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1.
Sci Adv ; 8(16): eabl4602, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35452290

RESUMO

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.


Assuntos
Doença da Artéria Coronariana , Pleiotropia Genética , Pneumonia , Proteína ADAMTS7/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Pneumonia/genética , Pneumonia/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética
2.
Comput Math Methods Med ; 2022: 8660752, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35132333

RESUMO

Swine pneumonia commonly known as swine pasteurellosis is an infectious disease of swine caused by Pasteurella multocida infection. It has been reported that Toll-like receptors (TLRs) play a vital role in swine pneumonia progression. However, the underlying mechanism has not been elucidated. This research was aimed at investigating the molecular mechanism by which TLR9 regulates swine pneumonia progression. Our findings illustrated that the HD-13 strain of Pasteurella multocida D (HD-13) accelerated TLR9 expression in porcine alveolar macrophage 3D4/21 cells; HD-13 activated the inflammatory response via accelerating TLR9 expression. Mechanistically, HD-13 activated mitogen-activated protein kinase (MAPK) and nuclear factor kB (NF-κB) signals. In conclusion, HD-13 may activate MAPK and NF-κB pathways via accelerating TLR9 expression, thereby accelerating the inflammatory response in the progression of swine pneumonia. TLR9 may serve as a novel therapeutic target for swine pneumonia. Our research may provide a theoretical basis for the prevention and treatment of swine pneumonia.


Assuntos
Infecções por Pasteurella/veterinária , Pasteurella multocida/patogenicidade , Pneumonia/veterinária , Doenças dos Suínos/imunologia , Doenças dos Suínos/microbiologia , Receptor Toll-Like 9/imunologia , Animais , Células Cultivadas , Biologia Computacional , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Sistema de Sinalização das MAP Quinases/imunologia , NF-kappa B/imunologia , Infecções por Pasteurella/imunologia , Infecções por Pasteurella/microbiologia , Pasteurella multocida/classificação , Pasteurella multocida/imunologia , Pneumonia/imunologia , Pneumonia/microbiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/imunologia , Sus scrofa , Suínos , Doenças dos Suínos/genética , Receptor Toll-Like 9/genética , Regulação para Cima
3.
Sci Rep ; 12(1): 1943, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35121767

RESUMO

T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells. The essential trace element zinc has reported immunomodulatory capacity and high zinc concentrations interfere with T cell function. However, how high doses of zinc affect T cell gene networks and metabolism remained so far elusive. Herein, we demonstrate by means of transcriptomic analysis that zinc aspartate (UNIZINK), a registered pharmaceutical infusion solution with high bioavailability, negatively regulates gene networks controlling DNA replication and the energy metabolism of murine CD3/CD28-activated CD4+ T cells. Specifically, in the presence of zinc, CD4+ T cells show impaired expression of cell cycle, glycolytic and tricarboxylic acid cycle genes, which functionally cumulates in reduced glycolysis, oxidative phosphorylation, metabolic fitness and viability. Moreover, high zinc concentrations impaired nuclear expression of the metabolic transcription factor MYC, prevented Th1 and Th2 differentiation in vitro and reduced Th1 autoimmune central nervous system (CNS) inflammation and Th2 asthmatic airway inflammation induced by house dust mites in vivo. Together, we find that higher zinc doses impair the metabolic fitness of CD4+ T cells and prevent Th1 CNS autoimmunity and Th2 allergy.


Assuntos
Ácido Aspártico/análogos & derivados , Asma/tratamento farmacológico , Sistema Nervoso Central/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Compostos de Zinco/farmacologia , Animais , Ácido Aspártico/farmacologia , Asma/genética , Asma/imunologia , Asma/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Metabolismo Energético/genética , Regulação da Expressão Gênica , Pulmão/imunologia , Pulmão/metabolismo , Ativação Linfocitária/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/metabolismo , Pyroglyphidae/imunologia , Transdução de Sinais , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Transcrição Genética
4.
Front Immunol ; 13: 790043, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185885

RESUMO

Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.


Assuntos
Células Epiteliais/imunologia , Armadilhas Extracelulares/imunologia , Hemorragia/imunologia , Neutrófilos/imunologia , Pneumonia/imunologia , Alvéolos Pulmonares/imunologia , Animais , Modelos Animais de Doenças , Células Epiteliais/patologia , Feminino , Hemorragia/patologia , Humanos , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Pneumonia/etiologia , Pneumonia/patologia , Alvéolos Pulmonares/patologia , Terpenos/toxicidade
5.
Commun Biol ; 5(1): 162, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210549

RESUMO

T helper 17 (Th17) cells develop in response to T cell receptor signals (TCR) in the presence of specific environments, and produce the inflammatory cytokine IL17A. These cells have been implicated in a number of inflammatory diseases and represent a potential target for ameliorating such diseases. The kinase ITK, a critical regulator of TCR signals, has been shown to be required for the development of Th17 cells. However, we show here that lung inflammation induced by Saccharopolyspora rectivirgula (SR) induced Hypersensitivity pneumonitis (SR-HP) results in a neutrophil independent, and ITK independent Th17 responses, although ITK signals are required for γδ T cell production of IL17A. Transcriptomic analysis of resultant ITK independent Th17 cells suggest that the SR-HP-induced extrinsic inflammatory signals may override intrinsic T cell signals downstream of ITK to rescue Th17 responses in the absence of ITK. These findings suggest that the ability to pharmaceutically target ITK to suppress Th17 responses may be dependent on the type of inflammation.


Assuntos
Alveolite Alérgica Extrínseca , Pneumonia , Proteínas Tirosina Quinases , Células Th17 , Alveolite Alérgica Extrínseca/enzimologia , Alveolite Alérgica Extrínseca/imunologia , Alveolite Alérgica Extrínseca/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/imunologia , Pneumonia/metabolismo , Proteínas Tirosina Quinases/imunologia , Células Th17/enzimologia , Células Th17/imunologia , Células Th17/metabolismo
6.
Nature ; 603(7899): 145-151, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35045565

RESUMO

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Interferon Tipo I/imunologia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , SARS-CoV-2/imunologia , Animais , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Macrófagos/imunologia , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/patologia , Pneumonia/virologia , SARS-CoV-2/patogenicidade , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/patologia
7.
Life Sci ; 293: 120306, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35016883

RESUMO

Recent studies have shown that proper exercise significantly restricts inflammatory responses through regulation of the immune system. This review discusses mechanisms of protective effects of exercise in lipopolysaccharide (LPS)-induced lung injury. We performed a systematic search in PubMed, Scopus, and Web of Sciences using the search components "physical exercise", "lung" and "LPS" to identify preclinical studies, which assessed physical activity effects on LPS-induced pulmonary injury. Articles (n = 1240) were screened and those that had the eligibility criteria were selected for data extraction and critical appraisal. In all of the 21 rodent-model studies included, pulmonary inflammation was induced by LPS. Exercise protocols included low and moderate intensity treadmill training and swimming. The results showed that aerobic exercise would prevent LPS-induced oxidative stress and inflammation as well as airways resistance, exhaled nitric oxide, protein leakage, increase in total WBC, macrophage and neutrophil population, levels of interleukin (IL)-6, IL-1ß, IL-17, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor and CXCL1/KC, and improved IL-10 and IL-ra in lung tissue, bronchoalveolar lavage fluid (BALF) and serum. In addition, in trained animals, the expression of some anti-inflammatory factors such as heat shock protein72, IL-10, triggering receptor expressed on myeloid cells-2 and irisin was increased, thus ameliorating lung injury complications. Aerobic exercise was shown to alleviate the LPS-induced lung injury in rodent models by suppressing oxidative stress and lowering the ratio of pro-inflammatory to anti-inflammatory cytokines.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/terapia , Lipopolissacarídeos/toxicidade , Condicionamento Físico Animal/fisiologia , Pneumonia/induzido quimicamente , Pneumonia/terapia , Lesão Pulmonar Aguda/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Mediadores da Inflamação/imunologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/métodos , Pneumonia/imunologia
8.
Toxicology ; 465: 153026, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34774659

RESUMO

Exposure to fine particulate matter (PM2.5) induces airway inflammation and hyperreactivity that lead to asthma. The mechanisms involved are still under investigation. We investigated the effect of resveratrol (3,4',5-trihydroxystilbene) (RES) on airway hyperresponsiveness, inflammation and CYP1A1 protein expression (an aryl hydrocarbon receptor (AhR) target) induced by PM2.5 exposure in an allergic asthma experimental guinea pig model. The polyphenolic compound RES was used due to its antioxidant and anti-inflammatory properties and as an antagonist of the AhR; thus, providing mechanistic insights. Animals were sensitized with aluminum hydroxide and ovalbumin and exposed to filtered air or PM2.5. Exposure to PM2.5 was conducted using a whole-body chamber particle concentrator (5 h/day) for 15 days. Animals received saline solution or RES (10 mg/kg per day) orally for 21 days simultaneously to the OVA challenge or PM2.5 exposure. PM2.5 exposure (mean 433 ± 111 µg/m3 in the exposure chamber) in OVA challenged animals induced an asthma-like phenotype characterized by increased baseline lung resistance (Rrs) and central airway resistance (Rn) in response to acetylcholine (ACh) evaluated using a flexiVent system®. A parallel increase of pro-inflammatory cytokines (IL-6, IL-17, TNF-α and IFN-γ), inflammatory cells (eosinophils and neutrophils) in bronchoalveolar lavage fluid (BALF) and lung CYP1A1 increase also occurred. RES significantly inhibited airway hyperresponsiveness, inflammation, and CYP1A1 protein expression in the OVA-challenged PM2.5 exposed animals. In summary, with the use of RES we demonstrate that PM-induced airway hyperreactivity is modulated by the inflammatory response via the AhR pathway in an allergic asthma guinea pig model.


Assuntos
Asma/induzido quimicamente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Pneumonia/induzido quimicamente , Receptores de Hidrocarboneto Arílico/agonistas , Hidróxido de Alumínio , Animais , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Asma/imunologia , Asma/metabolismo , Asma/prevenção & controle , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Cobaias , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Ovalbumina , Tamanho da Partícula , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/prevenção & controle , Receptores de Hidrocarboneto Arílico/metabolismo , Resveratrol/farmacologia , Transdução de Sinais
9.
J Allergy Clin Immunol ; 149(1): 237-251.e12, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33964300

RESUMO

BACKGROUND: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms. OBJECTIVES: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1). METHODS: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice. RESULTS: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes. CONCLUSIONS: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.


Assuntos
Androgênios/farmacologia , Lectinas Tipo C/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , Receptores Imunológicos/imunologia , Testosterona/farmacologia , Animais , Feminino , Interleucina-33/imunologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/patologia , Caracteres Sexuais , Transdução de Sinais
10.
Shock ; 57(2): 298-308, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34107528

RESUMO

ABSTRACT: Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone positions. After approximately 7 h, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ±â€Š0.014 vs. PP: 0.029 ±â€Š0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ±â€Š0.013 vs. PP: 0.026 ±â€Š0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of its effect may be homogenization of lung tissue and that of mechanical forces.


Assuntos
Fluordesoxiglucose F18 , Neutrófilos , Pneumonia/diagnóstico por imagem , Pneumonia/imunologia , Tomografia por Emissão de Pósitrons , Decúbito Ventral , Compostos Radiofarmacêuticos , Lesão Pulmonar Induzida por Ventilação Mecânica/diagnóstico por imagem , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologia , Animais , Modelos Animais de Doenças , Masculino , Coelhos
11.
J Allergy Clin Immunol ; 149(1): 223-236.e6, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34144112

RESUMO

BACKGROUND: Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases. OBJECTIVE: Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s. METHODS: Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2-/-Il2rg-/- mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s. RESULTS: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model. CONCLUSION: Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.


Assuntos
Alternariose/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , Receptores Imunológicos/imunologia , Hipersensibilidade Respiratória/imunologia , Transferência Adotiva , Alternaria , Alternariose/fisiopatologia , Animais , Citocinas/imunologia , Feminino , Humanos , Imunidade Inata , Interleucina-33/farmacologia , Pulmão/imunologia , Pulmão/fisiopatologia , Transfusão de Linfócitos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/fisiopatologia , Receptores Imunológicos/genética , Hipersensibilidade Respiratória/fisiopatologia
12.
Neurol Res ; 44(3): 224-231, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34514954

RESUMO

BACKGROUND: Complete blood count derived indexes such as lymphocyte-to-neutrophil ratio (NLR) may help in predicting pneumonia and prognosis in acute stroke. However, the optimal time point for using these biomarkers is not known. METHODS: In 205 consecutive severe (NIHSS>10) acute ischemic stroke patients, daily leukocyte, lymphocyte, neutrophil, monocyte, platelet, albumin, fibrinogen, hematocrit, NLR, PLR (Platelet-to-lymphocyte-ratio), LMR (Lymphocyte-to-monocyte-ratio), and SII (systemic-immune-inflammation-index) were determined. General linear models for repeated measures (GLMR) and receiver operating characteristics [ROC] analyses were conducted to define their daily discriminative ability. RESULTS: GLMR-prognosis modeling documented that the main determinants of significant daily variations of 12 parameters studied were age and 24th-hour-NIHSS. In addition, daily changes of NLR, neutrophil, leukocyte (all increased on day-2 and remained higher) and platelet count (decreased after day-6 and stayed lower) were related significantly to survival status (mortality in 19.5%). Albumin levels (lower after day-2) were marginally associated by functional prognosis (modified-Rankin-Score≤3 in 28%). There was a borderline relationship (p = 0.05) between NLR (between day-1 and day-8) and pneumonia development (in 36%). Useful discrimination capability (95% confidence interval lower limit of area-under-curve of ROC≥0.7) was noted for NLR measured on day-6 for mortality, NLR (for 6 days, from day-3-to-day-7, and day-11) and albumin (for every day except day-11 after day-4) for reasonable prognosis and none for pneumonia development. CONCLUSIONS: Inflammatory parameters from peripheral routine blood tests showed significant variations during the first two weeks following stroke, but discriminative capacity of these changes is limited due to confounders such as age and post-treatment clinical stroke severity.


Assuntos
Inflamação , AVC Isquêmico , Linfócitos , Pneumonia , Adulto , Idoso , Feminino , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/imunologia , Inflamação/mortalidade , AVC Isquêmico/sangue , AVC Isquêmico/complicações , AVC Isquêmico/imunologia , AVC Isquêmico/mortalidade , Masculino , Pessoa de Meia-Idade , Pneumonia/sangue , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/mortalidade , Prognóstico , Índice de Gravidade de Doença
13.
Front Immunol ; 12: 738041, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867960

RESUMO

CpG-oligodeoxynucleotides (CpG-ODNs) constitute an attractive alternative for asthma treatment. However, very little evidence is available from studies on the oral administration of CpG-ODNs in animals. Previously, we developed acid-resistant particles (named ODNcap) as an oral delivery device for ODNs. Here, we showed that free feeding of an ODNcap-containing feed prophylactically attenuates allergic airway inflammation, hyperresponsiveness, and goblet cell hyperplasia in an ovalbumin-induced asthma model. Using transcriptomics-driven approaches, we demonstrated that injury of pulmonary vein cardiomyocytes accompanies allergen inhalation challenge, but is inhibited by ODNcap feeding. We also showed the participation of an airway antimicrobial peptide (Reg3γ) and fecal microbiota in the ODNcap-mediated effects. Collectively, our findings suggest that daily oral ingestion of ODNcap may provide preventive effects on allergic bronchopulmonary insults via regulation of mechanisms involved in the gut-lung connection.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hipersensibilidade/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Pneumonia/imunologia , Administração Oral , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/toxicidade , Proteínas Associadas a Pancreatite/imunologia
14.
Int J Mol Sci ; 22(23)2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34884648

RESUMO

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Pulmão/efeitos dos fármacos , Pneumonia/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Síndrome do Desconforto Respiratório/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Feminino , Ácido Clorídrico/toxicidade , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Prostaglandinas F/metabolismo , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/patologia
15.
mBio ; 12(6): e0322321, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34872353

RESUMO

Mice immunized with a combination of an adenovirus vector (Ad5-YFV) and live-attenuated (LMA)-based vaccines were evaluated for protective efficacy against pneumonic plague. While the Ad5-YFV vaccine harbors a fusion cassette of three genes encoding YscF, F1, and LcrV, LMA represents a mutant of parental Yersinia pestis CO92 deleted for genes encoding Lpp, MsbB, and Ail. Ad5-YFV and LMA were either administered simultaneously (1-dose regimen) or 21 days apart in various orders and route of administration combinations (2-dose regimen). The 2-dose regimen induced robust immune responses to provide full protection to animals against parental CO92 and its isogenic F1 deletion mutant (CAF-) challenges during both short- and long-term studies. Mice intranasally (i.n.) immunized with Ad5-YFV first followed by LMA (i.n. or intramuscularly [i.m.]) had higher T- and B-cell proliferative responses and LcrV antibody titers than those in mice vaccinated with LMA (i.n. or i.m.) first ahead of Ad5-YFV (i.n.) during the long-term study. Specifically, the needle- and adjuvant-free vaccine combination (i.n.) is ideal for use in plague regions of endemicity. Conversely, with a 1-dose regimen, mice vaccinated with Ad5-YFV i.n. and LMA by the i.m. route provided complete protection to animals against CO92 and its CAF- mutant challenges and elicited Th1/Th2, as well as Th17 responses, making it suitable for emergency vaccination during a plague outbreak or bioterrorist attack. This is a first study in which a viral vector-based and live-attenuated vaccines were effectively used in combination, representing adjuvant- and/or needle-free immunization, with each vaccine triggering a distinct cellular immune response. IMPORTANCE Yersinia pestis, the causative agent of plague, is a Tier-1 select agent and a reemerging human pathogen. A 2017 outbreak in Madagascar with >75% of cases being pneumonic and 8.6% causalities emphasized the importance of the disease. The World Health Organization has indicated an urgent need to develop new-generation subunit and live-attenuated plague vaccines. We have developed a subunit vaccine, including three components (YscF, F1, and LcrV) using an adenovirus platform (Ad5-YFV). In addition, we have deleted virulence genes of Y. pestis (e.g., lpp, msbB, and ail) to develop a live-attenuated vaccine (LMA). Both of these vaccines generated robust humoral and cellular immunity and were highly efficacious in several animal models. We hypothesized the use of a heterologous prime-boost strategy or administrating both vaccines simultaneously could provide an adjuvant- and/or a needle-free vaccine(s) that has attributes of both vaccines for use in regions of endemicity and during an emergency situation.


Assuntos
Adenoviridae/imunologia , Antígenos de Bactérias/administração & dosagem , Vacina contra a Peste/administração & dosagem , Peste/prevenção & controle , Pneumonia/prevenção & controle , Vacinas Atenuadas/administração & dosagem , Yersinia pestis/imunologia , Adenoviridae/genética , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Humanos , Camundongos , Peste/imunologia , Peste/microbiologia , Vacina contra a Peste/genética , Vacina contra a Peste/imunologia , Pneumonia/imunologia , Pneumonia/microbiologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Yersinia pestis/genética
16.
Sci Rep ; 11(1): 23216, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853374

RESUMO

This study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N = 302) or multiple time points (N = 229) 3-12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P < 0.01) and was higher in the pneumonia group than in the non-pneumonia/asymptomatic group at 6 months (P < 0.01), 9 months (P = 0.04), and 12 months (P = 0.04). The rate started to decline 6-12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r = 0.192, P < 0.01) but negatively correlated with interval between symptom onset and blood sampling (r = - 0.567, P < 0.01). These findings can guide vaccine strategies in recovered COVID-19 patients.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Imunoglobulina G/imunologia , Pneumonia/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , COVID-19/complicações , COVID-19/terapia , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Pneumonia/epidemiologia , Pneumonia/virologia , Estudos Retrospectivos , Tailândia/epidemiologia , Adulto Jovem
17.
Sci Immunol ; 6(66): eabj0474, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34932383

RESUMO

Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified. Here, we showed that inhalation of the parent leukotriene C4 (LTC4) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokine production, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4+ T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells required signaling through CysLT1R and partially CysLT2R. Tuft cell­specific deletion of Ltc4s, the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen Alternaria; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.


Assuntos
Cisteína/imunologia , Células Epiteliais/imunologia , Interleucinas/imunologia , Leucotrienos/imunologia , Pneumonia/imunologia , Animais , Camundongos , Camundongos Transgênicos
18.
Front Immunol ; 12: 784028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956213

RESUMO

Background: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. Methods: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. Results: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, padjusted<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, padjusted=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. Conclusion: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.


Assuntos
Biomarcadores/sangue , COVID-19/imunologia , Vesículas Extracelulares/imunologia , MicroRNAs/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/imunologia , Pneumonia/patologia , SARS-CoV-2 , Transdução de Sinais/imunologia
19.
Front Immunol ; 12: 772288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912341

RESUMO

Seasonal influenza epidemics represent a significant global health threat. The exacerbated immune response triggered by respiratory influenza virus infection causes severe pulmonary damage and contributes to substantial morbidity and mortality. Regulator of G-protein signaling 10 (RGS10) belongs to the RGS protein family that act as GTPase activating proteins for heterotrimeric G proteins to terminate signaling pathways downstream of G protein-coupled receptors. While RGS10 is highly expressed in immune cells, in particular monocytes and macrophages, where it has strong anti-inflammatory effects, its physiological role in the respiratory immune system has not been explored yet. Here, we show that Rgs10 negatively modulates lung immune and inflammatory responses associated with severe influenza H1N1 virus respiratory infection in a mouse model. In response to influenza A virus challenge, mice lacking RGS10 experience enhanced weight loss and lung viral titers, higher mortality and significantly faster disease onset. Deficiency of Rgs10 upregulates the levels of several proinflammatory cytokines and chemokines and increases myeloid leukocyte accumulation in the infected lung, markedly neutrophils, monocytes, and inflammatory monocytes, which is associated with more pronounced lung damage. Consistent with this, influenza-infected Rgs10-deficent lungs contain more neutrophil extracellular traps and exhibit higher neutrophil elastase activities than wild-type lungs. Overall, these findings propose a novel, in vivo role for RGS10 in the respiratory immune system controlling myeloid leukocyte infiltration, viral clearance and associated clinical symptoms following lethal influenza challenge. RGS10 also holds promise as a new, potential therapeutic target for respiratory infections.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae/imunologia , Pneumonia/imunologia , Proteínas RGS/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Feminino , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Pneumonia/patologia , Pneumonia/virologia , Proteínas RGS/genética
20.
Front Immunol ; 12: 733217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721395

RESUMO

The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b+ granulocytes and increased levels of MIP-1α, MIG, MCP-1, IL-8, and IL-6 in BAL relative to healthy control children. Proportions of systemic neutrophils positively correlated with age in children with CF, whilst systemic CD4 T cells and B cells were inversely associated with age. Inflammatory cells in the BAL from both CF and healthy children expressed higher levels of activation and migration markers relative to their systemic counterparts. This work highlights the utility of multiplex immune profiling and advanced analytical pipelines to understand mechanisms of lung disease in childhood.


Assuntos
Fibrose Cística/imunologia , Citocinas/sangue , Mediadores da Inflamação/sangue , Inflamação/imunologia , Leucócitos/imunologia , Pneumonia/imunologia , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Casos e Controles , Fibrose Cística/diagnóstico , Fibrose Cística/metabolismo , Citometria de Fluxo , Humanos , Imunofenotipagem , Inflamação/diagnóstico , Inflamação/metabolismo , Leucócitos/metabolismo , Fenótipo , Pneumonia/diagnóstico , Pneumonia/metabolismo
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