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1.
Life Sci ; 236: 116864, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518607

RESUMO

AIMS: To elucidate the role of alveolar macrophages (AM) in the pathogenesis of hypoxic pulmonary hypertension (HPH), we tested the effects of sustained hypoxia on AM polarization and on the formation of superoxide by AM in vivo and in vitro. MAIN METHODS: Rat AM were obtained by bronchoalveolar lavage. 4-day exposure to hypoxia (10% O2) was carried out in vivo (rats in isobaric hypoxic chamber, controls kept in air) or in vitro (control AM in 21% O2 and 5% CO2). Superoxide production was measured by luminol-orthovanadate chemiluminescence, AM polarization was detected immunocytochemically. To ascertain the effect of substances contained in the alveolar environment, we cultivated cells also in the presence of non-cellular components of the bronchoalveolar lavage fluid (BALF) either from controls or from rats exposed to 4 days of hypoxia. KEY FINDINGS: In vivo, but not in vitro, hypoxia increased AM superoxide production. Both types of hypoxia polarized AM into M2 (pro-proliferative) type. While the presence of control BALF attenuated superoxide production in AM cultivated in normoxia, BALF from the hypoxia-exposed rats had no effect. In AM cultivated in hypoxia, superoxide production was not altered by control BALF and elevated by BALF obtained from hypoxic rats. SIGNIFICANCE: Hypoxia does not influence superoxide production by AM directly but rather by modulating their milieu and their sensitivity to external influences.


Assuntos
Hipóxia/fisiopatologia , Macrófagos Alveolares/patologia , Superóxidos/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Células Cultivadas , Macrófagos Alveolares/metabolismo , Masculino , Ratos , Ratos Wistar
2.
Gene ; 721: 144095, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476403

RESUMO

Penehyclidine hydrochloride (PHC) is a novel anticholinergic drug applied broadly in surgeries as a preanesthetic medication. A substantial amount of research indicates that PHC has lung defensive properties. Considering that endoplasmic reticulum (ER) stress exerts a crucial function in cell apoptosis associated with the lipopolysaccharides (LPS)-induced acute lung injury (ALI) model, we aimed to determine whether regulation of ER stress in the LPS-induced ALI model was associated with the lung defensive role of PHC. Adult male SD rats were administered LPS (5 mg/kg, intratracheally) followed by PHC (1.0 mg/kg, intravenously) for 24 h. The NR8383 alveolar macrophages were randomly separated into Sham, LPS (100 ng/mL), and PHC (1, 2.5, or 5 µg/mL) + LPS groups. PHC (1, 2.5, or 5 µg/mL) + LPS groups were treated with PHC alone for 1 h after LPS exposure. Posttreatment with PHC relieved LPS-induced pulmonary impairment and blocked LPS-mediated lung apoptosis, indicated by the downregulation of the lung apoptotic indicators malondialdehyde and superoxide dismutase in serum at 24 h after LPS-induced ALI. PHC (1-5 µg/mL) did not influence the activity of cultivated NR8383 alveolar macrophages in vitro. However, postconditioning with PHC dosage-dependently reduced LPS-mediated cell apoptosis. Additionally, many studies have indicated that PHC administration inhibits ER stress and initiates hairy and enhancer of split 1 (Hes1)/(Notch1) signaling by decreasing phosphorylated α subunit of eukaryotic initiation factor 2α (p-eIF2α)/eukaryotic translation initiation factor 2α (eIF2α) and Phospho-protein kinase R-like ER kinase (p-PERK)/ protein kinase R-like ER kinase (PERK) proportions; inhibiting C/EBP-homologous protein (CHOP), activating transcription factor 4 (ATF4), caspase-3, and Bcl2-associated x (Bax) activity; and enhancing notch1 intracellular domain (NICD), Notch1, B-cell lymphoma-2 (Bcl-2), and Hes1 activity in vivo and in vitro. In addition, the defensive functions of PHC on LPS-activated NR8383 alveolar macrophages were abrogated through the Notch1 pathway antagonist [(3,5-difluorophenacetyl)-1-alanyl] -phenylglycine-butyl ester (DAPT). In conclusion, PHC alleviates LPS-induced ALI by ameliorating ER stress-mediated apoptosis and promoting Hes1/Notch1 signaling in vivo and in vitro.


Assuntos
Lesão Pulmonar Aguda , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hialuronan Sintases/metabolismo , Lipopolissacarídeos/toxicidade , Quinuclidinas/farmacologia , Receptor Notch1/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
3.
Redox Biol ; 26: 101307, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31473487

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury.


Assuntos
Canais de Cálcio/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Adulto , Idoso , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/metabolismo , Consumo de Oxigênio , Fenótipo , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Int J Mol Med ; 44(4): 1309-1324, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432098

RESUMO

Sepsis is a highly heterogeneous syndrome that is caused by a dysregulated host response to infection. The disproportionate inflammatory response to invasive infection is a triggering event inducing sepsis. The activation of inflammasomes in sepsis can amplify inflammatory responses. It has been reported that damaged mitochondria contribute to NACHT, LRR and PYD domains­containing protein 3 (NLRP3) inflammasome­related sepsis. Our previous study revealed that hydrogen (H2) exerts anti­inflammatory effects in sepsis but the detailed mechanism remains to be elucidated. In the present study, septic mice induced by cecal ligation and puncture (CLP) and macrophages induced by lipopolysaccharide (LPS) were used as models of sepsis in vivo and in vitro, respectively. An inducer and inhibitor of autophagy and the NLRP3 inflammasome were administered to investigate the detailed mechanism of action of H2 treatment in sepsis. The results demonstrated that LPS and ATP led to NLRP3 inflammasome pathway activation, excessive cytokine release, mitochondrial dysfunction and the activation of autophagy. CLP induced organ injury and NLRP3 pathway activation. H2 treatment ameliorated vital organ damage, the inflammatory response, mitochondrial dysfunction and NLRP3 pathway activation, and promoted autophagy in macrophages induced by LPS and in CLP mice. However, the inhibitor of autophagy and the inducer of NLRP3 reversed the protective effect of H2 against organ damage, the inflammatory response and mitochondrial dysfunction in vivo and in vitro. Collectively, the results demonstrated that H2 alleviated mitochondrial dysfunction and cytokine release via autophagy­mediated NLRP3 inflammasome inactivation.


Assuntos
Autofagia , Hidrogênio/metabolismo , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/metabolismo , Animais , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Macrófagos Alveolares/ultraestrutura , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Sepse/diagnóstico , Sepse/etiologia , Sepse/mortalidade
5.
Biomed Pharmacother ; 118: 109230, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351434

RESUMO

Pulmonary fibrosis is a chronic and progressive interstitial lung disease of known and unknown etiology. Over the past decades, macrophages have been recognized to play a significant role in IPF pathogenesis. According to their anatomical loci, macrophages can be divided to alveolar macrophages (AMs) subtypes and interstitial macrophages subtypes (IMs) with different responsibility in the damage defense response. Depending on diverse chemokines and cytokines in local microenvironments, macrophages can be induced and polarized to either classically activated (M1) or alternatively activated (M2) phenotypes in different stages of immunity. Therefore, we hypothesize that there is a "phagocytosis-secretion-immunization" network regulation of pulmonary macrophages related to a number of chemokines and cytokines. In this paper, we summarize and discuss the role of chemokines and cytokines involved in the "phagocytosis-secretion-immunization" network regulation mechanism of pulmonary macrophages, pointing toward novel therapeutic approaches based on the network target regulation in the field. Therapeutic strategies focused on modifying the chemokines, cytokines and the network are promising for the pharmacotherapy of IPF. Some Traditional Chinese medicines may have more superiorities in delaying the progression of pulmonary fibrosis for their multi-target activities of this network regulation.


Assuntos
Imunização , Macrófagos Alveolares/patologia , Fagocitose , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/terapia , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos
6.
EBioMedicine ; 45: 563-577, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31278070

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and/or obstructive bronchiolitis. Deficiency in vitamin D3 (VD3), which regulates gene expression through binding to vitamin D receptor (VDR), is associated with high risks of COPD susceptibility. Alveolar macrophages (AM), which are generated during early ontogeny and maintained in alveoli by self-renewal in response to cytokine GM-CSF, are positively correlated with severity of emphysema. However, whether and how VD3, VDR and AM interact to contribute to COPD pathogenesis at the molecular and cellular levels are largely unknown. METHODS: We used systems biology approaches to analyze gene expression in mouse macrophages from different tissues to identify key transcription factors (TF) for AM and infer COPD disease genes. We used RNA-seq and ChIP-seq to identify genes that are regulated by VD3 in AM. We used VDR-deficient (Vdr-/-) mice to investigate the role of VD3-VDR axis in the pathogenesis of COPD and characterized the transcriptional and functional alterations of Vdr-/- AM. FINDINGS: We find that VDR is a key TF for AM and a COPD disease gene. VDR is highly expressed in AM and in response to VD3 inhibits GM-CSF-induced AM proliferation. In Vdr-/- AM, genes involved in proliferation and immune response are upregulated. Consistently, Vdr-/- mice progressively accumulate AM and concomitantly develop emphysema without apparent infiltration of immune cells into the lung tissue. Intratracheal transfer of Vdr-/- AM into wildtype mice readily induces emphysema. The production of reactive oxygen species at basal level and in response to heme or lipopolysaccharide is elevated in Vdr-/- AM and suppressed by VD3 in wildtype AM. INTERPRETATION: These results show that the VD3-VDR axis is critical to counteract GM-CSF-induced AM proliferation and defect in this regulation leads to altered AM homeostasis and function. Our findings identify that VD3 deficiency contributes to emphysema by altering AM function without contributing to bronchiolitis. Our findings also suggest possibilities of modulating the VD3-VDR axis for inhibiting emphysema in COPD patients.


Assuntos
Colecalciferol/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Receptores de Calcitriol/genética , Animais , Proliferação de Células/genética , Regulação da Expressão Gênica/genética , Homeostase/genética , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Ligação Proteica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Transdução de Sinais
7.
Nanotoxicology ; 13(2): 143-159, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31111787

RESUMO

Functionalization of multi-walled carbon nanotubes (MWCNT) is known to affect the biological response (e.g. toxicity, inflammation) in vitro and in vivo. However, the reasons for these changes in vivo are not well described. This study examined the degree of MWCNT functionalization with regard to in vivo mouse lung distribution, particle retention, and resulting pathology. A commercially available MWCNT (source MWCNT) was functionalized (f-MWCNT) by systematically varying the degree of carboxylation on the particle's surface. Following a pilot study using seven variants, two f-MWCNT variants were chosen and for lung pathology and particle distribution using oropharyngeal aspiration administration of MWCNT in Balb/c mice. Particle distribution in the lung was examined at 7 and 28 days post-instillation by bright-field microscopy, CytoViva hyperspectral dark-field imaging, and Stimulated Raman Scattering (SRS) microscopy. Examination of the lung tissue by bright-field microscopy showed some acute inflammation for all MWCNT that was highest with source MWCNT. Hyperspectral imaging and SRS were employed to assess the changes in particle deposition and retention. Highly functionalized MWCNT had a higher lung burden and were more disperse. They also appeared to be associated more with epithelial cells compared to the source and less functionalized MWCNT that were mostly interacting with alveolar macrophages (AM). These results showing a slightly reduced pathology despite the extended deposition have implications for the engineering of safer MWCNT and may establish a practical use as a targeted delivery system.


Assuntos
Pulmão/efeitos dos fármacos , Nanotubos de Carbono/química , Nanotubos de Carbono/toxicidade , Pneumonia/induzido quimicamente , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Exposição por Inalação , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/metabolismo , Pneumonia/patologia , Propriedades de Superfície , Distribuição Tecidual
8.
Cell Tissue Res ; 378(1): 97-111, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31037357

RESUMO

Patients suffering from severe acute pancreatitis (AP) can develop acute lung injury (ALI) with poor outcomes and the mechanisms involved remain incompletely understood. Pulmonary intravascular macrophages (PIMs), which are credited as promoters of ALI, are not constitutively present in humans and rodents; however, there is evidence of PIM recruitment in rodents during some pathological conditions, such as hepatic diseases. Therefore, this study assesses PIM recruitment in the lungs of a mouse model of acute necrotizing pancreatitis (ANP) induced with L-arginine monohydrochloride. Mice were euthanized after 24 h, 72 h and 120 h. Control mice received sham injections of saline. Pancreatic histopathological grading and plasma amylase were used to confirm the development of ANP in L-arginine-treated mice. Histopathological grading of lungs from the ANP mice at 72 h showed increased mononuclear phagocytes in alveolar septa, compared to that from the controls. Lungs from the ANP mice also showed increased numbers of CD68-immunopositive alveolar septal macrophages, suggestive of PIM recruitment, compared to those from the controls. Lungs from the ANP mice showed increased expression of IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1) and von Willebrand factor compared to those from the controls. The recruitment of CD68-positive septal macrophages was not observed in MCP-1 knockout mice with ANP at 72 h when compared to C57BL/6 wild-type mice. Taken together, we developed a mouse model of PIM recruitment dependent on MCP-1 that allows us to explore their roles in ANP-associated ALI.


Assuntos
Ativação de Macrófagos , Macrófagos Alveolares , Pancreatite Necrosante Aguda/imunologia , Pneumonia/imunologia , Animais , Modelos Animais de Doenças , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pancreatite Necrosante Aguda/patologia , Pneumonia/patologia
9.
Respir Res ; 20(1): 65, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940135

RESUMO

BACKGROUND: Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. METHODS: We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. RESULTS: The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. CONCLUSIONS: Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis.


Assuntos
Perfilação da Expressão Gênica/métodos , Macrófagos Alveolares/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/metabolismo , Análise de Sequência de RNA/métodos , Estudos de Coortes , Seguimentos , Humanos , Estudos Longitudinais , Macrófagos Alveolares/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia
10.
Arch Virol ; 164(5): 1323-1334, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877450

RESUMO

Porcine circovirus type 2 (PCV2) is the essential infectious agent causing porcine circovirus-associated disease (PCVD) in pigs and one of the important viruses that severely jeopardize the swine husbandry industry. PCV2 elicits the unfolded protein response (UPR) via activation of the PERK pathway, and its capsid protein (Cap) has also been found to induce UPR with subsequent activation of apoptosis. The open reading frame 5 (ORF5) protein is a recently discovered non-structural protein, and its function in PCV2 pathogenesis remains unknown. The aim of this study was to determine whether the PCV2 ORF5 protein could induce endoplasmic reticulum stress (ERS) and UPR in porcine alveolar macrophages (PAMs). pEGFP-tagged ORF5 protein was transiently overexpressed in PAMs. Transmission electron microscopy (TEM) was employed to examine changes in ER morphology, and quantitative real-time PCR and western blotting analysis were used to measure UPR-related cell signaling alterations. We found that the ORF5 protein triggers swelling and degranulation of the ER and upregulates the expression of ERS markers. Further experiments demonstrated that the PCV2 ORF5 protein induces ERS and UPR via the PERK (RNA-activated protein kinase-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6) and IRE1 (inositol requiring enzyme 1) signaling pathways. Together with previous studies, we provide new information on the ERS-UPR induced by the PCV2 ORF5 protein.


Assuntos
Circovirus/genética , Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático/ultraestrutura , Macrófagos Alveolares/patologia , Resposta a Proteínas não Dobradas/genética , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Linhagem Celular , Infecções por Circoviridae/patologia , Infecções por Circoviridae/veterinária , Retículo Endoplasmático/virologia , Endorribonucleases/metabolismo , Macrófagos Alveolares/virologia , Microscopia Eletrônica de Transmissão , Suínos , Doenças dos Suínos , Proteínas do Envelope Viral/metabolismo , eIF-2 Quinase/metabolismo
11.
Infect Immun ; 87(5)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30833339

RESUMO

Human Q fever is caused by the intracellular bacterial pathogen Coxiella burnetii Q fever presents with acute flu-like and pulmonary symptoms or can progress to chronic, severe endocarditis. After human inhalation, C. burnetii is engulfed by alveolar macrophages and transits through the phagolysosomal maturation pathway, resisting the acidic pH of lysosomes to form a parasitophorous vacuole (PV) in which to replicate. Previous studies showed that C. burnetii replicates efficiently in primary human alveolar macrophages (hAMs) in ex vivo human lung tissue. Although C. burnetii replicates in most cell types in vitro, the pathogen does not grow in non-hAM cells of human lung tissue. In this study, we investigated the interaction between C. burnetii and other pulmonary cell types apart from the lung environment. C. burnetii formed a prototypical PV and replicated efficiently in human pulmonary fibroblasts and in airway, but not alveolar, epithelial cells. Atypical PV expansion in alveolar epithelial cells was attributed in part to defective recruitment of autophagy-related proteins. Further assessment of the C. burnetii growth niche showed that macrophages mounted a robust interleukin 8 (IL-8), neutrophil-attracting response to C. burnetii and ultimately shifted to an M2-polarized phenotype characteristic of anti-inflammatory macrophages. Considering our findings together, this study provides further clarity on the unique C. burnetii-lung dynamic during early stages of human acute Q fever.


Assuntos
Coxiella burnetii/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Febre Q/imunologia , Febre Q/fisiopatologia , Humanos , Macrófagos Alveolares/microbiologia , Febre Q/microbiologia
13.
Nanotoxicology ; 13(3): 354-368, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30704318

RESUMO

Nanomaterials are widely used in an ever-increasing number of consumer and industrial products. It is therefore essential that the toxic effects of nanomaterials are understood in order to improve product safety. Here we evaluate the toxicity of inhaled halloysite nanotubes (HNTs) by applying a purpose designed inhalation exposure system and succeed in suppressing HNTs toxicity using trehalose. By assessing apoptosis, oxidative stress, inflammatory response, and autophagy, it is found that HNTs can cause sub-chronic toxicity in mice. Further investigations indicate that HNTs induce autophagy blockade that results in the accumulation of sequestosome-1 (p62), which is responsible for the excessive apoptosis, inflammatory response and oxidative stress. We found that p62 can be eliminated by trehalose and the application of trehalose in vitro and in vivo successfully inhibits toxicity by accelerating the clearance of p62. Trehalose shows great potential for reducing nanoparticle toxicity.


Assuntos
Autofagia/efeitos dos fármacos , Argila/química , Nanotubos/toxicidade , Proteína Sequestossoma-1/metabolismo , Trealose/farmacologia , Animais , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Relação Dose-Resposta a Droga , Exposição por Inalação/efeitos adversos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Nanotubos/química , Estresse Oxidativo/efeitos dos fármacos
14.
Am J Physiol Lung Cell Mol Physiol ; 316(4): L669-L678, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30702343

RESUMO

Smoking alters pulmonary reverse lipid transport and leads to intracellular lipid accumulation in alveolar macrophages. We investigated whether stimulating reverse lipid transport with an agonist of the liver X receptor (LXR) would help alveolar macrophages limit lipid accumulation and dampen lung inflammation in response to cigarette smoke. Mice were exposed to cigarette smoke and treated intraperitoneally with the LXR agonist T0901317. Expression of lipid capture and lipid export genes was assessed in lung tissue and alveolar macrophages. Pulmonary inflammation was assessed in the bronchoalveolar lavage (BAL). Finally, cholesterol efflux capacity and pulmonary surfactant levels were determined. In room air-exposed mice, T0901317 increased the expression of lipid export genes in macrophages and the whole lung and increased cholesterol efflux capacity without inducing inflammation or affecting the pulmonary surfactant. However, cigarette smoke-exposed mice treated with T0901317 showed a marked increase in BAL neutrophils, IL-1α, C-C motif chemokine ligand 2, and granulocyte-colony-stimulating factor levels. T0901317 treatment in cigarette smoke-exposed mice failed to increase the ability of alveolar macrophages to export cholesterol and markedly exacerbated IL-1α release. Finally, T0901317 led to pulmonary surfactant depletion only in cigarette smoke-exposed mice. This study shows that hyperactivation of LXR and the associated lipid capture/export mechanisms only have minor pulmonary effects on the normal lung. However, in the context of cigarette smoke exposure, where the pulmonary surfactant is constantly oxidized, hyperactivation of LXR has dramatic adverse effects, once again showing the central role of lipid homeostasis in the pulmonary response to cigarette smoke exposure.


Assuntos
Receptores X do Fígado/agonistas , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Surfactantes Pulmonares/metabolismo , Fumaça/efeitos adversos , Tabaco/toxicidade , Animais , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , Fumar Cigarros/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Sulfonamidas/farmacologia
15.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30787149

RESUMO

Alveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-γ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-γ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-γ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-γ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-γ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-γ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-γ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-γ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-γ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-γ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections.


Assuntos
Vírus da Influenza A/metabolismo , Macrófagos Alveolares/metabolismo , Infecções por Orthomyxoviridae/metabolismo , PPAR gama/biossíntese , Pneumonia Viral/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sinciciais Respiratórios/metabolismo , Animais , Regulação da Expressão Gênica , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Inflamação/virologia , Macrófagos Alveolares/patologia , Macrófagos Alveolares/virologia , Camundongos , Camundongos Knockout , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , PPAR gama/genética , Pneumonia Viral/genética , Pneumonia Viral/patologia , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/patologia
16.
Toxicol Appl Pharmacol ; 366: 10-16, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653976

RESUMO

Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis.


Assuntos
Bleomicina , Citocinas/metabolismo , Fibroblastos/enzimologia , Pulmão/enzimologia , Macrófagos Alveolares/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Fibrose Pulmonar/enzimologia , Animais , Linhagem Celular , Movimento Celular , Técnicas de Cocultura , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Fibroblastos/patologia , Pulmão/patologia , Macrófagos Alveolares/patologia , Camundongos Endogâmicos ICR , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais , Fatores de Tempo
17.
PLoS Pathog ; 15(1): e1007560, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682165

RESUMO

Bacterial lung infections, particularly with methicillin-resistant Staphylococcus aureus (MRSA), increase mortality following influenza infection, but the mechanisms remain unclear. Here we show that expression of TLR9, a microbial DNA sensor, is increased in murine lung macrophages, dendritic cells, CD8+ T cells and epithelial cells post-influenza infection. TLR9-/- mice did not show differences in handling influenza nor MRSA infection alone. However, TLR9-/- mice have improved survival and bacterial clearance in the lung post-influenza and MRSA dual infection, with no difference in viral load during dual infection. We demonstrate that TLR9 is upregulated on macrophages even when they are not themselves infected, suggesting that TLR9 upregulation is related to soluble mediators. We rule out a role for elevations in interferon-γ (IFNγ) in mediating the beneficial MRSA clearance in TLR9-/- mice. While macrophages from WT and TLR9-/- mice show similar phagocytosis and bacterial killing to MRSA alone, following influenza infection, there is a marked upregulation of scavenger receptor A and MRSA phagocytosis as well as inducible nitric oxide synthase (Inos) and improved bacterial killing that is specific to TLR9-deficient cells. Bone marrow transplant chimera experiments and in vitro experiments using TLR9 antagonists suggest TLR9 expression on non-hematopoietic cells, rather than the macrophages themselves, is important for regulating myeloid cell function. Interestingly, improved bacterial clearance post-dual infection was restricted to MRSA, as there was no difference in the clearance of Streptococcus pneumoniae. Taken together these data show a surprising inhibitory role for TLR9 signaling in mediating clearance of MRSA that manifests following influenza infection.


Assuntos
Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Humanos , Influenza Humana/imunologia , Pulmão/imunologia , Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Fagocitose , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Receptor Toll-Like 9/genética
18.
Am J Physiol Lung Cell Mol Physiol ; 316(4): L608-L620, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30675803

RESUMO

Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4+CD28- and CD8+CD28- T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.


Assuntos
Envelhecimento/imunologia , Envelhecimento/patologia , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/patologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Desmosina/metabolismo , Modelos Animais de Doenças , Elastina/administração & dosagem , Elastina/metabolismo , Feminino , Inflamação/imunologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/patologia , Proteólise , Enfisema Pulmonar/etiologia
19.
Immunopharmacol Immunotoxicol ; 41(3): 370-379, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30442050

RESUMO

Lung cancer continues to be the leading cause of cancer deaths and more than one million lung cancer patients will die every year worldwide. Radiotherapy (RT) plays an important role in lung cancer treatment, but the side effects of RT are pneumonitis and pulmonary fibrosis. RT-induced lung injury causes damage to alveolar-epithelial cells and vascular endothelial cells. Macrophages play an important role in the development of pulmonary fibrosis despite its role in immune response. These injury activated macrophages develop into classically activated M1 macrophage or alternative activated M2 macrophage. It secretes cytokines, interleukins, interferons, and nitric oxide. Several pro-inflammatory lipids and pro-apoptotic proteins cause lipotoxicity such as LDL, FC, DAG, and FFA. The overall findings in this review conclude the importance of macrophages in inducing toxic/inflammatory effects during RT of lung cancer, which is clinically vital to treat the radiation-induced fibrosis.


Assuntos
Metabolismo dos Lipídeos , Neoplasias Pulmonares , Macrófagos Alveolares , Alvéolos Pulmonares , Fibrose Pulmonar , Pneumonite por Radiação , Animais , Citocinas/imunologia , Humanos , Metabolismo dos Lipídeos/imunologia , Metabolismo dos Lipídeos/efeitos da radiação , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Óxido Nítrico/imunologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/lesões , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Pneumonite por Radiação/imunologia , Pneumonite por Radiação/patologia , Radioterapia/efeitos adversos
20.
Proc Natl Acad Sci U S A ; 115(51): 13057-13062, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30510003

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has generally been considered a non-Th2-type lung disorder, characterized by progressive airflow limitation with inflammation and emphysema, but its cellular and molecular mechanism remains ill defined, compared with that of asthma characterized by reversible airway obstruction. Here we show a previously unappreciated role for basophils at the initiation phase of emphysema formation in an elastase-induced murine model of COPD in that basophils represent less than 1% of lung-infiltrating cells. Intranasal elastase instillation elicited the recruitment of monocytes to the lung, followed by differentiation into interstitial macrophages (IMs) but rarely alveolar macrophages (AMs). Matrix metalloproteinase-12 (MMP-12) contributing to emphysema formation was highly expressed by IMs rather than AMs, in contrast to the prevailing assumption. Experiments using a series of genetically engineered mice suggested that basophil-derived IL-4, a Th2 cytokine, acted on lung-infiltrating monocytes to promote their differentiation into MMP-12-producing IMs that resulted in the destruction of alveolar walls and led to emphysema development. Indeed, mice deficient for IL-4 only in basophils failed to generate pathogenic MMP-12-producing IMs and hence develop emphysema. Thus, the basophil-derived IL-4/monocyte-derived IM/MMP-12 axis plays a crucial role in emphysema formation and therefore may be a potential target to slow down emphysema progression at the initiation phase of COPD.


Assuntos
Basófilos/patologia , Interleucina-4/metabolismo , Macrófagos Alveolares/patologia , Macrófagos/patologia , Metaloproteinase 12 da Matriz/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/etiologia , Animais , Basófilos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neutrófilos , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia
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