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1.
Ecotoxicol Environ Saf ; 281: 116637, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38941663

RESUMO

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation.


Assuntos
Poluentes Atmosféricos , Material Particulado , Transdução de Sinais , Material Particulado/toxicidade , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Camundongos Endogâmicos C57BL , Sistema Respiratório/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos
2.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891820

RESUMO

Chronic obstructive pulmonary disease (COPD), the major leading cause of mortality worldwide, is a progressive and irreversible respiratory condition characterized by peripheral airway and lung parenchymal inflammation, accompanied by fibrosis, emphysema, and airflow limitation, and has multiple etiologies, including genetic variance, air pollution, and repetitive exposure to harmful substances. However, the precise mechanisms underlying the pathogenesis of COPD have not been identified. Recent multiomics-based evidence suggests that the plasticity of alveolar macrophages contributes to the onset and progression of COPD through the coordinated modulation of numerous transcription factors. Therefore, this review focuses on understanding the mechanisms and functions of macrophage polarization that regulate lung homeostasis in COPD. These findings may provide a better insight into the distinct role of macrophages in COPD pathogenesis and perspective for developing novel therapeutic strategies targeting macrophage polarization.


Assuntos
Macrófagos Alveolares , Doença Pulmonar Obstrutiva Crônica , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Macrófagos Alveolares/imunologia , Animais , Ativação de Macrófagos , Macrófagos/metabolismo , Macrófagos/imunologia , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologia
3.
Am J Pathol ; 191(6): 1118-1134, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33753024

RESUMO

Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1α (HIF1α) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation in vivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1α represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1α expression in macrophages. Collectively, this study uncovers that macrophage-HIF1α deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages.


Assuntos
Estenose das Carótidas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Transdução de Sinais/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL
4.
FASEB J ; 35(10): e21940, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34551158

RESUMO

Macrophages are the principal innate immune cells that populate all major organs and provide the first line of cellular defense against infections and/or injuries. The immediate and early-responding macrophages must mount a robust pro-inflammatory response to protect the host by eliminating deleterious agents. The effective pro-inflammatory macrophage response requires the activation of complex transcriptional programs that modulate the dynamic regulation of inflammatory and metabolic gene expression. Therefore, transcription factors that govern pro-inflammatory and metabolic gene expression play an essential role in shaping the macrophage inflammatory response. Herein, we identify the basic helix-loop-helix family member e40 (BHLHE40), as a critical transcription factor that promotes broad pro-inflammatory and glycolytic gene expression by elevating HIF1α levels in macrophages. Our in vivo studies revealed that myeloid-BHLHE40 deficiency significantly attenuates macrophage and neutrophil recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies show that BHLHE40 deficiency broadly curtails inflammatory signaling pathways, hypoxia response, and glycolytic gene expression in macrophages. Utilizing complementary gain- and loss-of-function studies, our analyses uncovered that BHLHE40 promotes LPS-induced HIF1α mRNA and protein expression in macrophages. More importantly, forced overexpression of oxygen stable form of HIF1α completely reversed attenuated pro-inflammatory and glycolytic gene expression in BHLHE40-deficient macrophages. Collectively, these results demonstrate that BHLHE40 promotes macrophage pro-inflammatory gene expression and functions by elevating HIF1α expression in macrophages.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Inflamação/genética , Macrófagos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Células Sanguíneas/metabolismo , Feminino , Glicólise/efeitos dos fármacos , Glicólise/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Substâncias Protetoras , Zimosan/efeitos adversos , Zimosan/antagonistas & inibidores
5.
FASEB J ; 35(9): e21833, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365659

RESUMO

Macrophages are the principal component of the innate immune system. They play very crucial and multifaceted roles in the pathogenesis of inflammatory vascular diseases. There is an increasing recognition that transcriptionally dynamic macrophages are the key players in the pathogenesis of inflammatory vascular diseases. In this context, the accumulation and aberrant activation of macrophages in the subendothelial layers govern atherosclerotic plaque development. Macrophage-mediated inflammation is an explicitly robust biological response that involves broad alterations in inflammatory gene expression. Thus, cell-intrinsic negative regulatory mechanisms must exist which can restrain inflammatory response in a spatiotemporal manner. In this study, we identified CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as one such cell-intrinsic negative regulator of inflammation. Our in vivo studies show that myeloid-CITED2-deficient mice on the Apoe-/- background have larger atherosclerotic lesions on both control and high-fat/high-cholesterol diets. Our integrated transcriptomics and gene set enrichment analyses studies show that CITED2 deficiency elevates STAT1 and interferon regulatory factor 1 (IRF1) regulated pro-inflammatory gene expression in macrophages. At the molecular level, our studies identify that CITED2 deficiency elevates IFNγ-induced STAT1 transcriptional activity and STAT1 enrichment on IRF1 promoter in macrophages. More importantly, siRNA-mediated knockdown of IRF1 completely reversed elevated pro-inflammatory target gene expression in CITED2-deficient macrophages. Collectively, our study findings demonstrate that CITED2 restrains the STAT1-IRF1 signaling axis in macrophages and limits the development of atherosclerotic plaques.


Assuntos
Aterosclerose/genética , Fator Regulador 1 de Interferon/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT1/genética , Transdução de Sinais/genética , Transativadores/genética , Animais , Feminino , Inflamação/genética , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Células RAW 264.7 , Transcrição Gênica/genética
6.
FASEB J ; 34(2): 3209-3223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31908054

RESUMO

Macrophages are the professional phagocytes that protect the host from infection or injury. Tissue microenvironment at the site of injury and inflammation is characterized by low oxygen concentration and poor supply of nutrients. The responding macrophages have to advance against oxygen and nutrient gradients to reach the site of inflammation to perform host protection, and tissue repair functions. Thus, evolution has fashioned macrophages to orchestrate a coordinated inflammatory and hypoxic gene program to mount an effective immune response. Here, we discovered that Kruppel-like factor 6 (KLF6) governs macrophage functions by promoting inflammatory and hypoxic response gene programming. Our in vivo studies revealed that myeloid-KLF6-deficient mice were highly resistant to endotoxin-induced systemic inflammatory response syndrome symptomatology and mortality. Using complementary gain- and loss-of-function studies, we observed that KLF6 overexpression elevate and KLF6 deficiency attenuate inducible HIF1α expression in macrophages. Our integrated transcriptomics and gene set enrichment analysis studies uncovered that KLF6 deficiency attenuates broad inflammatory and glycolytic gene expression in macrophages. More importantly, overexpression of oxygen stable HIF1α reversed attenuated proinflammatory and glycolytic gene expression in KLF6-deficient macrophages. Collectively, our studies uncovered that KLF6 govern inflammatory and hypoxic response by regulating HIF1α expression in macrophage.


Assuntos
Citocinas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 6 Semelhante a Kruppel/metabolismo , Animais , Hipóxia Celular , Células Cultivadas , Citocinas/genética , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fator 6 Semelhante a Kruppel/genética , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Transcriptoma
7.
FASEB J ; 34(9): 12100-12113, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32697413

RESUMO

Monocyte-derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro-inflammatory response. However, macrophage pro-inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro-inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro-inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid-CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS-induced NFκB transcriptional activity and NFκB-p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro-inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro-inflammatory gene programs in myeloid cells.


Assuntos
Regulação da Expressão Gênica , Macrófagos/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/metabolismo , Transcrição Gênica , Animais , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/patologia , Camundongos , Neutrófilos/metabolismo , Neutrófilos/patologia , Células RAW 264.7 , Proteínas Repressoras/genética , Transativadores/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
8.
FASEB J ; 33(10): 10902-10915, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31262200

RESUMO

Macrophage-mediated inflammation is an explicitly robust biologic response that plays a critical role in maintaining tissue homeostasis by eliminating deleterious agents. These tissue macrophages tailor appropriate responses to external cues by altering inflammatory gene expression. Therefore, transcription factors and regulators that modulate inflammatory gene expression play an essential role in shaping the macrophage inflammatory response. Here, we identify that Kruppel-like factor (KLF)6 promotes inflammation by restraining microRNA-223 (miR-223) expression in macrophages. We uncovered that pro- and anti-inflammatory agents oppositely regulate KLF6 and miR-223 expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that overexpression of KLF6 attenuates and deficiency of KLF6 elevates miR-223 expression in macrophages. Furthermore, heightened miR-223 expression in KLF6-deficient macrophages significantly attenuates inducible proinflammatory gene expression. Concordantly, myeloid-Klf6 deficiency significantly curbs diet-induced adipose tissue inflammation, obesity, glucose intolerance, and insulin resistance. At the molecular level, KLF6 directly represses miR-223 expression by occupying its promoter region. More importantly, genetic inhibition of miR-223-3P in KLF6-deficient macrophages completely reversed attenuated proinflammatory gene expression in macrophages. Collectively, our studies reveal that KLF6 promotes proinflammatory gene expression and functions by repressing miR-223 expression in macrophages.-Kim, G.-D., Ng, H. P., Patel, N., Mahabeleshwar, G. H. Kruppel-like factor 6 and miR-223 signaling axis regulates macrophage-mediated inflammation.


Assuntos
Fator 6 Semelhante a Kruppel/metabolismo , Macrófagos/imunologia , MicroRNAs/genética , Obesidade/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Células Cultivadas , Feminino , Humanos , Imunidade Inata , Fator 6 Semelhante a Kruppel/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Células RAW 264.7
9.
J Biol Chem ; 291(40): 21271-21282, 2016 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-27539853

RESUMO

Macrophages are the predominant innate immune cells recruited to tissues following injury or infection. These early-responding, pro-inflammatory macrophages play an essential role in the amplification of inflammation. However, macrophage pro-inflammatory gene expression should be tightly regulated to avert host tissue damage. In this study, we identify the Kruppel-like transcription factor 6 (KLF6)-B cell leukemia/lymphoma 6 (BCL6) signaling axis as a novel regulator of macrophage inflammatory gene expression and function. Utilizing complementary gain- and loss-of-function studies, we observed that KLF6 is essential for macrophage motility under ex vivo and in vivo conditions. Concordant with these observations, myeloid-specific deficiency of KLF6 significantly attenuates macrophage pro-inflammatory gene expression, recruitment, and progression of inflammation. At the molecular level, KLF6 suppresses BCL6 mRNA and protein expression by elevating PR domain-containing 1 with ZNF domain (PRDM1) levels in macrophages. Interestingly, pharmacological or genetic inhibition of BCL6 in KLF6-deficient macrophages completely abrogated the attenuation of pro-inflammatory cytokine/chemokine expression and cellular motility. Collectively, our observations reveal that KLF6 repress BCL6 to enhance macrophage inflammatory gene expression and function.


Assuntos
Quimiocinas/biossíntese , Regulação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Macrófagos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Animais , Células Cultivadas , Quimiocinas/genética , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Macrófagos/patologia , Camundongos , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
J Cardiovasc Pharmacol ; 66(1): 108-17, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25815672

RESUMO

Consumption of omega-3 polyunsaturated fatty acid, particularly eicosapentaenoic acid (EPA), is associated with a significant reduction in the risk of developing cardiovascular disease. The aim of this study was to investigate whether heme oxygenase-1 (HO-1) induction contributes to the cytoprotective effects of EPA in endothelial cells threatened with oxidative damage. In this study, we investigated the effect of EPA on the induction of HO-1 by NF-E2-related factor 2 (Nrf2) in human umbilical vein endothelial cells. In cells treated with low concentrations of EPA (10-25 µM), HO-1 expression increased in a time- and concentration-dependent manner. Additionally, EPA treatment increased Nrf2 nuclear translocation and antioxidant response element activity, leading to the upregulation of HO-1 expression. Furthermore, treatment with EPA reduced hydrogen peroxide (H(2)O(2))-induced cell death. The reduction in cell death was reversed by treatment with zinc protoporphyrin, an inhibitor of HO-1, indicating that HO-1 contributed to the protective effect of EPA. These data suggest that EPA protects against H(2)O(2)-induced oxidative stress in endothelial cells by activating Nrf2 and inducting HO-1 expression.


Assuntos
Citoproteção/fisiologia , Ácido Eicosapentaenoico/farmacologia , Heme Oxigenase-1/fisiologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Citoproteção/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos
11.
Appl Microbiol Biotechnol ; 99(5): 2083-92, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25620368

RESUMO

Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) is a naturally occurring hydroxylated compound commonly found in species of the subfamily Nepetoideae of the Lamiaceae and Boraginaceae, such as Rosmarinus officinalis, Salvia officinalis, and Perilla frutescens. RA is biosynthesized from the amino acids L-phenylalanine and L-tyrosine by eight enzymes that include phenylalanine ammonia lyase and cinnamic acid 4-hydroxylase. RA can also be chemically produced by the esterification of caffeic acid and 3,4-dihydroxyphenyllactic acid. RA and its numerous derivatives containing one or two RA with other aromatic moieties are well known and include lithospermic acid, yunnaneic acid, salvianolic acid, and melitric acid. Recently, RA and its derivatives have attracted interest for their biological activities, which include anti-inflammatory, anti-oxidant, anti-angiogenic, anti-tumor, and anti-microbial functions. Clinically, RA attenuates T cell receptor-mediated signaling, attenuates allergic diseases like allergic rhinitis and asthma, and 2,4-dinitrofluorobenzene-induced atopic dermatitis-like symptoms, protects from neurotoxicity, and slows the development of Alzheimer's disease. These attributes have increased the demand for the biotechnological production and application of RA and its derivatives. The present review discusses the function and application of RA and its derivatives including the molecular mechanisms underlying clinical efficacy.


Assuntos
Vias Biossintéticas , Biotecnologia/métodos , Cinamatos/metabolismo , Depsídeos/metabolismo , Fatores Imunológicos/metabolismo , Cinamatos/síntese química , Depsídeos/síntese química , Fatores Imunológicos/química , Perilla frutescens/metabolismo , Rosmarinus/metabolismo , Salvia officinalis/metabolismo , Tecnologia Farmacêutica/métodos , Ácido Rosmarínico
12.
Food Funct ; 15(13): 6975-6987, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38853660

RESUMO

Atopic dermatitis (AD) is a chronic immune disease that requires long-term management owing to its relative ease of recurrence. However, steroid treatment is limited owing to the side effects. Therefore, research on therapeutics with proven safety is required. Here, we evaluated the anti-allergic activity of the probiotic strain Pediococcus pentosaceus KF159 (PPKF159) with an ex vivo mouse model sensitized with ovalbumin (OVA) and a mouse model of AD induced by house dust mites. Changes in pathological symptoms were confirmed based on the clinical status of the AD-induced lesion site and the levels of T helper type 2 (Th2)-derived cytokines and immunoglobulin E (IgE). In addition, cell-mediated responses and related mechanisms were elucidated using various kinds of primary cells including splenocytes, mesenteric lymph nodes, Peyer's patch, and bone marrow-derived dendritic cells (BMDCs) in vitro and ex vivo. Oral administration of PPKF159 alleviated AD-like clinical symptoms such as erythema, edema, hemorrhage, and increased tissue thickness, and suppressed the production of Th2-associated cytokines and serum IgE while increasing T helper type 1 (Th1)-mediated cytokine production. PPKF159 induced tolerogenic dendritic cells (tol-DCs) by increasing the expression of ICOS-L, PD-L1, and IDO which were closely related to Treg induction in PPKF159-treated BMDCs. In addition, BMDCs and naive T cells co-cultured in the presence of PPKF159 had elevated IL10 production and increased proportions of CD4+CD25+Foxp3+ Tregs compared to the absence of PPKF159. This study showed that PPKF159 relieved AD-like clinical symptoms, modulated the Th1/Th2 immune balance, and inhibited IgE production in a mouse AD model. PPKF159 induced the transformation of dendritic cells into tolerogenic versions. These induced tol-DCs directly enhanced the production of IL10 or improved the secretion of IL10 through the induction of CD4+CD25+Foxp3+ Treg cells, thereby improving AD. These results suggest that PPKF159 can be applied as a functional food material for the treatment and prevention of AD.


Assuntos
Dermatite Atópica , Pediococcus pentosaceus , Probióticos , Pyroglyphidae , Linfócitos T Reguladores , Animais , Feminino , Camundongos , Citocinas/metabolismo , Dermatite Atópica/imunologia , Modelos Animais de Doenças , Imunoglobulina E , Interleucina-10 , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Probióticos/administração & dosagem , Pyroglyphidae/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
13.
Antioxidants (Basel) ; 12(11)2023 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-38001869

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary condition characterized by the sudden onset of respiratory failure, pulmonary edema, dysfunction of endothelial and epithelial barriers, and the activation of inflammatory cascades. Despite the increasing number of deaths attributed to ARDS, a comprehensive therapeutic approach for managing patients with ARDS remains elusive. To elucidate the pathological mechanisms underlying ARDS, numerous studies have employed various preclinical models, often utilizing lipopolysaccharide as the ARDS inducer. Accumulating evidence emphasizes the pivotal role of reactive oxygen species (ROS) in the pathophysiology of ARDS. Both preclinical and clinical investigations have asserted the potential of antioxidants in ameliorating ARDS. This review focuses on various sources of ROS, including NADPH oxidase, uncoupled endothelial nitric oxide synthase, cytochrome P450, and xanthine oxidase, and provides a comprehensive overview of their roles in ARDS. Additionally, we discuss the potential of using antioxidants as a strategy for treating ARDS.

14.
Antioxidants (Basel) ; 12(8)2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37627586

RESUMO

Particulate matter (PM) induces and augments oxidative stress and inflammation, leading to respiratory diseases. Although Artemisia gmelinii Weber ex Stechm has antioxidant and anti-inflammatory effects, there are no reports on whether Artemisia gmelinii extract (AGE) regulates lung inflammation in a PM-induced model. Thus, we investigated the protective effects of AGE using a PM-induced mouse lung inflammation model. AGE significantly decreased the expression of inflammatory chemokines, neutrophil extracellular trap formation, and the total number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). Furthermore, AGE attenuated lung inflammation through the suppression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, while promoting the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway in lung tissues. Concordant with these observations, AGE suppressed inflammatory cytokines, chemokines, reactive oxygen species, NETosis, myeloperoxidase, and neutrophil elastase by decreasing the mRNA expression of High mobility group box 1, Runt-related transcription factor 1, and Kruppel-like factor 6 in differentiated HL-60 cells. In summary, our data demonstrated that AGE suppresses PM-induced neutrophil infiltration, lung damage, and pulmonary inflammation by suppressing NF-κB/MAPK signaling pathways and enhancing the NRF2/HO-1 signaling pathway. These findings suggest that AGE administration is an effective approach for preventing and treating PM-induced respiratory inflammation.

15.
J Microbiol Biotechnol ; 33(5): 634-643, 2023 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-36804255

RESUMO

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is caused by repeated exposure to harmful matter, such as cigarette smoke. Although Lilium longiflorum Thunb (LLT) has anti-inflammatory effects, there is no report on the fermented LLT bulb extract regulating lung inflammation in COPD. Thus, we investigated the protective effect of LLT bulb extract fermented with Lactobacillus acidophilus 803 in COPD mouse models induced by cigarette smoke extract (CSE) and porcine pancreas elastase (PPE). Oral administration of the fermented product (LS803) suppressed the production of inflammatory mediators and the infiltration of immune cells involving neutrophils and macrophages, resulting in protective effects against lung damage. In addition, LS803 inhibited CSE- and LPS-induced IL-6 and IL-8 production in airway epithelial H292 cells as well as suppressed PMA-induced formation of neutrophil extracellular traps in HL-60 cells. In particular, LS803 significantly repressed the elevated IL-6 and MIP-2 production after CSE and LPS stimulation by suppressing the activity of the nuclear factor kappa-light-chain-enhancer of activated B (NFκB) in mouse peritoneal macrophages. Therefore, our results suggest that the fermented product LS803 is effective in preventing and alleviating lung inflammation.


Assuntos
Lilium , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Animais , Camundongos , Lactobacillus acidophilus , Interleucina-6/farmacologia , Lipopolissacarídeos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , Pulmão , Inflamação/tratamento farmacológico , Pneumonia/complicações
16.
J Pineal Res ; 52(3): 356-64, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21951103

RESUMO

Cigarette smoke (CS) causes harmful alterations in the lungs and airway structures and functions that characterize chronic obstructive pulmonary disease (COPD). In addition to COPD, active cigarette smoking causes other respiratory diseases and diminishes health status. Furthermore, recent studies show that, α, ß-unsaturated aldehyde acrolein in CS induces the production of interleukin (IL)-8, which is known to be related to bronchitis, rhinitis, pulmonary fibrosis, and asthma. In addition, lung and pulmonary fibroblasts secrete IL-8, which has a chemotactic effect on leukocytes, and which in turn, play a critical role in lung inflammation. On the other hand, melatonin regulates circadian rhythm homeostasis in humans and has many other effects, which include antioxidant and anti-inflammatory effects, as demonstrated by the reduced expressions of iNOS, IL-1ß, and IL-6 and increased glutathione (GSH) and superoxide dismutase activities. In this study, we investigated whether melatonin suppresses acrolein-induced IL-8 secretion in human pulmonary fibroblasts (HPFs). It was found that acrolein-induced IL-8 production was accompanied by increased levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK1/2) in HPFs, and that melatonin suppressed IL-8 production in HPFs. These results suggest that melatonin suppresses acrolein-induced IL-8 production via ERK1/2 and phosphatidylinositol 3-kinase (PI3K)/Akt signal inhibition in HPFs.


Assuntos
Acroleína/toxicidade , Interleucina-8/biossíntese , Pulmão/metabolismo , Melatonina/fisiologia , Apoptose , Sequência de Bases , Western Blotting , Citocinas/metabolismo , Primers do DNA , Fibroblastos/patologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Antioxidants (Basel) ; 11(3)2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35326218

RESUMO

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease (COPD), and continuous CS exposure causes lung inflammation and deterioration. To investigate the protective effects of Artemisia gmelinii against lung inflammation in this study, cigarette smoke extract (CSE)/lipopolysaccharide (LPS)-treated alveolar macrophages (AMs) and mice stimulated with CSE/porcine pancreas elastase (PPE) were used. Artemisia gmelinii ethanol extract (AGE) was effective in decreasing the levels of cytokines, chemokine, inducible nitric oxide synthase, and cyclooxygenase-2 by inhibiting mitogen-activated protein (MAP) kinases/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in AMs. Additionally, oral administration of AGE suppressed inflammatory cells' infiltration and secretion of inflammatory cytokines, chemokines, matrix metallopeptidase 9, and neutrophil extracellular traps in bronchoalveolar lavage fluid from the COPD model. Moreover, the obstruction of small airways, the destruction of the lung parenchyma, and expression of IL-6, TNF-α, IL-1ß, and MIP-2 were suppressed by inhibiting NF-κB activation in the lung tissues of the AGE group. These effects are associated with scopolin, chlorogenic acid, hyperoside, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 4,5-di-O-caffeoylquinic acid, which are the main components of AGE. These data demonstrate the mitigation effect of AGE on lung inflammation via inhibition of MAPK and NF-κB pathways, suggesting that AGE may be instrumental in improving respiratory and lung health.

18.
Antioxidants (Basel) ; 11(9)2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36139757

RESUMO

Cigarette smoke (CS) is the major factor in the development of chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. Furthermore, although Camellia sinensis (CN) has been known as an anti-inflammatory material, the effect of CN has not yet been known on pulmonary inflammation in COPD. Thus, we investigated the protective effects of Camellia sinensis L. extract (CLE) against pulmonary inflammation in porcine pancreas elastase (PPE) and a cigarette smoke extract (CSE)-induced COPD mouse model. Oral administration of CLE suppressed the symptoms such as infiltration of immune cells, cytokines/chemokines secretion, mucus hypersecretion, and injuries of the lung parenchyma. Increased inflammatory responses in COPD are mediated by various immune cells such as airway epithelial cells, neutrophils, and alveolar macrophages. Thus, we investigated the effect and mechanisms of CLE in H292, HL-60, and MH-S cells. The CLE inhibited the expression of IL-6, IL-8, MUC5AC and MUC5B on CSE/LPS-stimulated H292 cells and also suppressed the formation of neutrophil extracellular traps and secretion of neutrophil elastase by inhibiting reactive oxygen species in PMA-induced HL-60 cells. In particular, the CLE suppressed the release of cytokines and chemokines caused by activating the nuclear factor kappa-light-chain-enhancer of activated B via the activation of nuclear factor erythroid-2-related factor 2 and the heme oxygenase-1 pathway in CSE/LPS-stimulated MH-S cells. Therefore, we suggest that the CLE administration be the effective approach for treating or preventing chronic pulmonary diseases such as COPD induced by CS.

19.
Exp Dermatol ; 20(2): 97-101, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21166725

RESUMO

Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen-free conditions, repeated epicutaneous treatment of 2-4-dinitrofluorobenzene (DNFB) evokes AD-like clinical symptoms in NC/Nga mice. α-Lipoic acid (α-LA; 1, 2-dithiolane-3-pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α-LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α-LA suppresses AD-like skin lesions induced by repeated DNFB application in NC/Nga mice. α-LA significantly suppressed production of interferon (IFN)-γ and interleukin (IL)-4 by activated CD4(+) T cells. We found that the oral administration of α-LA reduced AD-like clinical symptoms and inhibited increases of epidermal thickness in DNFB-induced AD-like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α-LA treatment. Our findings suggest that oral administration of α-LA suppresses the development of AD in DNFB-treated NC/Nga mice and reduces IFN-γ and IL-4 production from activated CD4(+) T cells as well as total serum IgE levels.


Assuntos
Antioxidantes/uso terapêutico , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dinitrofluorbenzeno/efeitos adversos , Ácido Tióctico/uso terapêutico , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/sangue , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Ácido Tióctico/administração & dosagem , Ácido Tióctico/farmacologia
20.
Antioxidants (Basel) ; 10(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34356353

RESUMO

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf-ERK1/2-Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

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