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1.
Cell ; 143(6): 911-23, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-21145458

RESUMO

Defective transepithelial electrolyte transport is thought to initiate cystic fibrosis (CF) lung disease. Yet, how loss of CFTR affects electrolyte transport remains uncertain. CFTR⁻(/)⁻ pigs spontaneously develop lung disease resembling human CF. At birth, their airways exhibit a bacterial host defense defect, but are not inflamed. Therefore, we studied ion transport in newborn nasal and tracheal/bronchial epithelia in tissues, cultures, and in vivo. CFTR⁻(/)⁻ epithelia showed markedly reduced Cl⁻ and HCO3⁻ transport. However, in contrast to a widely held view, lack of CFTR did not increase transepithelial Na(+) or liquid absorption or reduce periciliary liquid depth. Like human CF, CFTR⁻(/)⁻ pigs showed increased amiloride-sensitive voltage and current, but lack of apical Cl⁻ conductance caused the change, not increased Na(+) transport. These results indicate that CFTR provides the predominant transcellular pathway for Cl⁻ and HCO3⁻ in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease.


Assuntos
Ânions/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/metabolismo , Transporte de Íons , Sistema Respiratório/patologia , Animais , Animais Recém-Nascidos , Epitélio/metabolismo , Humanos , Sistema Respiratório/metabolismo , Sus scrofa
2.
Am J Respir Crit Care Med ; 195(12): 1617-1628, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28222269

RESUMO

RATIONALE: Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. OBJECTIVES: To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. METHODS: We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS: Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. CONCLUSIONS: Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.


Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Fibrose Cística/tratamento farmacológico , Inflamação/prevenção & controle , Quinolonas/uso terapêutico , Infecções Respiratórias/prevenção & controle , Adulto , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Masculino , Infecções Respiratórias/metabolismo , Escarro/efeitos dos fármacos , Escarro/metabolismo , Tomografia Computadorizada por Raios X
3.
Ann Otol Rhinol Laryngol ; 131(9): 1013-1020, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34674574

RESUMO

OBJECTIVES: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF. METHODS: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period. RESULTS: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolens detected, but increased the amount of Corynebacterium pseudodiphtheriticum recovered on nasal swabs. A reduction in Staphylococcus aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum. CONCLUSIONS: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities. CLINICAL TRIAL REGISTRATION: NCT00928135 (https://clinicaltrials.gov/ct2/show/NCT00928135).


Assuntos
Fibrose Cística , Microbiota , Adulto , Regulador de Condutância Transmembrana em Fibrose Cística , Humanos , Concentração de Íons de Hidrogênio , Projetos Piloto
4.
Am J Respir Cell Mol Biol ; 45(4): 874-81, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21441383

RESUMO

Recent reports postulate that the dual oxidase (DUOX) proteins function as part of a multicomponent oxidative pathway used by the respiratory mucosa to kill bacteria. The other components include epithelial ion transporters, which mediate the secretion of the oxidizable anion thiocyanate (SCN(-)) into airway surface liquid, and lactoperoxidase (LPO), which catalyzes the H(2)O(2)-dependent oxidation of the pseudohalide SCN(-) to yield the antimicrobial molecule hypothiocyanite (OSCN(-)). We hypothesized that this oxidative host defense system is also active against respiratory viruses. We evaluated the activity of oxidized LPO substrates against encapsidated and enveloped viruses. When tested for antiviral properties, the LPO-dependent production of OSCN(-) did not inactivate adenovirus or respiratory syncytial virus (RSV). However, substituting SCN(-) with the alternative LPO substrate iodide (I(-)) resulted in a marked reduction of both adenovirus transduction and RSV titer. Importantly, well-differentiated primary airway epithelia generated sufficient H(2)O(2) to inactivate adenovirus or RSV when LPO and I(-) were supplied. The administration of a single dose of 130 mg of oral potassium iodide to human subjects increased serum I(-) concentrations, and resulted in the accumulation of I(-) in upper airway secretions. These results suggest that the LPO/I(-)/H(2)O(2) system can contribute to airway antiviral defenses. Furthermore, the delivery of I(-) to the airway mucosa may augment innate antiviral immunity.


Assuntos
Adenoviridae/efeitos dos fármacos , Antivirais/farmacologia , Imunidade nas Mucosas/efeitos dos fármacos , Iodeto de Potássio/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Infecções Respiratórias/tratamento farmacológico , Iodeto de Sódio/farmacologia , Adenoviridae/imunologia , Adenoviridae/patogenicidade , Animais , Antivirais/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Compostos de Iodo/metabolismo , Lactoperoxidase/metabolismo , Oxirredução , Iodeto de Potássio/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Iodeto de Sódio/metabolismo , Suínos , Tiocianatos/metabolismo , Fatores de Tempo , Ativação Viral/efeitos dos fármacos
5.
J Cyst Fibros ; 20(3): 540-550, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33309058

RESUMO

BACKGROUND: Approximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO3- secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people. METHODS: To determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators. RESULTS: AmB increased transepithelial Cl- current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation. CONCLUSIONS: Our results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Fibrose Cística/tratamento farmacológico , Canais de Ânion Dependentes de Voltagem/efeitos dos fármacos , Administração Intranasal , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Células Cultivadas , Códon sem Sentido , Fibrose Cística/genética , Humanos , Mucosa Respiratória/citologia
6.
J Cyst Fibros ; 19(1): 108-113, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327670

RESUMO

BACKGROUND: Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and recurrent pulmonary exacerbations. Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration and augment innate immunity. We examined the safety and efficacy of aerosolized xylitol use for 2 weeks in subjects hospitalized with a pulmonary exacerbation of CF. METHODS: In a 2-week study, 60 subjects with cystic fibrosis and FEV1 > 30% predicted were enrolled to receive aerosolized 7% hypertonic saline (4 ml) or 15% xylitol (5 ml) twice a day for 14 days. Outcomes assessed included change from baseline in FEV1% predicted, change in sputum microbial density, revised CF quality of life questionnaire including the respiratory symptom score, time to next hospitalization for a pulmonary exacerbation, and frequency of adverse events. RESULTS: 59 subjects completed the study (one subject in the saline group withdrew before any study product administration). No significant differences were noted between the 2 arms in mean changes in lung function, sputum microbial density for Pseudomonas aeruginosa and Staphylococcus aureus, body weight, quality of life, and frequency of adverse events. CONCLUSIONS: Aerosolized hypertonic xylitol was well-tolerated among subjects hospitalized for CF pulmonary exacerbation. Future studies examining efficacy for long term use in patients with CF lung disease would be worthwhile. The clinical trial registration number for this study is NCT00928135.


Assuntos
Fibrose Cística , Pulmão , Infecções Respiratórias , Escarro , Xilitol , Administração por Inalação , Adulto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/fisiopatologia , Masculino , Testes de Função Respiratória/métodos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Escarro/efeitos dos fármacos , Escarro/microbiologia , Propriedades de Superfície/efeitos dos fármacos , Edulcorantes/administração & dosagem , Edulcorantes/efeitos adversos , Resultado do Tratamento , Xilitol/administração & dosagem , Xilitol/efeitos adversos
7.
JCI Insight ; 1(8)2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27390778

RESUMO

In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3- and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3- increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3--independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease.

8.
JCI Insight ; 1(4): e86183, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27158673

RESUMO

BACKGROUND: Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS: To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS: Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS: Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING: This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

9.
Int Forum Allergy Rhinol ; 5(2): 178-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25363320

RESUMO

BACKGROUND: Chronic sinusitis is universal in cystic fibrosis (CF) and our current treatments are ineffective in reversing sinus disease. The objective of this work was to determine if increasing CF transmembrane conductance regulator (CFTR) activity by ivacaftor could treat CF sinus disease and assess its effect on primary sinus epithelial cultures. METHODS: Case report of 1 patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). We discuss clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor. We then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment. RESULTS: Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH, and resolved sinus symptoms after 10 months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures. CONCLUSION: This report documents the reversal of CF sinus disease. Based on our in vivo and in vitro results, we speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity. These studies suggest that CFTR modulation may be effective in treating CF and perhaps non-CF sinusitis.


Assuntos
Aminofenóis/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fibrose Cística/complicações , Quinolonas/uso terapêutico , Sinusite/tratamento farmacológico , Células Cultivadas , Criança , Doença Crônica , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Concentração de Íons de Hidrogênio , Transporte de Íons/efeitos dos fármacos , Mutação/genética , Mucosa Respiratória/fisiologia , Sinusite/complicações , Resultado do Tratamento , Viscosidade
10.
J Cyst Fibros ; 13(4): 373-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24418186

RESUMO

BACKGROUND: Disrupted HCO3(-) transport and reduced airway surface liquid (ASL) pH in cystic fibrosis (CF) may initiate airway disease. We hypothesized that ASL pH is reduced in neonates with CF. METHODS: In neonates with and without CF, we measured pH of nasal ASL. We also measured nasal pH in older children and adults. RESULTS: In neonates with CF, nasal ASL (pH5.2 ± 0.3) was more acidic than in non-CF neonates (pH6.4 ± 0.2). In contrast, nasal pH of CF children and adults was similar to values measured in people without CF. CONCLUSIONS: At an age when infection, inflammation and airway wall remodeling are minimal, neonates with CF had an acidic nasal ASL compared to babies without CF. The CF:non-CF pH difference disappeared in older individuals, perhaps because secondary manifestations of disease increase ASL pH. These results aid understanding of CF pathogenesis and suggest opportunities for therapeutic intervention and monitoring of disease.


Assuntos
Líquidos Corporais/química , Fibrose Cística/metabolismo , Mucosa Nasal/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Feminino , Seguimentos , Genótipo , Humanos , Concentração de Íons de Hidrogênio , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Estudos Retrospectivos , Adulto Jovem
11.
Sci Transl Med ; 2(29): 29ra31, 2010 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-20427821

RESUMO

Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes. We now report that, within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. In humans, the temporal and causal relations between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation but were less often sterile than controls. Moreover, after introduction of bacteria into their lungs, pigs with CF failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Our finding that pigs with CF have a host defense defect against bacteria within hours of birth provides an opportunity to further investigate CF pathogenesis and to test therapeutic and preventive strategies that could be deployed before secondary consequences develop.


Assuntos
Fibrose Cística/microbiologia , Fibrose Cística/patologia , Pulmão/microbiologia , Pulmão/patologia , Suínos/crescimento & desenvolvimento , Suínos/microbiologia , Animais , Animais Recém-Nascidos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico por imagem , Modelos Animais de Doenças , Íleus/cirurgia , Inflamação/complicações , Inflamação/patologia , Pulmão/anormalidades , Pulmão/diagnóstico por imagem , Mecônio , Muco/metabolismo , Pancreatopatias/patologia , Radiografia Torácica , Análise de Sobrevida , Fatores de Tempo
13.
J Crit Care ; 24(1): 114-21, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19272547

RESUMO

OBJECTIVE: The study aimed to describe the patterns and density of early tracheal colonization among intubated patients and to correlate colonization status with levels of antimicrobial peptides and inflammatory cytokines. DESIGN: The was a prospective cohort study. SETTING: The study was conducted in medical and cardiovascular intensive care units of a tertiary referral hospital. PATIENTS: Seventy-four adult patients admitted between March 2003 and May 2006 were recruited for the study. INTERVENTIONS: Tracheal aspirates were collected daily for the first 4 days of intubation using standardized, sterile technique and sent for quantitative culture and cytokines, lactoferrin and lysozyme measurements. MEASUREMENTS AND MAIN RESULTS: The mean acute physiology and chronic health evaluation (APACHE II) score in this cohort was 24 +/- 7. Proportion of subjects colonized by any microorganism increased over the first 4 days of intubation (47%, 60%, 70%, 70%, P = .08), but density of colonization for bacteria or yeast did not change significantly. No known risk factors predicted tracheal colonization on day 1 of intubation. Several patterns of colonization were observed (persistent, transient, new colonization, and clearance of initial colonization).The most common organisms cultured were Candida albicans and coagulase-negative Staphylococcus. Levels of cytokines, lactoferrin, or lysozyme did not change over time and were not correlated with tracheal colonization status. Four subjects (6%) had ventilator-associated pneumonia. CONCLUSIONS: The density of tracheal colonization did not change significantly over the first 4 days of intubation in medical intensive care unit patients. There was no correlation between tracheal colonization and the levels of antimicrobial peptides or cytokines. Several different patterns of colonization may have to be considered while planning interventions to reduce airway colonization.


Assuntos
Infecção Hospitalar/microbiologia , Unidades de Terapia Intensiva , Intubação Intratraqueal/efeitos adversos , Respiração Artificial/efeitos adversos , Mucosa Respiratória/microbiologia , Traqueia/microbiologia , APACHE , Adulto , Candidíase/microbiologia , Estudos de Casos e Controles , Contagem de Colônia Microbiana , Infecção Hospitalar/diagnóstico , Citocinas/análise , Feminino , Humanos , Inflamação , Lactoferrina/análise , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Muramidase/análise , Pneumonia Associada à Ventilação Mecânica/etiologia , Estudos Prospectivos , Mucosa Respiratória/metabolismo , Fatores de Risco , Infecções Estafilocócicas/microbiologia , Estatísticas não Paramétricas , Sucção , Fatores de Tempo , Traqueia/metabolismo
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