/or endoscopic abnormalities. DISCUSSION: MC density is increased in patients with endoscopic and epithelial abnormalities, as well as a few symptoms, despite resolution of esophageal eosinophilia after treatment. This association warrants further study to ascertain whether MCs play an eosinophil independent role in EoE.


Assuntos
Esofagite Eosinofílica/patologia , Eosinófilos/patologia , Mastócitos/patologia , Adolescente , Corticosteroides/uso terapêutico , Criança , Pré-Escolar , Dietoterapia/métodos , Edema/patologia , Esofagite Eosinofílica/fisiopatologia , Esofagite Eosinofílica/terapia , Esofagoscopia , Exsudatos e Transudatos , Feminino , Humanos , Masculino
16.
PLoS One ; 15(1): e0226701, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940364

RESUMO

IgE-primed mast cells in peripheral tissues, including the skin, lung, and intestine, are key initiators of allergen-triggered edema and inflammation. Particularly in severe forms of allergy, this inflammation becomes strongly neutrophil dominated, and yet how mast cells coordinate this type of response is unknown. We and others have reported that activated mast cells--a hematopoietic cell type--can produce IL-33, a cytokine known to participate in allergic responses but generally considered as being of epithelial origin and driving Type 2 immune responses (e.g., ILC2 and eosinophil activation). Using models of skin anaphylaxis, our data reveal that mast cell-derived IL-33 also initiates neutrophilic inflammation. We demonstrate a cellular crosstalk mechanism whereby activated mast cells crosstalk to IL-33 receptor-bearing basophils, driving these basophils to adopt a unique response signature rich in neutrophil-associated molecules. We further establish that basophil expression of CXCL1 is necessary for IgE-driven neutrophilic inflammation. Our findings thus unearth a new mechanism by which mast cells initiate local inflammation after antigen triggering and might explain the complex inflammatory phenotypes observed in severe allergic diseases. Moreover, our findings (i) establish a functional link from IL-33 to neutrophilic inflammation that extends IL-33-mediated biology well beyond that of Type 2 immunity, and (ii) demonstrate the functional importance of hematopoietic cell-derived IL-33 in allergic pathogenesis.


Assuntos
Basófilos/patologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Interleucina-33/metabolismo , Mastócitos/patologia , Animais , Comunicação Celular , Quimiocina CXCL1/metabolismo , Regulação da Expressão Gênica/imunologia , Hipersensibilidade/complicações , Inflamação/complicações , Camundongos , Infiltração de Neutrófilos
17.
Cancer Sci ; 111(3): 817-825, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925976

RESUMO

Recent studies have reported that tumor-infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine-based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine-based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM-activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell-related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine-based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.


Assuntos
Neoplasias da Vesícula Biliar/patologia , Linfócitos do Interstício Tumoral/patologia , Mastócitos/patologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Quimioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/efeitos dos fármacos
18.
Cancer Sci ; 111(4): 1218-1227, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31997472

RESUMO

Enhanced degradation of tryptophan (Trp) and thus decreased plasma Trp levels are common in several types of cancers. Although it is well known that Trp catabolism is induced in the tumor microenvironment by the enzymes expressed in cancer cells, immune cells, or both, few studies have examined systemic Trp catabolism in cancer pathophysiology. The present study aimed to evaluate Trp catabolism in both tumor and peripheral tissues using tumor-engrafted Copenhagen rats that were s.c. inoculated with AT-2 rat prostate cancer cells negative for expression of Trp catabolic enzymes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics showed significantly decreased plasma Trp levels in AT-2 engrafted rats, accompanied by increased kynurenine/Trp ratios in spleen and thymus and serotonin levels in liver and thymus. Quantitative PCR and enzymatic activity assays showed indoleamine-2, 3-dioxygenase, an inducible enzyme that catalyzes Trp to kynurenine, was increased in tumor tissues, whereas tryptophan-2,3-dioxygenase, a major Trp catabolic enzyme that regulates systemic level of Trp, tended to be increased in the liver of AT-2 engrafted rats. Furthermore, tryptophan hydroxylase-1 (TPH1), an enzyme that catalyzes the reaction of Trp to serotonin, was significantly increased in liver and spleen of AT-2 engrafted rats. Further histochemical analysis revealed that the induction of TPH1 in the liver could be attributed to infiltration of mast cells. A similar phenomenon was observed with nonneoplastic liver samples from colorectal cancer patients. These results suggested that Trp catabolism toward serotonin synthesis might be induced in peripheral remote tissues in cancer, which could have a pathophysiological effect on cancer.


Assuntos
Neoplasias Hepáticas/genética , Fígado/metabolismo , Neoplasias da Próstata/genética , Triptofano Hidroxilase/genética , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Humanos , Cinurenina/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Metabolismo/genética , Metabolômica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos , Serotonina/genética , Serotonina/metabolismo , Baço/metabolismo , Espectrometria de Massas em Tandem , Timo/metabolismo , Microambiente Tumoral/genética
19.
Arterioscler Thromb Vasc Biol ; 40(3): 682-696, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31893950

RESUMO

OBJECTIVE: Activated perivascular mast cells (MCs) participate in different cardiovascular diseases. Many factors provoking MC degranulation have been described, while physiological counterregulators are barely known. Endothelial CNP (C-type natriuretic peptide) participates in the maintenance of vascular barrier integrity, but the target cells and mechanisms are unclear. Here, we studied whether MCs are regulated by CNP. Approach and Results: In cultured human and murine MCs, CNP activated its specific GC (guanylyl cyclase)-B receptor and cyclic GMP signaling. This enhanced cyclic GMP-dependent phosphorylation of the cytoskeleton-associated VASP (vasodilator-stimulated phosphoprotein) and inhibited ATP-evoked degranulation. To elucidate the relevance in vivo, mice with a floxed GC-B (Npr2) gene were interbred with a Mcpt5-CreTG line to generate mice lacking GC-B in connective tissue MCs (MC GC-B knockout). In anesthetized mice, acute ischemia-reperfusion of the cremaster muscle microcirculation provoked extensive MC degranulation and macromolecule extravasation. Superfusion of CNP markedly prevented MC activation and endothelial barrier disruption in control but not in MC GC-B knockout mice. Notably, already under resting conditions, such knockout mice had increased numbers of degranulated MCs in different tissues, together with elevated plasma chymase levels. After transient coronary occlusion, their myocardial areas at risk and with infarction were enlarged. Moreover, MC GC-B knockout mice showed augmented perivascular neutrophil infiltration and deep vein thrombosis in a model of inferior vena cava ligation. CONCLUSIONS: CNP, via GC-B/cyclic GMP signaling, stabilizes resident perivascular MCs at baseline and prevents their excessive activation under pathological conditions. Thereby CNP contributes to the maintenance of vascular integrity in physiology and disease.


Assuntos
Degranulação Celular , Células Endoteliais/metabolismo , Mastócitos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Comunicação Parácrina , Receptores do Fator Natriurético Atrial/metabolismo , Trombose/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Permeabilidade Capilar , Moléculas de Adesão Celular/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Peptídeo Natriurético Tipo C/farmacologia , Infiltração de Neutrófilos , Fosfoproteínas/metabolismo , Fosforilação , Receptores do Fator Natriurético Atrial/agonistas , Receptores do Fator Natriurético Atrial/genética , Transdução de Sinais , Trombose/genética , Trombose/patologia
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