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1.
Proc Natl Acad Sci U S A ; 117(46): 28719-28726, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33139541

RESUMO

The early onset of weaning in modern humans has been linked to the high nutritional demand of brain development that is intimately connected with infant physiology and growth rate. In Neanderthals, ontogenetic patterns in early life are still debated, with some studies suggesting an accelerated development and others indicating only subtle differences vs. modern humans. Here we report the onset of weaning and rates of enamel growth using an unprecedented sample set of three late (∼70 to 50 ka) Neanderthals and one Upper Paleolithic modern human from northeastern Italy via spatially resolved chemical/isotopic analyses and histomorphometry of deciduous teeth. Our results reveal that the modern human nursing strategy, with onset of weaning at 5 to 6 mo, was present among these Neanderthals. This evidence, combined with dental development akin to modern humans, highlights their similar metabolic constraints during early life and excludes late weaning as a factor contributing to Neanderthals' demise.


Assuntos
Esmalte Dentário/crescimento & desenvolvimento , Homem de Neandertal/crescimento & desenvolvimento , Desmame , Animais , Esmalte Dentário/química , Humanos , Lactente , Recém-Nascido
2.
Transfus Apher Sci ; 59(5): 102874, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32713628

RESUMO

Worldwide iron anemia is a common disorder with a significant economic burden on health-care systems. Red blood cell transfusion is the mainstay to correct anemia in surgical settings, but it is also an overused procedure and recent data support its possible role in worsening patient outcomes. Patient Blood Management (PBM) is a multidisciplinary approach to optimize hemostasis, manage anemia, minimize iatrogenic blood loss, and improve tolerance to anemia. The present paper aims to provide a "bundles" approach, based on several preoperative anemia management measures, to implement PBM Pillar 1 in clinical practice.


Assuntos
Transfusão de Sangue/métodos , Prova Pericial , Humanos , Itália
3.
Transfus Apher Sci ; 57(2): 282-284, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29779981

RESUMO

Iron deficiency anemia is one of the widespread forms of anemia worldwide with important consequences on public health in general and in the management of the hospital blood supply in particular. In this context we decided to "de novo"organize a new hospital service specifically dedicated to iron therapy to correctly diagnose iron deficiency anemia and support patients with the latest generation of i.v. iron formulation. We describe the organizational and educational solutions we adopted to start the new service. The initial results in terms of safety, increase in Hb value, and RBC units saved were encouraging and it has led us to expand the categories of patients to be supported.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Hospitais/normas , Ferro/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Ferro/farmacologia , Masculino , Pessoa de Meia-Idade
4.
Am J Phys Anthropol ; 162(2): 370-376, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27704536

RESUMO

OBJECTIVES: The aim of the study is the assessment of Nadale 1, a Neanderthal deciduous tooth recently discovered in Northeastern Italy in the De Nadale cave (Middle Palaeolithic). Together with the clear archaeological context of the site, this study brings new insight on Neanderthal behavior and dental morphological variability. MATERIALS AND METHODS: We used microCT data to provide a morphological description and morphometric analysis (diameter measurements and dental tissue volumes) of the Nadale 1 human tooth. Microwear analysis, taphonomical investigation and caries identification were performed using a stereomicroscope and Scanning Electron Microscope. RESULTS: In terms of morphology (i.e., incipient tuberculum molare, marked mesial marginal ridge and well-developed mid-trigonid crest connecting the protoconid and the metaconid, deep anterior fovea) and size, Nadale 1 presents features frequently observed in Neanderthal lower first deciduous molars. Microscope investigations reveal the presence of a small pit which could be correlated to an incipient caries. CONCLUSION: Nadale 1 expands the Italian Middle Palaeolithic fossil record and provides further information on Neanderthal dm1s in terms of dimensional and morphological variability. Furthermore, the presence of an incipient caries brings further data on Neanderthal diet.


Assuntos
Cárie Dentária/patologia , Dente Molar/patologia , Homem de Neandertal , Dente Decíduo/patologia , Animais , Arqueologia , Cavernas , Fósseis , Itália , Paleodontologia
5.
J Biol Chem ; 285(35): 26945-26955, 2010 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-20566636

RESUMO

Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (betaENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function betaENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, betaENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Nat channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and betaENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in betaENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Canais Epiteliais de Sódio/biossíntese , Regulação da Expressão Gênica , Síndrome de Liddle/metabolismo , Mutação , Sódio/metabolismo , Animais , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Canais Epiteliais de Sódio/genética , Humanos , Transporte de Íons/genética , Síndrome de Liddle/patologia , Camundongos , Camundongos Knockout , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Técnicas de Cultura de Órgãos , Traqueia/metabolismo , Traqueia/patologia
6.
J Immunol ; 182(7): 4357-67, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19299736

RESUMO

Overexpression of the epithelial Na(+) channel beta subunit (Scnn1b gene, betaENaC protein) in transgenic (Tg) mouse airways dehydrates mucosal surfaces, producing mucus obstruction, inflammation, and neonatal mortality. Airway inflammation includes macrophage activation, neutrophil and eosinophil recruitment, and elevated KC, TNF-alpha, and chitinase levels. These changes recapitulate aspects of complex human obstructive airway diseases, but their molecular mechanisms are poorly understood. We used genetic and pharmacologic approaches to identify pathways relevant to the development of Scnn1b-Tg mouse lung pathology. Genetic deletion of TNF-alpha or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4Ralpha abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4Ralpha deficiency decreased MuSC and eosinophils in neonatal Scnn1b-Tg mice, which correlated with improved neonatal survival. However, chronic lung pathology in adult Scnn1b-Tg mice was not affected by IL-4Ralpha status. Prednisolone treatment ablated eosinophilia and MuSC in adult Scnn1b-Tg mice, but did not decrease mucus plugging or neutrophilia. These studies demonstrate that: 1) normal neonatal mouse airway development entails an IL-4Ralpha-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4Ralpha improved neonatal survival of Scnn1b-Tg mice, likely reflecting decreased formation of asphyxiating mucus plugs; and 3) in Scnn1b-Tg mice, neutrophilia, mucus obstruction, and airspace enlargement are IL-4Ralpha- and TNF-alpha-independent, and only MuSC and eosinophilia are sensitive to glucocorticoids. Thus, manipulation of multiple pathways will likely be required to treat the complex pathogenesis caused by airway surface dehydration.


Assuntos
Imunidade nas Mucosas/fisiologia , Receptores de Superfície Celular/metabolismo , Mucosa Respiratória/fisiopatologia , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Quimiocinas/análise , Desidratação/complicações , Modelos Animais de Doenças , Eosinofilia/tratamento farmacológico , Eosinofilia/etiologia , Canais Epiteliais de Sódio/genética , Glucocorticoides/uso terapêutico , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Prednisolona/uso terapêutico , Receptores de Superfície Celular/genética , Mucosa Respiratória/crescimento & desenvolvimento , Mucosa Respiratória/metabolismo , Sistema Respiratório/crescimento & desenvolvimento , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismo
7.
Blood Transfus ; 19(6): 448-455, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34739371

RESUMO

BACKGROUND: Pharmacological treatment of iron deficiency anaemia can reduce red blood cell (RBC) transfusions. Intravenous iron provides a more effective and quicker correction of iron deficiency anaemia than oral iron, and third-generation high-dose intravenous iron formulations allow the complete correction of iron deficiency with just one or two drug infusions, thus facilitating iron supplementation therapy and reducing transfusion requirement. MATERIAL AND METHODS: In an observational, retrospective study we compared RBC transfusion requirement during hospitalisation and within 3 months of hospital discharge in 88 patients with iron deficiency anaemia treated with high-dose ferric carboxymaltose and in 85 patients treated with ferric gluconate while hospitalised in the Internal Medicine unit of our Institution. RESULTS: Ferric carboxymaltose reduced the number of RBC units given to each transfused patient during hospitalisation (1.81±0.84 vs 2.39±1.49, p=0.011). At hospital discharge, fewer ferric carboxymaltose patients were prescribed home therapy with iron. No differences between treatment groups were observed in the proportion of patients or the number of RBC units transfused within 3 months of discharge. At one month from discharge, however, only 2 ferric carboxymaltose patients had been transfused compared with 7 ferric gluconate patients (p=0.078). Patients transfused post-discharge were more likely to have an underlying malignancy and/or higher serum creatinine concentrations. DISCUSSION: Treatment with ferric carboxymaltose reduced the number of RBC units per transfused patient. Larger studies are required to define risk factors associated with post-discharge transfusion requirement and to establish if home therapy with iron will reduce subsequent transfusions in patients treated with ferric carboxymaltose.


Assuntos
Anemia Ferropriva , Deficiências de Ferro , Assistência ao Convalescente , Anemia Ferropriva/tratamento farmacológico , Suplementos Nutricionais , Transfusão de Eritrócitos , Compostos Férricos , Hospitais , Humanos , Ferro , Maltose , Alta do Paciente , Estudos Retrospectivos
8.
Am J Respir Crit Care Med ; 177(7): 730-42, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18079494

RESUMO

RATIONALE: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in beta-epithelial Na(+) channel (betaENaC)-overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors. OBJECTIVES: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration. METHODS: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in betaENaC-overexpressing mice. MEASUREMENTS AND MAIN RESULTS: Mucus obstruction in betaENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving betaENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-alpha and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. betaENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance. CONCLUSIONS: Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Mucosa Respiratória/metabolismo , Animais , Animais Recém-Nascidos , Bronquite Crônica/fisiopatologia , Desidratação , Progressão da Doença , Expressão Gênica , Inflamação , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos , Depuração Mucociliar , Enfisema Pulmonar/fisiopatologia
9.
Am J Respir Crit Care Med ; 178(8): 822-31, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18658107

RESUMO

RATIONALE: High-mobility group box 1 (HMGB1) is a potent inflammatory mediator elevated in sepsis and rheumatoid arthritis, although its role in cystic fibrosis (CF) lung disease is unknown. OBJECTIVES: To determine whether HMGB1 contributes to CF lung inflammation, including neutrophil chemotaxis and lung matrix degradation. METHODS: We used sputum and serum from subjects with CF and a Scnn1b-transgenic (Scnn1b-Tg) mouse model that overexpresses beta-epithelial Na(+) channel in airways and mimics the CF phenotype, including lung inflammation. Human secretions and murine bronchoalveolar lavage fluid (BALF) was assayed for HMGB1 by Western blot and ELISA. Neutrophil chemotaxis was measured in vitro after incubation with human neutrophils. The collagen fragment proline-glycine-proline (PGP) was measured by tandem mass spectroscopy. MEASUREMENTS AND MAIN RESULTS: HMGB1 was detected in CF sputum at higher levels than secretions from normal individuals. Scnn1b-Tg mice had elevated levels of HMGB1 by Western blot and ELISA. We demonstrated that dose-dependent chemotaxis of human neutrophils stimulated by purified HMGB1 was partially dependent on CXC chemokine receptors and that this could be duplicated in CF sputum and BALF from Scnn1b-Tg mice. Neutralization by anti-HMGB1 antibody, in both the sputum and BALF-reduced chemotaxis, which suggested that HMGB1 contributed to the chemotactic properties of these samples. Intratracheal administration of purified HMGB1 induced neutrophil influx into the airways of mice and promoted the release of PGP. PGP was also elevated in Scnn1b-Tg mice and CF serum. CONCLUSIONS: HMGB1 expression contributes to pulmonary inflammation and lung matrix degradation in CF airway disease and deserves further investigation as a biomarker and potential therapeutic target.


Assuntos
Fibrose Cística/metabolismo , Proteína HMGB1/biossíntese , Adulto , Animais , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Quimiotaxia de Leucócito/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Neutrófilos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Escarro/metabolismo
10.
Am J Respir Cell Mol Biol ; 38(4): 423-34, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17989361

RESUMO

In cystic fibrosis (CF), the absence of functional CFTR leads to dysregulated Na(+) absorption across airway epithelia. We established an in vitro model of dysregulated Na(+) absorption by treating polarized normal human bronchial epithelial cells (HBEs) with nystatin (Nys), a polyene antibiotic that enables monovalent cations to permeate biological membranes. Acute mucosal Nys produced a rapid increase in short circuit current (I(sc)) that reflected increased transepithelial Na(+) absorption and required Na(+)/K(+)ATPase activity. The acute increase in I(sc) was associated with increased mucosal liquid absorption. Prolonged mucosal Nys treatment resulted in sustained Na(+) hyperabsorption, associated with increased mucosal liquid absorption in comparison with naïve (nontreated, kept under air-liquid interface conditions) or vehicle-treated cultures. Nys treatment was not toxic. Increased lactate accumulation in Nys-treated culture media suggested a higher metabolic rate associated with the higher energy demand for Na(+) transport. After chronic Nys treatment, the increased I(sc) was rapidly lost when the cultures were mounted in Ussing chambers, indicating that Nys could be rapidly removed from the apical membrane. Importantly, chronic Nys treatment promoted sustained mucosal liquid depletion and caused mucus dehydration, compaction, and adhesion to the apical surface of Nys-treated cultures. We conclude that mucosal Nys treatment of HBEs provides a simple in vitro model to recapitulate the Na(+) and volume hyperabsorptive features of CF airway epithelia.


Assuntos
Células Epiteliais/metabolismo , Modelos Biológicos , Mucosa/efeitos dos fármacos , Nistatina/farmacologia , Sistema Respiratório/citologia , Sistema Respiratório/metabolismo , Sódio/metabolismo , Absorção/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Desidratação , Condutividade Elétrica , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Ácido Láctico/metabolismo , Mucosa/patologia , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/enzimologia , Membrana Serosa/efeitos dos fármacos , Membrana Serosa/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo
11.
J Cyst Fibros ; 5(2): 113-9, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16481223

RESUMO

BACKGROUND: It is not clear whether cystic fibrosis (CF) airway inflammation is a consequence of bacterial infection or is intrinsically dysregulated. The aim of this study was to investigate IL-8 secretion and NF-kappaB activity in primary respiratory epithelial cells cultured from nasal polyps obtained from CF and non-CF subjects. METHODS: NF-kappaB activity was studied by electrophoretic mobility-shift and quantitative colorimetric assays in nuclear extracts. Immunoreactive IL-8 levels were assessed by ELISA in cell culture supernatants. Both parameters were studied at baseline and following challenge with Pseudomonas aeruginosa or stimulation with pro-inflammatory cytokines. RESULTS: Under basal conditions, CF cells presented a significant higher activity of NF-kappaB than non-CF cells (P=0.0004). P. aeruginosa challenge and IL-1beta/H2O2 co-stimulation caused four and two fold induction of NF-kappaB activity in non-CF and CF cells, respectively. IL-8 levels in unstimulated CF cells were significantly higher than in non-CF cells (P=0.0025). Upon incubation with P. aeruginosa and IL-1beta/H2O2, non-CF cells produced 6.3 times more IL-8 than unstimulated cells, whereas IL-8 secretion increased only of 1.4 times in CF cells. CONCLUSIONS: CF respiratory epithelial cells exhibit a basal dysregulated production of IL-8 that partially correlates to enhanced NF-kappaB activity. Our data corroborate the hypothesis of a basal exaggerated inflammatory response in the CF respiratory epithelium.


Assuntos
Fibrose Cística/metabolismo , Interleucina-8/metabolismo , NF-kappa B/metabolismo , Mucosa Nasal/metabolismo , Células Cultivadas , Humanos , Peróxido de Hidrogênio/farmacologia , Interleucina-1/farmacologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/microbiologia , Pseudomonas aeruginosa/fisiologia
12.
J Gen Physiol ; 122(4): 377-87, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14517269

RESUMO

In airway epithelia, purinergic receptor (P2Y2-R) stimulation of intracellular calcium (Ca2+i)-regulated ion transport is restricted to the membrane domain ipsilateral to receptor activation, implying compartmentalization of Ca2+i signaling. Because mitochondria can spatially restrict cellular Ca2+i signals, immunocytochemical, electron microscopic, and fluorescent studies of mitochondria localization were performed in human airway epithelia. Although concentrated at the apical domain, mitochondria were found distributed at both the apical and the basolateral poles and in close association with the endoplasmic reticulum. The role of mitochondria in locally restricting P2Y2-R-induced Ca2+i signals was investigated by measuring changes in mitochondrial Ca2+ (Ca2+m) in human airway epithelial monolayers. P2Y2-R activation induced Ca2+m accumulation in mitochondria confined to the domain ipsilateral to P2Y2-R stimulation, which was blocked by mitochondrial uncoupling with 1 microM CCCP and 2.5 microg/ml oligomycin. The role of mitochondria in restricting the cellular cross-talk between basolateral P2Y2-R-dependent Ca2+i mobilization and apical membrane Ca2+-activated Cl- secretion was investigated in studies simultaneously measuring Ca2+i and Cl- secretion in cystic fibrosis human airway epithelial monolayers. Activation of basolateral P2Y2-Rs produced similar increases in Ca2+i in monolayers without and with pretreatment with uncouplers, whereas Ca2+i-activated Cl- secretion was only efficiently triggered in mitochondria-uncoupled conditions. We conclude that (a) mitochondria function as a Ca2+i-buffering system in airway epithelia, compartmentalizing Ca2+i-dependent functions to the membrane ipsilateral to receptor stimulation; and (b) the mitochondria provide structural barriers that protect the airway epithelia against nonspecific activation of Ca2+i-modulated functions associated with Ca2+i signals emanating from the apical or the basolateral membrane domains.


Assuntos
Brônquios/fisiologia , Cálcio/fisiologia , Mitocôndrias/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Cloretos/metabolismo , Corantes , Eletrofisiologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/fisiologia , Humanos , Potenciais da Membrana/fisiologia , Microscopia Confocal , Microscopia Eletrônica , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Técnicas de Patch-Clamp , Perfusão , Agonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2Y2 , Desacopladores/farmacologia , Uridina Trifosfato/fisiologia
13.
J Mol Med (Berl) ; 80(8): 499-506, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12185450

RESUMO

The effect of interferon (IFN) gamma on cationic liposome-mediated gene transfer into primary respiratory epithelial cells was investigated. Treatment of primary respiratory epithelial cells with IFN-gamma resulted in a dose-dependent increase in the intermediate filament cytokeratin 13 and a decrease in cellular proliferation, indicating that respiratory cells underwent squamous differentiation. IFN-gamma pretreatment resulted in a dramatic inhibition of transfection efficiency mediated by a cationic liposome (DOTAP). Incubation of squamous nasal cells with DOTAP/DNA complexes for various periods at 4 degrees C and evaluation of luciferase levels suggested that IFN-gamma pretreatment inhibits complex binding to the cells. In primary nasal and bronchial cells cytofluorimetric analysis demonstrated that IFN-gamma reduces binding of FITC-labeled complexes. The data indicate that differentiation of respiratory epithelial cells to a squamous phenotype, which may occur in chronic respiratory diseases such as cystic fibrosis, induces a refractory condition to gene transfer by nonviral cationic liposomes.


Assuntos
Células Epiteliais/efeitos dos fármacos , Técnicas de Transferência de Genes , Vetores Genéticos/efeitos dos fármacos , Interferon gama/farmacologia , Lipossomos , Resinas de Troca de Cátion , Linhagem Celular Transformada , Células Cultivadas , Citocinas/genética , Células Epiteliais/fisiologia , Humanos , Interferon gama/metabolismo , Luciferases/metabolismo , Sistema Respiratório/citologia , Transfecção
14.
Toxicol Pathol ; 35(1): 116-29, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17325980

RESUMO

Exposed to a diverse array of potentially noxious agents, the respiratory tract is protected by a highly developed innate defense system. Physiologically regulated epithelial ion and water transport coordinated with mucin secretion, beating cilia, and cough results in continuous flow of fluid and mucus over airway surfaces toward the larynx. This cleansing action is the initial and perhaps most quantitatively important innate defense mechanism. Repeated lung infections and eventual respiratory insufficiency characteristic of human cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) illustrate the consequences of impaired mucus clearance. Altered mucus clearance likely contributes to the initiation, progression, and chronicity of other airway diseases characterized by inflammation and mucous secretory cell hyper/metaplasia that afflict millions worldwide, including chronic obstructive pulmonary disease (COPD). This review concisely discusses the pathophysiology of human diseases characterized by genetic defects that impair mucus clearance. It then explores animal models in which components of the mucus clearance system have been disrupted. These models firmly establish the importance of mucus clearance for respiratory health, and will help elucidate disease mechanisms and therapeutic strategies in CF, PCD and COPD.


Assuntos
Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Depuração Mucociliar , Muco/metabolismo , Sistema Respiratório/fisiopatologia , Animais , Cílios/fisiologia , Fibrose Cística/metabolismo , Modelos Animais de Doenças , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Depuração Mucociliar/genética , Sistema Respiratório/metabolismo
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