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1.
J Nanobiotechnology ; 22(1): 190, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637808

RESUMO

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.


Assuntos
Lesão Pulmonar Aguda , Plantas Medicinais , Pneumonia Viral , Pneumonia , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Mitocôndrias/patologia , Ácido gama-Aminobutírico/metabolismo , Pneumonia/metabolismo
2.
Toxicol Appl Pharmacol ; 485: 116908, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38513841

RESUMO

Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.


Assuntos
Acetilcisteína , Metabolismo Energético , Lesão Pulmonar , Mecloretamina , Estresse Oxidativo , Animais , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/farmacologia , Mecloretamina/toxicidade , Masculino , Metabolismo Energético/efeitos dos fármacos , Ratos , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Ratos Sprague-Dawley , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Substâncias para a Guerra Química/toxicidade
3.
Mol Nutr Food Res ; 68(5): e2300667, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38282089

RESUMO

SCOPE: Particulate matter (PM) contains toxic organic matter and heavy metals that enter the entire body through blood flow and may cause mortality. Ganoderma formosanum mycelium, a valuable traditional Chinese medicine that has been used since ancient times, contains various active ingredients that can effectively impede inflammatory responses on murine alveolar macrophages induced by PM particles. METHODS AND RESULTS: An experimental study assessing the effect of G. formosanum mycelium extract's water fraction (WA) on PM-exposed murine alveolar macrophages using ROS measurement shows that WA reduces intracellular ROS by 12% and increases cell viability by 16% when induced by PM particles. According to RNA-Sequencing, western blotting, and real-time qPCR are conducted to analyze the metabolic pathway. The WA reduces the protein ratio in p-NF-κB/NF-κB by 18% and decreases the expression of inflammatory genes, including IL-1ß by 38%, IL-6 by 29%, and TNF-α by 19%. Finally, the identification of seven types of anti-inflammatory compounds in the WA fraction is achieved through UHPLC-ESI-Orbitrap-Elite-MS/MS analysis. These compounds include anti-inflammatory compounds, namely thiamine, adenosine 5'-monophosphate, pipecolic acid, L-pyroglutamic acid, acetyl-L-carnitine, D-mannitol, and L-malic acid. CONCLUSIONS: The study suggests that the WA has the potential to alleviate the PM -induced damage in alveolar macrophages, demonstrating its anti-inflammatory properties.


Assuntos
Ganoderma , Macrófagos Alveolares , NF-kappa B , Camundongos , Animais , Macrófagos Alveolares/química , Macrófagos Alveolares/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Massas em Tandem , Material Particulado/toxicidade , Material Particulado/análise , Anti-Inflamatórios/farmacologia , Pulmão/química , Pulmão/metabolismo
4.
Phytomedicine ; 124: 155256, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38181527

RESUMO

BACKGROUND: Alveolar macrophages are one of the momentous regulators in pulmonary inflammatory responses, which can secrete extracellular vesicles (EVs) packing miRNAs. Ferroptosis, an iron-dependent cell death, is associated with cigarette smoke-induced lung injury, and EVs have been reported to regulate ferroptosis by transporting intracellular iron. However, the regulatory mechanism of alveolar macrophage-derived EVs has not been clearly illuminated in smoking-related pulmonary ferroptosis. Despite the known anti-ferroptosis effects of naringenin in lung injury, whether naringenin controls EVs-mediated ferroptosis has not yet been explored. PURPOSE: We explore the effects of EVs from cigarette smoke-stimulated alveolar macrophages in lung epithelial ferroptosis, and elucidate the EV miRNA-mediated pharmacological mechanism of naringenin. STUDY DESIGN AND METHODS: Differential and ultracentrifugation were conducted to extract EVs from different alveolar macrophages treatment groups in vitro. Both intratracheal instilled mice and treated epithelial cells were used to investigate the roles of EVs from alveolar macrophages involved in ferroptosis. Small RNA sequencing analysis was performed to distinguish altered miRNAs in EVs. The ferroptotic effects of EV miRNAs were examined by applying dual-Luciferase reporter assay and miRNA inhibitor transfection experiment. RESULTS: Here, we firstly reported that EVs from cigarette smoke extract-induced alveolar macrophages (CSE-EVs) provoked pulmonary epithelial ferroptosis. The ferroptosis inhibitor ferrostatin-1 treatment reversed these changes in vitro. Moreover, EVs from naringenin and CSE co-treated alveolar macrophages (CSE+Naringenin-EVs) markedly attenuated the lung epithelial ferroptosis compared with CSE-EVs. Notably, we identified miR-23a-3p as the most dramatically changed miRNA among Normal-EVs, CSE-EVs, and CSE+Naringenin-EVs. Further experimental investigation showed that ACSL4, a pro-ferroptotic gene leading to lipid peroxidation, was negatively regulated by miR-23a-3p. The inhibition of miR-23a-3p diminished the efficacy of CSE+Naringenin-EVs. CONCLUSION: Our findings firstly provided evidence that naringenin elevated the EV miR-23a-3p level from CSE-induced alveolar macrophages, thereby inhibiting the mouse lung epithelial ferroptosis via targeting ACSL4, and further complemented the mechanism of cigarette-induced lung injury and the protection of naringenin in a paracrine manner. The administration of miR-23a-3p-enriched EVs has the potential to ameliorate pulmonary ferroptosis.


Assuntos
Fumar Cigarros , Vesículas Extracelulares , Ferroptose , Flavanonas , Lesão Pulmonar , MicroRNAs , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Fumar Cigarros/efeitos adversos , Pulmão/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Ferro/metabolismo
5.
Front Immunol ; 14: 1274147, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38022527

RESUMO

Introduction: Phagocytosis of inhaled crystalline silica (cSiO2) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO2-triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO2-induced eicosanoids. Methods: We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction. Results: DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO2-induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO2 elicited marked IL-1α, IL-1ß, and TNF-α release after 1.5 and 4 h of cSiO2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO2-triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs. Discussion: FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO2-triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.


Assuntos
Ácidos Docosa-Hexaenoicos , Ácidos Graxos Ômega-3 , Camundongos , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Oxilipinas/farmacologia , Oxilipinas/metabolismo , Macrófagos Alveolares/metabolismo , Lipopolissacarídeos , Dióxido de Silício , Camundongos Endogâmicos C57BL , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/farmacologia , Ácido Araquidônico , Suplementos Nutricionais
6.
Chem Biodivers ; 20(11): e202300999, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37933979

RESUMO

Dendrobium officinale Kimura et Migo is a valuable and homologous medicine and food traditional Chinese medicine. Currently there are few studies on the anti-inflammatory activity of lipophilic components. The aim of this study was to explore the anti-inflammatory effect and mechanism of the lipophilic compounds in Dendrobium officinale. Six compounds were isolated and identified, including three bibenzyl compounds, dendrocandin U, dendronbibisline B, erianin, and three lignans, (-)-syringaresinol, (+)-syringaresinol-O-ß-D-glucopyranoside, 5-methoxy-(+)-isolariciresinol. Among them, dendronbibisline B and 5-methoxy-(+)-isolariciresinol were isolated from Dendrobium officinale for the first time. Besides, we found dendrocandin U, dendronbibisline B and (-)-syringaresinol exhibited the anti-inflammation to inhibit nitric oxide secretion induced by lipopolysaccharide (LPS)/interferon (IFN-γ) in MH-S cells. Furthermore, dendrocandin U could inhibit the expression of tumor necrosis factor-α (TNF-α), Cluster of Differentiation 86 (CD86), and reduce inflammatory morphological changes of macrophages. Meanwhile, we confirmed that the anti-inflammation mechanism of dendrocandin U was to inhibit M1 polarization by suppressing toll-like receptor 4 (TLR4)/recombinant myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. In this paper, dendrocandin U with significant anti-inflammatory activity was found from Dendrobium officinale, which could provide a basis for the study of its anti-inflammatory drugs.


Assuntos
Dendrobium , NF-kappa B , NF-kappa B/metabolismo , Macrófagos Alveolares/metabolismo , Transdução de Sinais , Anti-Inflamatórios/farmacologia
7.
Br J Pharmacol ; 180(8): 1056-1071, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36440573

RESUMO

BACKGROUND AND PURPOSE: Alveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti-inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)-induced asthma mouse model. EXPERIMENTAL APPROACH: The effects of CalD on AMs in contributing to anti-inflammatory effects in asthma were investigated through in vivo, ex vivo, and in vitro experiments. KEY RESULTS: CalD reduced total bronchoalveolar lavage fluid and differential cell count, serum IgE levels, mucus hypersecretion, and airway hyperresponsiveness in HDM-challenged mice. Additionally, CalD affected a wide array of pro-inflammatory cytokines and chemokines and oxidative damage markers in isolated lung tissues. CalD suppressed the HDM-induced increase in Arg1 (M2 macrophage marker) in AMs from lung tissue and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by reducing CD80 expression, reduced AM-derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4+ T-cells from asthma lung digest. CalD blocked the HDM-induced FoxO1/IRF4 pathway and restored impaired the Nrf2/HO-1 antioxidant pathway in lung tissues. CalD inhibited IL-4/IL-13-stimulated JAK1/STAT6 pathway, FoxO1 protein expression, and chemokine production in primary AMs. Structure-activity relationship study revealed the α,ß-unsaturated γ-butyrolactone in CalD is capable of forming covalent bonds with cellular protein targets essential for its action. CONCLUSION AND IMPLICATIONS: Our results demonstrate for the first time that CalD is a novel anti-inflammatory natural compound for allergic asthma that modulates AM function.


Assuntos
Asma , Diterpenos , Animais , Camundongos , Macrófagos Alveolares/metabolismo , Asma/tratamento farmacológico , Pulmão/metabolismo , Pyroglyphidae , Citocinas/metabolismo , Líquido da Lavagem Broncoalveolar , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C
8.
Phytomedicine ; 108: 154504, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36332388

RESUMO

BACKGROUND: Mycoplasma-associated pneumonia is characterized by severe lung inflammation and immunological dysfunction. However, current anti-mycoplasma agents used in clinical practice do not prevent dysfunction of alveolar macrophages caused by the high level of the cytokine tumor necrosis factor-α (TNF-α) after mycoplasma infection. Apigenin inhibits the production of TNF-α in variet inflammation associated disease. PURPOSE: This study aimed to investigate apigenin's effect on mycoplasma-induced alveolar immune cell injury and the mechanism by which it inhibits TNF-α transcription. METHODS: In this study, we performed a mouse model of Mycoplasma hyopneumoniae infection to evaluate the effect of apigenin on reducing mycoplasma-induced alveolar immune cell injury. Furthermore, we carried out transcriptome analysis, RNA interference assay, methylated DNA bisulfite sequencing assay, and chromatin immunoprecipitation assay to explore the mechanism of action for apigenin in reducing TNF-α. RESULTS: We discovered that M. hyopneumoniae infection-induced necroptosis in alveolar macrophages MH-S cells and primary mouse alveolar macrophages, which was activated by TNF-α autocrine. Apigenin inhibited M. hyopneumoniae-induced elevation of TNF-α and necroptosis in alveolar macrophages. Apigenin inhibited TNF-a mRNA production via increasing ubiquitin-like with PHD and RING finger domains 1 (Uhrf1)-dependent DNA methylation of the TNF-a promotor. Finally, we demonstrated that apigenin regulated Uhrf1 transcription via peroxisome proliferator activated receptor gamma (PPARγ) activation, which acts as a transcription factor binding to the Uhrf1 promoter and protected infected mice's lungs, and promoted alveolar macrophage survival. CONCLUTSION: This study identified a novel mechanism of action for apigenin in reducing alveolar macrophage necroptosis via the PPARγ/ Uhrf1/TNF-α pathway, which may have implications for the treatment of Mycoplasma pneumonia.


Assuntos
Macrófagos Alveolares , Mycoplasma , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Apigenina/farmacologia , Mycoplasma/metabolismo , Metilação , Necroptose , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
9.
Phytomedicine ; 107: 154474, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36194973

RESUMO

BACKGROUND: Impaired alveolar macrophages phagocytosis can contribute to pathogenesis of acute respiratory distress syndrome (ARDS) and negatively impacts clinical outcomes. Chlorogenic acid (CGA) is a naturally occurring polyphenolic compound with potential anti-inflammatory and antioxidant bioactivities. Studies have shown that CGA plays a protective role in ARDS, however, the precise protective mechanism of CGA against ARDS, is still unclear. PURPOSE: The aim of this study was to investigate whether CGA enhances alveolar macrophages phagocytosis to attenuate lung injury during ARDS. METHODS: RAW264.7 cells were stimulated with lipopolysaccharides (100 µg/ml for 24 h) and treated with CGA (100, 200, and 400 µM CGA for 1 h) to measure pro-inflammatory cytokine levels, GPR37 expression and macrophages phagocytosis. Mouse models of ARDS induced by cecal ligation and perforation (CLP) surgery were treated with CGA (100 or 200 mg/kg) to investigate lung inflammatory injury and alveolar macrophages phagocytosis. Computational modeling was performed to examine potential binding sites of G protein-coupled receptor 37 (GPR37) with CGA, and the results were validated by interfering with the binding sites. RESULT: In vitro, CGA notably ameliorated inflammatory response and increased phagocytosis in lipopolysaccharides-induced RAW264.7 cells. In vivo, CGA administration significantly alleviated lung inflammatory injury, decreased the bacteria load in the lung, promoted alveolar macrophages phagocytosis and improved the survival rate in mice with CLP-induced ARDS. Moreover, CGA markedly upregulated the expression of GPR37 in vivo and in vitro. However, the protective effect of CGA against ARDS were reversed after silencing the expression of GPR37. CONCLUSION: CGA has a protective effect against ARDS and may enhance alveolar macrophages phagocytosis and attenuate lung inflammatory injury by upregulating GPR37 expression.


Assuntos
Lesão Pulmonar , Síndrome do Desconforto Respiratório , Animais , Antioxidantes/farmacologia , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Lesão Pulmonar/tratamento farmacológico , Macrófagos Alveolares/metabolismo , Camundongos , Fagocitose , Receptores Acoplados a Proteínas G/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico
10.
J Ethnopharmacol ; 297: 115568, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-35868548

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zukamu Granules (ZKMG) is one of the representative Uygur patent drugs widely used in China, which is included in the National Essential Drugs List (2018 edition). As the first choice for common cold treatment in Uygur medicine theory, it has unique anti-inflammatory and antitussive efficacy. AIM OF THE STUDY: According to the recent inflammatory hypothesis, the abnormal proliferation, autophagy and apoptosis process of lung cells especially alveolar macrophages (AMs) may play an important role in the progress of idiopathic pulmonary fibrosis (IPF). Therefore, we came up with a novel treatment approach for IPF by regulating the balance of AMs "autophagy - apoptosis", and took ZKMG as the sample drug for our research. MATERIALS AND METHODS: Network pharmacology approach was conducted to predict the active components and intersected targets between ZKMG and inflammation. PPI network, GO and KEGG enrichment analysis were screened and analyzed to predict the anti-inflammatory mechanism of ZKMG. Biological experiment adopted from 128 rats, and hematoxylin-eosin staining, flow cytometry and RT-PCR were performed to examine the pathological morphology, HYP contents in lung tissue, AMs counting, AMs apoptosis, AMs phagocytosis rate, mRNA relative quantity determination of 3 key factors associated with AMs "autophagy - apoptosis" and mRNA relative quantity determination of AMs surface receptor signaling pathway. RESULTS: The predicted results showed that the mechanism of ZKMG in anti-inflammatory was related to the response and elimination of inflammatory stimuli, the intervention of apoptosis and surface receptor signaling pathways of cells. The verification experiments showed that excessive apoptosis and insufficient autophagy of AMs always existed in the progression of IPF. ZKMG could inhibit AMs proliferation, significantly reduce AMs apoptosis rate, intervene the binding of the Bcl-2 to Beclin 1, inhibit the Caspase 3 activation, stimulate the enhancement of AMs phagocytosis, and inhibit the high expression of TLR4/MyD88/NF-κB surface receptor signaling pathway, which may partly retard the fibrosis process. CONCLUSION: By inhibiting proliferation, enhancing phagocytosis, inhibiting the formation of Bcl-2 complex, and inhibiting the high expression of MYD88-dependent TLR4 signaling pathway, ZKMG can regulate the balance of AMs "autophagy - apoptosis" in the alveolitis stage to retard the fibrosis process partly. With a comprehensive strategy of "target prediction - experimental verification", we have demonstrated that inhibiting the apoptosis and promoting autophagy activity of AMs may suggest a new perspective for IPF treatment, which would provide reference for the subsequent development.


Assuntos
Fibrose Pulmonar Idiopática , Macrófagos Alveolares , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose , Autofagia , Fibrose , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Macrófagos Alveolares/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptor 4 Toll-Like/metabolismo
11.
Pharmacol Res Perspect ; 9(5): e00873, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34632734

RESUMO

We hypothesized whether propofol or active propofol component (2,6-diisopropylphenol [DIPPH] and lipid excipient [LIP-EXC]) separately may alter inflammatory mediators expressed by macrophages and neutrophils in lean and obese rats. Male Wistar rats (n = 10) were randomly assigned to receive a standard (lean) or obesity-inducing diet (obese) for 12 weeks. Animals were euthanized, and alveolar macrophages and neutrophils from lean and obese animals were exposed to propofol (50 µM), active propofol component (50 µM, 2,6-DIPPH), and lipid excipient (soybean oil, purified egg phospholipid, and glycerol) for 1 h. The primary outcome was IL-6 expression after propofol and its components exposure by alveolar macrophages extracted from bronchoalveolar lavage fluid. The secondary outcomes were the production of mediators released by macrophages from adipose tissue, and neutrophils from lung and adipose tissues, and neutrophil migration. IL-6 increased after the exposure to both propofol (median [interquartile range] 4.14[1.95-5.20]; p = .04) and its active component (2,6-DIPPH) (4.09[1.67-5.91]; p = .04) in alveolar macrophages from obese animals. However, only 2,6-DIPPH increased IL-10 expression (7.59[6.28-12.95]; p = .001) in adipose tissue-derived macrophages. Additionally, 2,6-DIPPH increased C-X-C chemokine receptor 2 and 4 (CXCR2 and CXCR4, respectively) in lung (10.08[8.23-29.01]; p = .02; 1.55[1.49-3.43]; p = .02) and adipose tissues (8.78[4.15-11.57]; p = .03; 2.86[2.17-3.71]; p = .01), as well as improved lung-derived neutrophil migration (28.00[-3.42 to 45.07]; p = .001). In obesity, the active component of propofol affected both the M1 and M2 markers as well as neutrophils in both alveolar and adipose tissue cells, suggesting that lipid excipient may hinder the effects of active propofol.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Excipientes/farmacologia , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Obesidade/metabolismo , Propofol/farmacologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Quimiotaxia de Leucócito/efeitos dos fármacos , Glicerol/farmacologia , Interleucina-10/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Neutrófilos/metabolismo , Fosfolipídeos/farmacologia , Ratos , Receptores CXCR4/efeitos dos fármacos , Receptores CXCR4/metabolismo , Receptores de Interleucina-8B/efeitos dos fármacos , Receptores de Interleucina-8B/metabolismo , Óleo de Soja/farmacologia
12.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502407

RESUMO

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a successful intracellular pathogen that is responsible for the highest mortality rate among diseases caused by bacterial infections. During early interaction with the host innate cells, M. tuberculosis cell surface antigens interact with Toll like receptor 4 (TLR4) to activate the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) canonical, and non-canonical inflammasome pathways. NLRP3 inflammasome activation in the alveoli has been reported to contribute to the early inflammatory response that is needed for an effective anti-TB response through production of pro-inflammatory cytokines, including those of the Interleukin 1 (IL1) family. However, overstimulation of the alveolar NLRP3 inflammasomes can induce excessive inflammation that is pathological to the host. Several studies have explored the use of medicinal plants and/or their active derivatives to inhibit excessive stimulation of the inflammasomes and its associated factors, thus reducing immunopathological response in the host. This review describes the molecular mechanism of the NLRP3 inflammasome activation in the alveoli during M. tuberculosis infection. Furthermore, the mechanisms of inflammasome inhibition using medicinal plant and their derivatives will also be explored, thus offering a novel perspective on the alternative control strategies of M. tuberculosis-induced immunopathology.


Assuntos
Macrófagos Alveolares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tuberculose/tratamento farmacológico , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação , Interleucina-1beta/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Plantas Medicinais , Alvéolos Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Tuberculose/metabolismo
13.
J Tradit Chin Med ; 40(6): 917-921, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33258342

RESUMO

OBJECTIVE: To establish an in vitro model of radiation-induced lung injury using rat lung alveolar macrophages (NR8383). METHODS: Using a medical electronic linear accelerator, cells were irradiated with either 0 Gy or 6 Gy X-rays. At 6, 12, 24, 30 and 48 h, the DNA damage index (8-OHdG) and lipid damage index (MDA) were measured in the two groups. We also determined the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor-ß (TGF-ß). RESULTS: The levels of 8-OHdG and MDA in the 6 Gy irradiation group were higher than those in the 0 Gy group at 6, 12, 24, 30 and 48 h after irradiation. The levels reached the highest value -6 h after irradiation, and then gradually decreased. The levels of the inflammatory factors TNF-α, TGF-ß and IL-6 were higher in the 6 Gy irradiation group than those in the 0 Gy group at 6, 12, 24, 30 and 48 h after irradiation. CONCLUSION: Six Gy X-ray irradiated NR8383 cells can be used to establish an in-vitro model of radiation-induced lung injury. The levels of 8-OHdG, MDA, TNF-α, TGF-ß and IL-6 can be used as effective evaluation indicators.


Assuntos
Lesão Pulmonar/etiologia , Macrófagos Alveolares/efeitos da radiação , Neoplasias/radioterapia , Lesões por Radiação/metabolismo , Radioterapia/efeitos adversos , Animais , Linhagem Celular , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Macrófagos Alveolares/metabolismo , Modelos Biológicos , Lesões por Radiação/etiologia , Lesões por Radiação/genética , Radiação Ionizante , Ratos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
J Ethnopharmacol ; 263: 113152, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32755652

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sojadodamgangki-tang (SDG) is a traditional East-Asian herbal medicine mainly composed of Pinellia ternate (Thunb.) Makino, Perilla frutescens (L.) Britt and 10 kinds of medicinal herbs. It has been used to treat asthma and mucus secretion including lung and bronchi. AIM OF THE STUDY: The aim of this study was to investigate the anti-inflammatory effects of Sojadodamgangki-tang (SDG) on allergic lung inflammation in vitro and in vivo as well as the underlying mechanisms. MATERIALS AND METHODS: We used an ovalbumin (OVA)-induced murine allergic airway inflammation model. Five groups of 8-week-old female BALB/C mice were divided into the following groups: saline control group, the vehicle (allergic) group that received OVA only, groups that received OVA and SDG (200 mg/kg or 400 mg/kg), and a positive control group that received OVA and Dexamethasone (5 mg/kg). In vitro experiments include T helper 2 (TH2) polarization system, murine macrophage cell culture, and human bronchial epithelial cell line (BEAS-2B) culture. RESULTS: SDG administration reduced allergic airway inflammatory cell infiltration, especially of eosinophils, mucus production, Th2 cell activation, OVA-specific immunoglobulin E (IgE), and total IgE production. Moreover, the activation of alveolar macrophages, which leads to immune tolerance in the steady state, was promoted by SDG treatment. Interestingly, SDG treatment also reduced the production of alarmin cytokines by the human bronchial epithelial cell line BEAS-2B stimulated with urban particulate matter. CONCLUSION: Our findings indicate that SDG has potential as a therapeutic drug to inhibit Th2 cell activation and promote alveolar macrophage activation.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Antiasmáticos/isolamento & purificação , Antiasmáticos/farmacologia , Asma/induzido quimicamente , Asma/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Perilla , Pinellia , Células Th2/metabolismo
15.
Life Sci ; 259: 118285, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798556

RESUMO

AIMS: Interleukin-1ß (IL-1ß) contributes to the development of bronchopulmonary dysplasia (BPD). Thioredoxin reductase-1 (Txnrd1) inhibition activates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent responses. Txnrd1 activity is selenium (Se) dependent and Se deficiency is common in prematurity. Auranofin (AFN), a Txnrd1 inhibitor, decreases IL-1ß levels and increases Nrf2 activation in lipopolysaccharide (LPS) treated alveolar macrophages. In lung epithelia, AFN-induced Nrf2 activation is Se dependent. We tested the hypothesis that the effects of Txnrd1 inhibition in alveolar macrophages are Se dependent. MAIN METHODS: To establish Se sufficient (Se+) and deficient (Se-) conditions, alveolar (MH-S) macrophages were cultured in 2.5% fetal bovine serum (FBS) ± 25 nM Na2SeO3. Se- (2.5% FBS) and Se+ (2.5% FBS + 25 nM Na2SeO3) cells were cultured in the presence or absence of 0.05 µg/mL LPS and/or 0.5 µM AFN. Nrf2 activation was determined by measuring NADPH quinone oxidoreductase-1 (Nqo1) and glutathione levels. IL-1ß mRNA (Il1b) and protein levels were measured using qRT-PCR and ELISA. Data were analyzed by ANOVA followed by Tukey's post-hoc. KEY FINDINGS: We detected an independent effect of AFN, but not LPS, on Nqo1 expression and GSH levels in Se+ and Se- cells. LPS significantly increased Il1b and IL-1ß levels in both groups. AFN-mediated attenuation of this effect was not impacted by Se status. SIGNIFICANCE: The beneficial effects of Txnrd1 inhibition in alveolar macrophages are Se-independent and therefore unlikely to be diminished by clinical Se deficiency.


Assuntos
Auranofina/farmacologia , Macrófagos Alveolares/metabolismo , Tiorredoxina Redutase 1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Auranofina/metabolismo , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Glutationa/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Macrófagos/metabolismo , Macrófagos Alveolares/fisiologia , Camundongos , Cultura Primária de Células , Selênio/metabolismo , Selênio/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo
16.
J Transl Med ; 17(1): 304, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488203

RESUMO

BACKGROUND: Infection by antibiotic-resistant microorganisms is common in intensive care units and has become a global problem. Here, we determined the effect of aryl hydrocarbon receptor (AhR) stimulation on antibiotics-induced systemic defense impairment and its mechanisms. METHODS: C57BL/6 wild-type (WT) mice received combined antibiotics with or without Ahr ligands (tryptophan and indole), or dead Lactobacillus plantarum supplementation. The defense mechanisms against Pseudomonas aeruginosa infection in the lung were examined. RESULTS: Antibiotic treatments decreased the phagocytic activity, physiological activity, and the peroxynitrite production of alveolar macrophage (AMs). It also enhanced P. aeruginosa pneumonia-induced bacterial counts in the lung. Tryptophan and dead L. plantarum supplementation reversed antibiotic-induced intracellular adhesion molecule (ICAM) as well as IL-6 expression, and increased P. aeruginosa pneumonia-induced bacterial counts in the lung and increased phagocytic activity and peroxynitrite production of AMs. Moreover, these treatments reversed the antibiotics-induced reduction of Ahr expression, antibacterial proteins, reactive oxygen species (ROS) production, and NF-κB DNA binding activity of the intestinal mucosa and plasma IL-6 levels. P. aeruginosa counts increased and phagocytic activity of AMs and myeloperoxidase (MPO) activity decreased in intestinal IKKß depleted mice. Antibiotics, antibiotic with tryptophan feeding, or antibiotic with dead L. plantarum feeding treatments did not change the phagocytic activity and peroxynitrite production of AMs, plasma IL-6 levels, and the expression of Ahr of intestine in intestinal IKKß depleted mice. CONCLUSION: Antibiotic treatment impairs lung immune defenses by decreasing Ahr expression in the intestine and peroyxnitrite production of the AMs. Ahr ligands reverses antibiotic-induced lung defense against bacterial infection through intestinal ROS production and NF-κB activation. The gut is critical in maintaining lung defense mechanism through the intestinal IKKß pathways.


Assuntos
Quinase I-kappa B/metabolismo , Intestinos/fisiologia , Pulmão/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Administração Oral , Animais , Antibacterianos/farmacologia , Contagem de Colônia Microbiana , Indóis/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Lactobacillus plantarum/fisiologia , Ligantes , Pulmão/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Ácido Peroxinitroso/metabolismo , Fagocitose/efeitos dos fármacos , Pneumonia/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Triptofano/administração & dosagem , Triptofano/farmacologia
17.
J Nat Prod ; 82(4): 1002-1008, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30892032

RESUMO

Imperatorin is one of the furanocoumarin derivatives and exists in many medicinal herbs with anticancer, antiviral, antibacterial, and antihypertensive activities. In this study, we examined the anti-inflammatory effects of imperatorin on inflammation-associated lung diseases. Imperatorin reduced iNOS and COX-2 expression and also IL-6 and TNFα production enhanced by zymosan. Imperatorin also inhibited the signaling pathways of JAK/STAT and NF-κB. Moreover, in vivo study also revealed that zymosan-induced immune cell infiltration, pulmonary fibrosis, and edema were relieved by imperatorin in mice. We found that imperatorin exerts anti-inflammatory effects that are associated with amelioration of lung inflammation, edema, and rapid fibrosis. Studies on alveolar macrophages also reveal that imperatorin reduced the production of pro-inflammatory mediators and cytokines and inhibited pro-inflammatory JAK1/STAT3 and NF-κB signaling pathways. These results indicate that imperatorin may be a potential anti-inflammatory agent for inflammatory-associated lung diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Furocumarinas/farmacologia , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Animais , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Camundongos
18.
Allergy ; 74(1): 100-110, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29888398

RESUMO

BACKGROUND: There is an increasing interest in targeted application of probiotic bacteria for prevention and treatment of airway diseases, including allergies. Here, we investigated the beneficial effects of preventive intranasal treatment with probiotics Lactobacillus rhamnosus GG and L. rhamnosus GR-1 in a mouse model of allergic asthma. METHODS: Lactobacillus rhamnosus was administered intranasally eight times on days 1-4 and 8-11 at 5 × 108  CFU/dose, followed by a 2-week asthma induction protocol with birch pollen extract on alternating days. Effects of preventive treatment were analyzed based on serum antibody levels, bronchoalveolar lavage cell counts, lung histology, lung cytokine levels, and airway hyperreactivity. Colonization and translocation of L. rhamnosus were assessed by bacterial cell counts in nasal mucosa, fecal samples, cervical lymph nodes, and blood. Binding of fluorescent L. rhamnosus to fixed murine nasal mucosal cells and airway macrophages was visualized by fluorescence microscopy. RESULTS: Transient colonization of the murine upper airways by L. rhamnosus GG was demonstrated and was approximately ten times higher compared to L. rhamnosus GR-1. Marked binding of fluorescent L. rhamnosus GG to murine nasal mucosal cells and airway macrophages was visualized. Preventive treatment with L. rhamnosus GG (but not L. rhamnosus GR-1) resulted in a significant decrease in bronchoalveolar lavage eosinophil counts, lung interleukin-13 and interleukin-5 levels, and airway hyperreactivity. A tendency toward a decrease in serum Bet v 1-specific immunoglobulin G1 was likewise observed. CONCLUSION: Intranasally administered L. rhamnosus GG prevents the development of cardinal features of birch pollen-induced allergic asthma in a strain-specific manner.


Assuntos
Asma/prevenção & controle , Lactobacillus/citologia , Probióticos/uso terapêutico , Administração Intranasal , Animais , Asma/imunologia , Aderência Bacteriana , Betula/imunologia , Modelos Animais de Doenças , Macrófagos Alveolares/metabolismo , Camundongos , Mucosa Nasal/metabolismo , Pólen/imunologia , Especificidade da Espécie
19.
Int J Pharm ; 551(1-2): 212-222, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30227240

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and poor prognosis. Curcumin shows anti-inflammatory effect by suppressing pro-inflammatory cytokines and inhibiting NF-κB mediated inflammation. Here, we developed inhalable curcumin-loaded poly(lactic-co-glycolic)acid (PLGA) large porous microparticles (LPMPs) for the treatment of IPF. Curcumin LPMPs were rough and loose particles with many pores on the surfaces and channels in the inner spaces. The mean geometric diameter of them was larger than 10 µm while the aerodynamic diameter was only 3.12 µm due to their porous structures. They showed a fine particle fraction (FPF) <4.46 µm of 13.41%, 71% cumulative release after 9 h, and more importantly, they avoided uptake by alveolar macrophages. Therefore, most of released curcumin had opportunities to enter lung tissues. Rat pulmonary fibrosis models were established via once intratracheal administration of bleomycin. Curcumin powders and curcumin LPMPs were administered on Days 2, 7, 14, and 21. Curcumin LPMPs remarkably attenuated lung injuries, decreased hydroxyproline contents, reduced the synthesis of collagen I, and inhibited the expressions of TNF-α, TGF-ß1, NF-κB p65 and MMP9. Moreover, curcumin LPMPs showed higher antifibrotic activity than curcumin powders. Curcumin LPMPs are a promising inhalable medication for the treatment of IPF.


Assuntos
Curcumina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Administração por Inalação , Animais , Colágeno Tipo I/metabolismo , Curcumina/química , Hidroxiprolina/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Porosidade , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Nat Commun ; 9(1): 3333, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127354

RESUMO

Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.


Assuntos
Interações Hospedeiro-Patógeno , Ferro/metabolismo , Pulmão/microbiologia , Macrófagos Alveolares/metabolismo , Rhizopus/fisiologia , Animais , Parede Celular/metabolismo , Regulação da Expressão Gênica , Macrófagos Alveolares/ultraestrutura , Melaninas/metabolismo , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Modelos Biológicos , Mucormicose/genética , Mucormicose/microbiologia , Mucormicose/patologia , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Rhizopus/crescimento & desenvolvimento , Esporos Fúngicos/fisiologia
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