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1.
J Ethnopharmacol ; 290: 115093, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35149129

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica. AIM OF THE STUDY: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. MATERIALS AND METHODS: EAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. RESULTS: Data received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. CONCLUSION: Our results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.


Assuntos
Acalypha , Asma/patologia , Broncoconstrição/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antialérgicos/farmacologia , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Broncodilatadores/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Caliciformes/efeitos dos fármacos , Cobaias , Hipersensibilidade/patologia , Mediadores da Inflamação/metabolismo , Mastócitos/efeitos dos fármacos , Camundongos , Folhas de Planta , Ratos , Ratos Wistar
2.
Int J Mol Sci ; 23(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163137

RESUMO

Mast cells are involved in allergic and other inflammatory diseases. The polyphenol resveratrol is known for its anti-inflammatory properties and may be used as nutraceutical in mast cell associated diseases. We analyzed the effect of resveratrol on mast cells in vivo in ovalbumin-induced allergic enteritis as well as experimental colitis in IL-10-/- mice which received resveratrol via drinking water. Treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis in duodenum as well as in colon. Further, it delayed the onset of diseases symptoms and ameliorated diseases associated parameters such as tissue damage as well as inflammatory cell infiltration in affected colon sections. In addition to the findings in vivo, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in IgE/DNP-activated as well as in LPS-activated bone marrow-derived mast cells. These results indicate that resveratrol may be considered as an anti-allergic and anti-inflammatory plant-derived component for the prevention or treatment of mast cell-associated disorders of the gastrointestinal tract.


Assuntos
Antialérgicos/farmacologia , Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Interleucina-10/fisiologia , Mastócitos/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Degranulação Celular , Colite/etiologia , Colite/patologia , Enterite/tratamento farmacológico , Enterite/etiologia , Enterite/patologia , Hipersensibilidade/etiologia , Hipersensibilidade/patologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/toxicidade
3.
Nat Commun ; 13(1): 875, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169129

RESUMO

Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.


Assuntos
Dor Crônica/patologia , Histona Desacetilases/metabolismo , Neuralgia/patologia , Dor Nociceptiva/patologia , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Animais , Células Cultivadas , Dependovirus/genética , Feminino , Hipersensibilidade/patologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Corno Dorsal da Medula Espinal/citologia
4.
EBioMedicine ; 75: 103778, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35007819

RESUMO

BACKGROUND: Treatment of degenerating tendons still presents a major challenge, since the aetiology of tendinopathies remains poorly understood. Besides mechanical overuse, further known predisposing factors include rheumatoid arthritis, diabetes, obesity or smoking all of which combine with a systemic inflammation. METHODS: To determine whether the systemic inflammation accompanying these conditions contributes to the onset of tendinopathy, we studied the effect of a systemic inflammation induced by an allergic episode on tendon properties. To this end, we induced an allergic response in mice by exposing them to a timothy grass pollen allergen and subsequently analysed both their flexor and Achilles tendons. Additionally, we analysed data from a health survey comprising data from more than 10.000 persons for an association between the occurrence of an allergy and tendinopathy. FINDINGS: Biomechanical testing and histological analysis revealed that tendons from allergic mice not only showed a significant reduction of both elastic modulus and tensile stress, but also alterations of the tendon matrix. Moreover, treatment of 3D tendon-like constructs with sera from allergic mice resulted in a matrix-remodelling expression profile and the expression of macrophage-associated markers and matrix metalloproteinase 2 (MMP2) was increased in allergic Achilles tendons. Data from the human health study revealed that persons suffering from an allergy have an increased propensity to develop a tendinopathy. INTERPRETATION: Our study demonstrates that the presence of a systemic inflammation accompanying an allergic condition negatively impacts on tendon structure and function. FUNDING: This study was financially supported by the Fund for the Advancement of Scientific Research at Paracelsus Medical University (PMU-FFF E-15/22/115-LEK), by the Land Salzburg, the Salzburger Landeskliniken (SALK, the Health Care Provider of the University Hospitals Landeskrankenhaus and Christian Doppler Klinik), the Paracelsus Medical University, Salzburg and by unrestricted grants from Bayer, AstraZeneca, Sanofi-Aventis, Boehringer-Ingelheim.


Assuntos
Tendão do Calcâneo , Hipersensibilidade , Tendinopatia , Tendão do Calcâneo/patologia , Animais , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Inflamação/patologia , Metaloproteinase 2 da Matriz , Camundongos , Tendinopatia/etiologia , Tendinopatia/patologia
5.
Clin Exp Allergy ; 52(2): 324-333, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34570395

RESUMO

BACKGROUND: Deaths attributed to Coronavirus Disease 2019 (COVID-19) are mainly due to severe hypoxemic respiratory failure. Although the inflammatory storm has been considered the main pathogenesis of severe COVID-19, hypersensitivity may be another important mechanism involved in severe cases, which have a perfect response to corticosteroids (CS). METHOD: We detected the serum level of anti-SARS-CoV-2-spike S1 protein-specific IgE (SP-IgE) and anti-SARS-CoV-2 nucleocapsid protein-specific IgE (NP-IgE) in COVID-19. Correlation of levels of specific IgE and clinical severity were analysed. Pulmonary function test and bronchial provocation test were conducted in early convalescence of COVID-19. We also obtained histological samples via endoscopy to detect the evidence of mast cell activation. RESULT: The levels of serum SP-IgE and NP-IgE were significantly higher in severe cases, and were correlated with the total lung severity scores (TLSS) and the PaO2 /FiO2 ratio. Nucleocapsid protein could be detected in both airway and intestinal tissues, which was stained positive together with activated mast cells, binded with IgE. Airway hyperresponsiveness (AHR) exists in the early convalescence of COVID-19. After the application of CS in severe COVID-19, SP-IgE and NP-IgE decreased, but maintained at a high level. CONCLUSION: Hypersensitivity may be involved in severe COVID-19.


Assuntos
Brônquios/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Duodeno/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Mastócitos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brônquios/metabolismo , Brônquios/patologia , COVID-19/metabolismo , COVID-19/patologia , COVID-19/fisiopatologia , Estudos de Casos e Controles , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Duodeno/metabolismo , Duodeno/patologia , Feminino , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Hipersensibilidade/fisiopatologia , Pulmão/fisiopatologia , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Recuperação de Função Fisiológica , Hipersensibilidade Respiratória/fisiopatologia , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto Jovem
6.
J Allergy Clin Immunol ; 149(4): 1358-1372, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34543653

RESUMO

BACKGROUND: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). OBJECTIVE: We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. METHODS: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. RESULTS: Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. CONCLUSIONS: This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.


Assuntos
Hipersensibilidade , Síndrome de Netherton , Dermatopatias , Epiderme/patologia , Humanos , Hipersensibilidade/patologia , Interferon-alfa , Interleucina-17/genética , Síndrome de Netherton/genética , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Pele/patologia , Dermatopatias/patologia
8.
Int Arch Allergy Immunol ; 183(2): 127-141, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34818243

RESUMO

Memory T cells play a central role in regulating inflammatory responses during asthma. However, tissue distribution of effector memory (TEM) and central memory (TCM) T-cell subtypes, their differentiation, and their contribution to the persistence of lung tissue inflammation during asthma are not well understood. Interestingly, an increase in survival and persistence of memory T cells was reported in asthmatic lungs, which may suggest a shift toward the more persistent TCM phenotype. In this report, we investigated the differential distribution of memory T-cell subtypes during allergic lung inflammation and the mechanism regulating that. Using an OVA-sensitized asthma mouse model, we observed a significant increase in the frequency of TCM cells in inflamed lungs compared to healthy controls. Interestingly, adoptive transfer techniques confirmed substantial infiltration of TCM cells to lung tissues during allergic airway inflammation. Expression levels of TCM homing receptors, CD34 and GlyCAM-1, were also significantly upregulated in the lung tissues of OVA-sensitized mice, which may facilitate the increased TCM infiltration into inflamed lungs. Moreover, a substantial increase in the relative expression of TCM profile-associated genes (EOMES, BCL-6, ID3, TCF-7, BCL-2, BIM, and BMI-1) was noted for TEM cells during lung inflammation, suggesting a shift for TEM into the TCM state. To our knowledge, this is the first study to report an increased infiltration of TCM cells into inflamed lung tissues and to suggest differentiation of TEM to TCM cells in these tissues. Therapeutic interference at TCM infiltration or differentiations could constitute an alternative treatment approach for lung inflammation.


Assuntos
Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , /metabolismo , Animais , Asma/etiologia , Asma/metabolismo , Asma/patologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Hipersensibilidade/patologia , Imuno-Histoquímica , Imunofenotipagem , Mediadores da Inflamação , Pulmão/patologia , Contagem de Linfócitos , Camundongos
9.
Cell Rep ; 37(13): 110178, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34965421

RESUMO

Lipopolysaccharide (LPS) can either promote or prevent T helper 2 (Th2) cell allergic responses. However, the underlying mechanism remains unknown. We show here that LPS activity switches from pro-pathogenic to protective depending on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by non-classical monocytes. In the absence of GM-CSF, LPS can favor pathogenic Th2 cell responses by supporting the trafficking of lung-migratory dendritic cells (mDC2s) into the lung-draining lymph node. However, when non-classical monocytes produce GM-CSF, LPS and GM-CSF synergize to differentiate monocyte-derived DCs from classical Ly6Chi monocytes that instruct mDC2s for Th2 cell suppression. Importantly, only allergens with cysteine protease activity trigger GM-CSF production by non-classical monocytes. Hence, the therapeutic effect of LPS is restricted to allergens with this enzymatic activity. Treatment with GM-CSF, however, restores the protective effects of LPS. Thus, GM-CSF produced by non-classical monocytes acts as a rheostat that fine-tunes the pathogenic and therapeutic functions of LPS.


Assuntos
Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Hipersensibilidade/imunologia , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Células Th2/imunologia , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/patologia
10.
Int J Mol Sci ; 22(21)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34769327

RESUMO

Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been extensively studied in cancer. Allergic diseases include asthma, rhinoconjunctivitis, atopic dermatitis, drug allergy, and anaphylaxis. These overactive immune responses involve IgE-dependent activation and increased CD4+ T helper type 2 (Th2) lymphocytes. Recent studies have shown that PD-L1 and PD-L2 act to regulate T-cell activation and function. However, the main role of PD-1 and its ligands is to balance the immune response; however, the inflammatory process of allergic diseases is poorly understood. These immune checkpoint molecules can function as a brake or a kick-start to regulate the adaptive immune response. These findings suggest that PD-1 and its ligands may be a key factor in studying the exaggerated response in hypersensitivity reactions in allergies. This review summarizes the current understanding of the role of PD-1 and PD-L1 and PD-L2 pathway regulation in allergic diseases and how this immunomodulatory pathway is currently being targeted to develop novel therapeutic immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Hipersensibilidade/patologia , Imunidade Inata/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígeno B7-H1/imunologia , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/imunologia
11.
PLoS One ; 16(10): e0258051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34618857

RESUMO

Subcutaneous immunotherapy (SCIT) is a classic form of allergen-specific immunotherapy that is used to treat birch pollen induced allergic asthma. To investigate the underlying molecular mechanisms of SCIT, we aimed to profile lung samples to explore changes in the differential proteome before and after SCIT in mice with allergic asthma. Fresh lungs were collected from three groups of female BALB/c mice: 1) control mice, 2) birch pollen-induced allergic mice, and 3) birch pollen-induced allergic mice with SCIT. Tandem mass tag (TMT) labelling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the lung proteome in the mice. Ingenuity pathway analysis (IPA) and Gene Ontology (GO) classification analysis were applied to identify differentially expressed proteins (DEPs) and crucial pathways. The screened DEPs were validated by immunohistochemistry analysis. A total of 317 proteins were upregulated and 184 proteins were downregulated in the asthma group compared to those of the control group. In contrast, 639 DEPs (163 upregulated and 456 downregulated proteins) were identified after SCIT in comparison with those of the asthma group. Among the 639 DEPs, 277 proteins returned to similar levels as those of the relative non-asthma condition. Bioinformatic analysis revealed that the 277 proteins played a significant role in the leukocyte extravasation signaling pathway. The leukocyte extravasation signaling pathway and related DEPs were of crucial importance in birch pollen SCIT.


Assuntos
Asma/genética , Dessensibilização Imunológica , Pulmão/metabolismo , Proteoma/genética , Alérgenos/efeitos adversos , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Betula/efeitos adversos , Biologia Computacional , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipersensibilidade/genética , Hipersensibilidade/patologia , Infusões Subcutâneas , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Pulmão/patologia , Camundongos , Pólen/efeitos adversos , Proteoma/efeitos dos fármacos , Espectrometria de Massas em Tandem
12.
Front Immunol ; 12: 713304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659203

RESUMO

Crosstalk between T cells, dendritic cells, and macrophages in temporal leukocyte clusters within barrier tissues provides a new concept for T cell activation in the skin. Activated T cells from these leukocyte clusters play critical roles in the efferent phase of allergic contact hypersensitivity (CHS). However, the cytokines driving maintenance and survival of pathogenic T cells during and following CHS remain mostly unknown. Upon epicutaneous allergen challenge, we here report that macrophages produce IL-27 which then induces IL-15 production from epidermal keratinocytes and dermal myeloid cells within leukocyte clusters. In agreement with the known role of IL-15 as a T cell survival factor and growth cytokine, this signaling axis enhances BCL2 and survival of skin T cells. Genetic depletion or pharmacological blockade of IL-27 in CHS mice leads to abrogated epidermal IL-15 production resulting in a decrease in BCL2 expression in T cells and a decline in dermal CD8+ T cells and T cell cluster numbers. These findings suggest that the IL-27 pathway is an important cytokine for regulating cutaneous T cell immunity.


Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Interleucina-15/biossíntese , Interleucina-27/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Alérgenos/imunologia , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Hipersensibilidade/patologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células THP-1
13.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576095

RESUMO

Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.


Assuntos
Asma/patologia , Proteínas de Transporte/genética , Hipersensibilidade/patologia , Inflamação/patologia , Pulmão/patologia , Nanopartículas/toxicidade , Tiorredoxinas/genética , Titânio/toxicidade , Regulação para Cima/genética , Animais , Apoptose , Asma/sangue , Asma/complicações , Asma/genética , Líquido da Lavagem Broncoalveolar , Proteínas de Transporte/metabolismo , Caspase 3/metabolismo , Contagem de Células , Linhagem Celular , Fenômenos Químicos , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/complicações , Hipersensibilidade/genética , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/genética , Mediadores da Inflamação/metabolismo , MAP Quinase Quinase Quinase 5/metabolismo , Camundongos , Muco/metabolismo , Nanopartículas/ultraestrutura , Ovalbumina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Hipersensibilidade Respiratória/complicações , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
14.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572117

RESUMO

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.


Assuntos
Asma/complicações , Hipersensibilidade/complicações , Inflamação/prevenção & controle , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Pyroglyphidae/patogenicidade , Animais , Asma/patologia , Autofagia , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Hipersensibilidade/patologia , Imunoglobulina E/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/química , Proteína Sequestossoma-1/metabolismo
15.
Curr Med Sci ; 41(4): 827-831, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403109

RESUMO

OBJECTIVE: The characteristics of oxaliplatin-induced hypersensitivity reactions (HSRs) in Chinese patients were investigated to provide a reference for patients treated with oxaliplatin. METHODS: The study reviewed the records of patients who developed oxaliplatin-induced HSRs in 17 hospitals from May 2016 to May 2017. We collected and analyzed the basic information, history of oxaliplatin administration and premedication treatments, chemotherapy cycles, HSR symptoms, and the management and outcomes of these patients. RESULTS: Oxaliplatin-induced HSRs were recorded in 137 patients who had been treated with oxaliplatin-containing regimens. Five different chemotherapy regimens were applied. The median infusion cycle when oxaliplatin-induced HSRs occurred was 7, and HSRs occurred during or shortly after oxaliplatin infusion. Most of the patients experienced grade 1 or grade 2 HSRs with mild symptoms of pruritis (49.64%), flushing (46.72%), chest discomfort (26.28%), and urticaria (25.55%). The majority of the patients completely recovered from HSRs following treatment with antihistamines and dexamethasone. Seven patients completed chemotherapy with oxaliplatin after the symptoms resolved with proper management. CONCLUSION: The results indicate that oxaliplatin-induced HSRs remain an important issue in safely and successfully fulfilling oxaliplatin-containing chemotherapy. Further studies are needed to analyze the risk factors and establish prophylaxis for such reactions.


Assuntos
Antineoplásicos/efeitos adversos , Hipersensibilidade/epidemiologia , Oxaliplatina/efeitos adversos , Adulto , Idoso , Antineoplásicos/uso terapêutico , China/epidemiologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Oxaliplatina/uso terapêutico , Fatores de Risco , Neoplasias Gástricas/complicações , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto Jovem
16.
Hematol Oncol ; 39(5): 687-696, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34397119

RESUMO

Asparaginase (ASP) is an essential component for the acute lymphoblastic leukemia (ALL) treatment, but toxicities, such as allergy, frequently limit its use. Although the potentially lower PEG-ASP formulation immunogenicity, few studies with conflicting results have compared the allergy incidence between Escherichia coli-ASP and PEG-ASP in the same protocol. We aimed at comparing the allergy incidence in children receiving native E. coli-ASP versus PEG-ASP within the same clinical protocol (Spanish Society of Pediatric Hematology and Oncology ALL-SEHOP-PETHEMA 2013). One hundred and twenty-six children (1-19 years) diagnosed with ALL from 2013 to 2020 were included. Patients in group 1 received a sequential scheme of native E. coli-ASP 10,000 IU/m2 intramuscularly (IM) followed by PEG-ASP 1000 IU/m2 IM. Patients in group 2 received PEG-ASP 1000 IU/m2 IM upfront. Clinical allergy incidence was compared between both groups. Serum ASP activity (SAA) was measured in a subgroup of patients, and silent inactivation was recorded. The cumulative incidence of clinical allergy was significantly higher in group 1 (native followed by PEG-ASP) than in group 2 (PEG-ASP upfront), 24.7% versus 4.1% (p = 0.0085). Adequate ASP activity was achieved with PEG-ASP 1000 IU/m2 dose in most patients (median SAA 412.5 and 453.0 IU/L at days 7 and 14). The incidence of silent inactivation in PEG-ASP upfront patients was very low. PEG-ASP-used upfront was associated with a lower incidence of clinical allergy than that observed in the sequential use of native E. coli-ASP followed by PEG-ASP. PEG-ASP at 1000 IU/m2 was effective in achieving enough ASP activity in most patients.


Assuntos
Asparaginase/efeitos adversos , Escherichia coli/enzimologia , Hipersensibilidade/epidemiologia , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/patologia , Incidência , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Espanha/epidemiologia , Adulto Jovem
17.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445627

RESUMO

Epigenetics is a field of study investigating changes in gene expression that do not alter the DNA sequence. These changes are often influenced by environmental or social factors and are reversible. Epigenetic mechanisms include DNA methylation, histone modification, and noncoding RNA. Understanding the role of these epigenetic mechanisms in human diseases provides useful information with regard to disease severity and development. Several studies have searched for the epigenetic mechanisms that regulate allergies and asthma; however, only few studies have used samples of eosinophil, a proinflammatory cell type known to be largely recruited during allergic or asthmatic inflammation. Such studies would enable us to better understand the factors that influence the massive recruitment of eosinophils during allergic and asthmatic symptoms. In this review, we sought to summarize different studies that aimed to discover differential patterns of histone modifications, DNA methylation, and noncoding RNAs in eosinophil samples of individuals with certain diseases, with a particular focus on those with asthma or allergic diseases.


Assuntos
Asma/patologia , Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica , Código das Histonas , Hipersensibilidade/patologia , Animais , Asma/genética , Humanos , Hipersensibilidade/genética
18.
PLoS Pathog ; 17(8): e1009891, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34464425

RESUMO

Exposure to the mold, Aspergillus, is ubiquitous and generally has no adverse consequences in immunocompetent persons. However, invasive and allergic aspergillosis can develop in immunocompromised and atopic individuals, respectively. Previously, we demonstrated that mouse lung eosinophils produce IL-17 in response to stimulation by live conidia and antigens of A. fumigatus. Here, we utilized murine models of allergic and acute pulmonary aspergillosis to determine the association of IL-23, IL-23R and RORγt with eosinophil IL-17 expression. Following A. fumigatus stimulation, a population of lung eosinophils expressed RORγt, the master transcription factor for IL-17 regulation. Eosinophil RORγt expression was demonstrated by flow cytometry, confocal microscopy, western blotting and an mCherry reporter mouse. Both nuclear and cytoplasmic localization of RORγt in eosinophils were observed, although the former predominated. A population of lung eosinophils also expressed IL-23R. While expression of IL-23R was positively correlated with expression of RORγt, expression of RORγt and IL-17 was similar when comparing lung eosinophils from A. fumigatus-challenged wild-type and IL-23p19-/- mice. Thus, in allergic and acute models of pulmonary aspergillosis, lung eosinophils express IL-17, RORγt and IL-23R. However, IL-23 is dispensable for production of IL-17 and RORγt.


Assuntos
Eosinófilos/imunologia , Hipersensibilidade/imunologia , Interleucina-17/metabolismo , Interleucina-23/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/fisiologia , Aspergilose Pulmonar/imunologia , Receptores de Interleucina/metabolismo , Animais , Eosinófilos/metabolismo , Eosinófilos/patologia , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Interleucina-17/genética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Aspergilose Pulmonar/metabolismo , Aspergilose Pulmonar/patologia , Receptores de Interleucina/genética
19.
Cells ; 10(7)2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206914

RESUMO

Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.


Assuntos
Inflamação/imunologia , Inflamação/patologia , Queratinócitos/patologia , Linfócitos T/imunologia , Apresentação do Antígeno/imunologia , Biomarcadores/metabolismo , Comunicação Celular , Proliferação de Células , Forma Celular , Microambiente Celular , Dermatite de Contato/imunologia , Dermatite de Contato/patologia , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Queratinócitos/ultraestrutura , Modelos Biológicos , Pele/imunologia , Pele/patologia , Solubilidade , Linfócitos T/ultraestrutura
20.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209362

RESUMO

Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.


Assuntos
Degranulação Celular , Eosinófilos/metabolismo , Armadilhas Extracelulares/metabolismo , Hipersensibilidade/metabolismo , Eosinófilos/patologia , Humanos , Hipersensibilidade/patologia
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