RESUMO
Comparisons of infectivity among the clinically important nontuberculous mycobacteria (NTM) species have not been explored in great depth. Rapid-growing mycobacteria, including Mycobacterium abscessus and M. porcinum, can cause indolent but progressive lung disease. Slow-growing members of the M. avium complex are the most common group of NTM to cause lung disease, and molecular approaches can now distinguish between several distinct species of M. avium complex including M. intracellulare, M. avium, M. marseillense, and M. chimaera. Differential infectivity among these NTM species may, in part, account for differences in clinical outcomes and response to treatment; thus, knowing the relative infectivity of particular isolates could increase prognostication accuracy and enhance personalized treatment. Using human macrophages, we investigated the infectivity and virulence of nine NTM species, as well as multiple isolates of the same species. We also assessed their capacity to evade killing by the antibacterial peptide cathelicidin (LL-37). We discovered that the ability of different NTM species to infect macrophages varied among the species and among isolates of the same species. Our biochemical assays implicate modified phospholipids, which may include a phosphatidylinositol or cardiolipin backbone, as candidate antagonists of LL-37 antibacterial activity. The high variation in infectivity and virulence of NTM strains suggests that more detailed microbiological and biochemical characterizations are necessary to increase our knowledge of NTM pathogenesis.
Assuntos
Peptídeos Catiônicos Antimicrobianos/antagonistas & inibidores , Evasão da Resposta Imune/fisiologia , Lipídeos de Membrana/fisiologia , Micobactérias não Tuberculosas/patogenicidade , Fosfolipídeos/fisiologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Membrana Celular/imunologia , Cromatografia em Camada Fina , Escherichia coli/efeitos dos fármacos , Humanos , Macrófagos/microbiologia , Macrófagos Alveolares/microbiologia , Lipídeos de Membrana/isolamento & purificação , Micobactérias não Tuberculosas/efeitos dos fármacos , Micobactérias não Tuberculosas/fisiologia , Fosfolipídeos/isolamento & purificação , Filogenia , Especificidade da Espécie , Células THP-1 , Virulência , CatelicidinasRESUMO
Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
Assuntos
Pulmão/imunologia , Mucina-5B/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Animais , Asma/imunologia , Asma/metabolismo , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Cílios/fisiologia , Orelha Média/imunologia , Orelha Média/microbiologia , Feminino , Inflamação/patologia , Pulmão/metabolismo , Pulmão/microbiologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Mucina-5AC/deficiência , Mucina-5AC/metabolismo , Mucina-5B/deficiência , Mucina-5B/genética , Fagocitose , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Staphylococcus aureus/imunologia , Análise de SobrevidaRESUMO
RATIONALE: Lymphocytic alveolitis in HIV-1-infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8(+) T cells in the lung, its exact cause is unknown. OBJECTIVES: To determine if HIV-1-specific T cells are associated with lymphocytic alveolitis in HIV-1-infected individuals. METHODS: Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and untreated HIV-1-infected individuals, we examined the frequency and functional capacity of HIV-1-specific T cells. MEASUREMENTS AND MAIN RESULTS: We found that HIV-1-specific T cells were significantly elevated in the BAL compared with blood of HIV-1-infected individuals and strongly correlated with T-cell alveolitis. Expression of Ki67, a marker of in vivo proliferation, was significantly reduced on HIV-1-specific T cells in BAL compared with blood, suggesting a diminished proliferative capacity. In addition, HIV-1-specific CD4(+) and CD8(+) T cells in BAL had higher expression of programmed death 1 (PD-1) and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood. A strong correlation between PD-1, but not CTLA-4, and HIV-1-specific T-cell proliferation was seen, and blockade of the PD-1/PD-L1 pathway augmented HIV-1-specific T-cell proliferation, suggesting that the PD-1 pathway was the main cause of reduced proliferation in the lung. CONCLUSIONS: These findings suggest that alveolitis associated with HIV-1 infection is caused by the recruitment of HIV-1-specific CD4(+) and CD8(+) T cells to the lung. These antigen-specific T cells display an impaired proliferative capacity that is caused by increased expression of PD-1.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/imunologia , HIV-1/imunologia , Pneumopatias/virologia , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/virologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Citometria de Fluxo , Imunofluorescência , Antígenos HIV/imunologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Pulmão/imunologia , Pulmão/virologia , Pneumopatias/imunologia , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1/metabolismoRESUMO
RATIONALE: Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear. OBJECTIVES: We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects. METHODS: Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38). MEASUREMENTS AND MAIN RESULTS: Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects. CONCLUSIONS: The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.
Assuntos
Líquido da Lavagem Broncoalveolar/microbiologia , Infecções por HIV/microbiologia , Pulmão/microbiologia , Microbiota , Boca/microbiologia , Adulto , Terapia Antirretroviral de Alta Atividade , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
RATIONALE: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome. OBJECTIVES: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort. METHODS: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome. MEASUREMENTS AND MAIN RESULTS: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not. CONCLUSIONS: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.
Assuntos
Metagenoma , Sistema Respiratório/microbiologia , Fumar , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar/microbiologia , Estudos de Coortes , Feminino , Humanos , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Boca/microbiologia , Estudos Prospectivos , Valores de Referência , Análise de Sequência de DNA/métodos , Adulto JovemRESUMO
RATIONALE: Lung infections caused by opportunistic or virulent pathogens are a principal cause of morbidity and mortality in HIV infection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in individuals infected with HIV. OBJECTIVES: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. METHODS: We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage (BAL) and mouths of 82 HIV-positive and 77 HIV-negative subjects. MEASUREMENTS AND MAIN RESULTS: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple's disease, were significantly more frequent in BAL of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects, but only 1 HIV-negative individual (13.4 versus 1.3%; P = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on eight BAL samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lung-derived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple's disease. CONCLUSIONS: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.
Assuntos
Infecções por HIV/complicações , Pulmão/microbiologia , Tropheryma , Doença de Whipple/complicações , Doença de Whipple/microbiologia , Estudos de Coortes , Humanos , Estudos LongitudinaisRESUMO
Although reduced bioavailability of nitric oxide (NO) has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), its consequences on organellar structure and function within vascular cells is largely unexplored. We investigated the effect of reduced NO on the structure of the Golgi apparatus as assayed by giantin or GM130 immunofluorescence in human pulmonary arterial endothelial (HPAECs) and smooth muscle (HPASMCs) cells, bovine PAECs, and human EA.hy926 endothelial cells. Golgi structure was also investigated in cells in tissue sections of pulmonary vascular lesions in idiopathic PAH (IPAH) and in macaques infected with a chimeric simian immunodeficiency virus containing the human immunodeficiency virus (HIV)-nef gene (SHIV-nef) with subcellular three-dimensional (3D) immunoimaging. Compounds with NO scavenging activity including 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), methylene blue, N-acetylcysteine, and hemoglobin markedly fragmented the Golgi in all cell types evaluated as did monocrotaline pyrrole, while LY-83583, sildenafil, fasudil, Y-27632, Tiron, Tempol, or H(2)O(2) did not. Golgi fragmentation by NO scavengers was inhibited by diethylamine NONOate, was evident in HPAECs after selective knockdown of endothelial nitric oxide synthase using small interfering RNA (siRNA), was independent of microtubule organization, required the GTPase dynamin 2, and was accompanied by depletion of α-soluble N-ethylmaleimide-sensitive factor (NSF) acceptor protein (α-SNAP) from Golgi membranes and codispersal of the SNAP receptor (SNARE) Vti1a with giantin. Golgi fragmentation was confirmed in endothelial and smooth muscle cells in pulmonary arterial lesions in IPAH and the SHIV-nef-infected macaque with subcellular 3D immunoimaging. In SHIV-nef-infected macaques Golgi fragmentation was observed in cells containing HIV-nef-bearing endosomes. The observed Golgi fragmentation suggests that NO plays a significant role in modulating global protein trafficking patterns that contribute to changes in the cell surface landscape and functional signaling in vascular cells.
Assuntos
Endotélio Vascular/metabolismo , Complexo de Golgi/metabolismo , Óxido Nítrico/metabolismo , Animais , Bovinos , Linhagem Celular , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipertensão Pulmonar Primária Familiar , Sequestradores de Radicais Livres/metabolismo , Complexo de Golgi/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Macaca/metabolismo , Macaca/fisiologia , Macaca/virologia , Microtúbulos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genéticaRESUMO
BACKGROUND: Accelerated cardiovascular disease in patients with type I diabetes (TID) is a well-described condition and serious clinical obstacle. At present, the notion that early atherogenesis is largely dependent on sustained hyperglycemia remains in question. We hypothesize that an alteration in T lymphocyte homeostasis may result in early vascular inflammation, which might amplify subsequent blood vessel injury in euglycemia. METHODS: A murine model of carotid arterial ligation was employed to induce neointimal hyperplasia (NIH) in C57/Bl6 (non-autoimmune) and non-obese diabetic (NOD) mice. Additionally, adoptive transfer of NOD splenocytes into immunodeficient NOD mice (NOD.scid) was undertaken to evaluate the influence of restored autoimmunity on NIH development. RESULTS: Interestingly, compared with C57/Bl6 mice, the NOD demonstrate a significant increase in neointimal area. Conversely, the NOD.scid mice (immunodeficient control) reveal almost no evidence of vascular injury. While evidence of early vascular inflammation can be detected in the injured NOD vasculature, uninjured contralateral vessels and those of the NOD.scid have minimal T cell infiltration. Following reconstitution of autoimmune responses via NOD splenocyte adoptive transfer, accelerated vascular pathology is restored. CONCLUSIONS: These observations suggest that autoimmunity, in the setting of impending hyperglycemia, may contribute to accelerated vascular inflammation and subsequent pathology.
Assuntos
Doenças das Artérias Carótidas/imunologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/imunologia , Linfócitos T/fisiologia , Transferência Adotiva , Animais , Contagem de Linfócito CD4 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neointima/imunologia , Baço/imunologiaRESUMO
Diversity-focused committees continue to play essential roles in the efforts of professional scientific societies to foster inclusion and facilitate the professional development of underrepresented minority (URM) young scientists in their respective scientific disciplines. Until recently, the efforts of these committees have remained independent and disconnected from one another. Funding from the National Science Foundation has allowed several of these committees to come together and form the Alliance to Catalyze Change for Equity in STEM Success, herein referred to as ACCESS. The overall goal of this meta-organization is to create a community in which diversity-focused committees can interact, synergize, share their collective experiences, and have a unified voice on behalf of URM trainees in science, technology, engineering, and mathematics disciplines. In this Essay, we compare and contrast the broad approaches that scientific societies in ACCESS use to implement and assess their travel award programs for URM trainees. We also report a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.
Assuntos
Distinções e Prêmios , Sociedades Científicas , Engenharia , Meio Ambiente , ViagemRESUMO
Scientific societies aiming to foster inclusion of scientists from underrepresented (UR) backgrounds among their membership often delegate primary responsibility for this goal to a diversity-focused committee. The National Science Foundation has funded the creation of the Alliance to Catalyze Change for Equity in STEM Success (ACCESS), a meta-organization bringing together representatives from several such STEM society committees to serve as a hub for a growing community of practice. Our goal is to coordinate efforts to advance inclusive practices by sharing experiences and making synergistic discoveries about what works. ACCESS has analyzed the approaches by which member societies have sought to ensure inclusivity through selection of annual meeting speakers. Here we discuss how inclusive speaker selection fosters better scientific environments for all and identify challenges and promising practices for societies striving to maximize inclusivity of speakers in their scientific programming.
Assuntos
Diversidade Cultural , Pesquisadores/ética , Sociedades Científicas/tendências , Demografia , Humanos , Sociedades Científicas/ética , Fala/éticaRESUMO
Pulmonary Arterial Hypertension (PAH) is overrepresented in People Living with Human Immunodeficiency Virus (PLWH). HIV protein gp120 plays a key role in the pathogenesis of HIV-PAH. Genetic changes in HIV gp120 determine viral interactions with chemokine receptors; specifically, HIV-X4 viruses interact with CXCR4 while HIV-R5 interact with CCR5 co-receptors. Herein, we leveraged banked samples from patients enrolled in the NIH Lung HIV studies and used bioinformatic analyses to investigate whether signature sequences in HIV-gp120 that predict tropism also predict PAH. Further biological assays were conducted in pulmonary endothelial cells in vitro and in HIV-transgenic rats. We found that significantly more persons living with HIV-PAH harbor HIV-X4 variants. Multiple HIV models showed that recombinant gp120-X4 as well as infectious HIV-X4 remarkably increase arachidonate 5-lipoxygenase (ALOX5) expression. ALOX5 is essential for the production of leukotrienes; we confirmed that leukotriene levels are increased in bronchoalveolar lavage fluid of HIV-infected patients. This is the first report associating HIV-gp120 genotype to a pulmonary disease phenotype, as we uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Altogether, our results allude to the supplementation of antiretroviral therapy with ALOX5 antagonists to rescue patients with HIV-X4 variants from fatal PAH.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Infecções por HIV/complicações , HIV-1/genética , Pulmão/metabolismo , Hipertensão Arterial Pulmonar/complicações , Tropismo Viral/genética , Adulto , Animais , Fármacos Anti-HIV/uso terapêutico , Células Cultivadas , Estudos de Coortes , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Genótipo , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Hipertensão Arterial Pulmonar/virologia , Artéria Pulmonar/citologia , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Receptores CXCR4/metabolismoRESUMO
Golgi dysfunction has been previously investigated as a mechanism involved in monocrotaline-induced pulmonary hypertension (PAH). In the present study, we addressed whether Golgi dysfunction might occur in pulmonary vascular cells in idiopathic PAH (IPAH) and whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH. Quantitative immunostaining for the Golgi tethers giantin and p115 on human lung tissue from patients with IPAH (n = 6) compared with controls demonstrated a marked cytoplasmic dispersal of giantin- and p115-bearing vesicular elements in vascular cells in the proliferative, obliterative, and plexiform lesions in IPAH and an increase in the amounts of these Golgi tethers/matrix proteins per cell. The causality question was approached by genetic means using human immunodeficiency virus (HIV)-Nef, a protein that disrupts endocytic and trans-Golgi trafficking. Macaques infected with a chimeric simian immunodeficiency virus (SIV) containing the HIV-nef gene (SHIV-nef), but not the nonchimeric SIV virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Giantin and p115 levels and their subcellular distribution in pulmonary vascular cells in lungs of SHIV-nef infected macaques (n = 4) were compared with SIV-infected (n = 3) and an uninfected macaque control. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and an increase in giantin and p115. Specifically, the HIV-Nef-positive cells showed increased giantin, p115, and the activated transcription factor PY-STAT3. These data represent the first test of the Golgi dysfunction hypothesis in IPAH and place trafficking and Golgi disruption in the chain of causality of pulmonary vasculopathies in the macaque model.
Assuntos
Endotélio Vascular/patologia , Produtos do Gene nef/fisiologia , Complexo de Golgi/patologia , Hipertensão Pulmonar/patologia , Macaca/virologia , Artéria Pulmonar/patologia , Doenças Vasculares/patologia , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Imunofluorescência , Complexo de Golgi/metabolismo , Proteínas da Matriz do Complexo de Golgi , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Hipertensão Pulmonar/metabolismo , Proteínas de Membrana/metabolismo , Artéria Pulmonar/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/isolamento & purificação , Doenças Vasculares/metabolismoRESUMO
The pathogenesis of cardiovascular disease in the setting of type 1 diabetes is not well-defined. The hypothesis that hyperglycemia is largely responsible for vascular endothelial dysfunction, and ultimately atherosclerosis, continues to evolve. However, despite tight glucose control, a subset of patients still develop clinically significant occlusive disease. While the specific mechanisms of persistent vascular injury are not clear, an increasing body of evidence suggests a dysregulated autoimmune response may contribute to the development of vascular injury. That is, the same inflammatory response that is responsible for pancreatic beta-cell destruction may facilitate chronic vascular endothelial injury prior to the onset of hyperglycemia. Herein, we discuss (1) the clinical experience with tight glycemic control and the risk of cardiovascular disease in patients with type 1 diabetes; (2) the cellular mechanisms involved in vascular endothelial injury; and (3) the long-term clinical implications of autoimmune-mediated vascular disease and current treatment strategies.
Assuntos
Aterosclerose/etiologia , Autoimunidade , Endotélio Vascular/fisiopatologia , Hiperglicemia/complicações , Estresse Oxidativo , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/metabolismo , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Humanos , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Inflamação/metabolismo , Linfócitos T Reguladores/fisiologiaRESUMO
Fatal pulmonary arterial hypertension (PAH) affects HIV-infected individuals at significantly higher frequencies. We previously showed plexiform-like lesions characterized by recanalized lumenal obliteration, intimal disruption, medial hypertrophy, and thrombosis consistent with PAH in rhesus macaques infected with chimeric SHIVnef but not with the parental SIVmac239, suggesting that Nef is implicated in the pathophysiology of HIV-PAH. However, the current literature on non-human primates as animal models for SIV(HIV)-associated pulmonary disease reports the ultimate pathogenic pulmonary outcomes of the research efforts; however, the variability and features in the actual disease progression remain poorly described, particularly when using different viral sources for infection. We analyzed lung histopathology, performed immunophenotyping of cells in plexogenic lesions pathognomonic of PAH, and measured cardiac hypertrophy biomarkers and cytokine expression in plasma and lung of juvenile SHIVnef-infected macaques. Here, we report significant hematopathologies, changes in cardiac biomarkers consistent with ventricular hypertrophy, significantly increased levels of interleukin-12 and GM-CSF and significantly decreased sCD40 L, CCL-2, and CXCL-1 in plasma of the SHIVnef group. Pathway analysis of inflammatory gene expression predicted activation of NF-κB transcription factor RelB and inhibition of bone morphogenetic protein type-2 in the setting of SHIVnef infection. Our findings highlight the utility of SHIVnef-infected macaques as suitable models of HIV-associated pulmonary vascular remodeling as pathogenetic changes are concordant with features of idiopathic, familial, scleroderma, and HIV-PAH.
Assuntos
Cardiomegalia/patologia , Citocinas/análise , Hipertensão Pulmonar/patologia , Pulmão/patologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Remodelação Vascular , Animais , Perfilação da Expressão Gênica , HIV/genética , HIV/crescimento & desenvolvimento , Histocitoquímica , Imunofenotipagem , Masculino , Plasma/química , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/crescimento & desenvolvimentoRESUMO
Although high glucose is an important contributor to diabetic vasculopathies, complications still occur in spite of tight glycemic control, suggesting that some critical event prior to or concurrent with hyperglycemia may contribute to early vascular changes. Utilizing previously published and new experimental evidence, this review will discuss how prior to the hyperglycemic state, an imbalance between oxidants and antioxidants may contribute to early vascular dysfunction and set in motion proinflammatory insults that are further amplified as the diabetes develops. This imbalance results from the resetting of the equilibrium between vessel superoxide/H(2)O(2) production and/or decreased antioxidant defenses. Such an imbalance may cause endothelial dysfunction, characterized by abnormal endothelium-dependent vasoreactivity, as the first sign of blood vessel damage, followed by morphological changes of the vessel wall and inflammation. As such, increased oxidant stress in preglycemic states may be a critically central initiating event that underlies the pathogenesis of life-threatening vascular diseases in autoimmune diabetes. This review focuses on the relationship between oxidative stress, immune dysregulation, and vascular injury in type 1 diabetes, and how the discovery of novel pathways of vascular disease in nonobese diabetic mice may direct future studies in patients with type 1 diabetes.
Assuntos
Doenças Autoimunes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Endotélio Vascular/metabolismo , Estresse Oxidativo , Animais , Doenças Autoimunes/patologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Peróxido de Hidrogênio/metabolismo , NADPH Oxidases/metabolismoRESUMO
Pulmonary disease remains a primary source of morbidity and mortality in persons living with HIV (PLWH), although the advent of potent combination antiretroviral therapy has resulted in a shift from predominantly infectious to noninfectious pulmonary complications. PLWH are at high risk for COPD, pulmonary hypertension, and lung cancer even in the era of combination antiretroviral therapy. The underlying mechanisms of this are incompletely understood, but recent research in both human and animal models suggests that oxidative stress, expression of matrix metalloproteinases, and genetic instability may result in lung damage, which predisposes PLWH to these conditions. Some of the factors that drive these processes include tobacco and other substance use, direct HIV infection and expression of specific HIV proteins, inflammation, and shifts in the microbiome toward pathogenic and opportunistic organisms. Further studies are needed to understand the relative importance of these factors to the development of lung disease in PLWH.
Assuntos
Infecções por HIV , HIV , Pneumopatias , Saúde Global , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Humanos , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Pneumopatias/metabolismo , Macrófagos Alveolares/metabolismo , Morbidade , Estresse Oxidativo , Taxa de SobrevidaRESUMO
RATIONALE: Committed to its mission of conducting and supporting research that addresses the health needs of all sectors of the nation's population, the Division of Lung Diseases, National Heart, Lung, and Blood Institute of the National Institutes of Health (NHLBI/NIH) seeks to identify issues that impact the training and retention of underrepresented individuals in the biomedical research workforce. OBJECTIVES: Early-stage investigators who received grant support through the NIH Research Supplements to Promote Diversity in Health Related Research Program were invited to a workshop held in Bethesda, Maryland in June, 2015, in order to (1) assess the effectiveness of the current NHLBI diversity program, (2) improve its strategies towards achieving its goal, and (3) provide guidance to assist the transition of diversity supplement recipients to independent NIH grant support. METHODS: Workshop participants participated in five independent focus groups to discuss specific topics affecting underrepresented individuals in the biomedical sciences: (1) Socioeconomic barriers to success for diverse research scientists; (2) role of the academic research community in promoting diversity; (3) life beyond a research project grant: non-primary investigator career paths in research; (4) facilitating career development of diverse independent research scientists through NHLBI diversity programs; and (5) effectiveness of current NHLBI programs for promoting diversity of the biomedical workforce. MEASUREMENTS AND MAIN RESULTS: Several key issues experienced by young, underrepresented biomedical scientists were identified, and solutions were proposed to improve on training and career development for diverse students, from the high school to postdoctoral trainee level, and address limitations of currently available diversity programs. Although some of the challenges mentioned, such as cost of living, limited parental leave, and insecure extramural funding, are also likely faced by nonminority scientists, these issues are magnified among diversity scientists and are complicated by unique circumstances in this group, such as limited exposure to science at a young age, absence of role models and mentors from underrepresented backgrounds, and social norms that relegate their career endeavors, particularly among women, to being subordinate to their expected cultural role. CONCLUSIONS: The factors influencing the participation of underrepresented minorities in the biomedical workforce are complex and span several continuous or overlapping stages in the professional development of scientists from these groups. Therefore, a multipronged approach is needed to enable the professional development and retention of underrepresented minorities in biomedical research. This approach should address both individual and social factors and should involve funding agencies, academic institutions, mentoring teams, professional societies, and peer collaboration. Implementation of some of the recommendations, such as access to child care, institutional support and health benefits for trainees, teaching and entrepreneurial opportunities, grant-writing webinars, and pre-NIH career development (Pre-K) pilot programs would not only benefit biomedical scientists from underrepresented groups but also improve the situation of nondiverse junior scientists. However, other issues, such as opportunities for early exposure to science of disadvantaged/minority groups, and identifying mentors/life coaches/peer mentors who come from similar cultural backgrounds and vantage points, are unique to this group.
Assuntos
Pesquisa Biomédica , Educação/economia , Financiamento Governamental , National Heart, Lung, and Blood Institute (U.S.) , Pesquisadores/educação , Feminino , Humanos , Masculino , Grupos Minoritários , Estados Unidos , Recursos HumanosRESUMO
INTRODUCTION: The disease spectrum for HIV-infected individuals has shifted toward comorbid non-AIDS conditions including chronic lung disease, but quantitative image analysis of lung disease has not been performed. OBJECTIVES: To quantify the prevalence of structural changes of the lung indicating emphysema or fibrosis on radiographic examination. METHODS: A cross-sectional analysis of 510 HIV-infected participants in the multicenter Lung-HIV study was performed. Data collected included demographics, biological markers of HIV, pulmonary function testing, and chest computed tomographic examinations. Emphysema and fibrosis-like changes were quantified on computed tomographic images based on threshold approaches. RESULTS: In our cohort, 69% was on antiretroviral therapy, 13% had a current CD4 cell count less than 200 cells per microliter, 39% had an HIV viral load greater than 500 copies per milliliter, and 25% had at least a trace level of emphysema (defined as >2.5% of voxels <-950HU). Trace emphysema was significantly correlated with age, smoking, and pulmonary function. Neither current CD4 cell count nor HIV viral load was significantly correlated with emphysema. Fibrosis-like changes were detected in 29% of the participants and were significantly correlated with HIV viral load (Pearson correlation coefficient = 0.210; P < 0.05); current CD4 cell count was not associated with fibrosis. In multivariable analyses including age, race, and smoking status, HIV viral load remained significantly correlated with fibrosis-like changes (coefficient = 0.107; P = 0.03). CONCLUSIONS: A higher HIV viral load was significantly associated with fibrosis-like changes, possibly indicating early interstitial lung disease, but emphysematous changes were not related to current CD4 cell count or HIV viral load.