RESUMO
Bacterial persisters represent a small subpopulation that tolerates high antibiotic concentrations without acquiring heritable resistance, and it may be generated by environmental factors. Here, we report the first antibiotic persistence mechanism in Streptococcus pneumoniae, which is induced by oxidative stress conditions and allows the pneumococcus to survive in the presence of fluoroquinolones. We demonstrated that fluoroquinolone persistence is prompted by both the impact of growth arrest and the oxidative stress response induced by H2O2 in bacterial cells. This process protected pneumococci against the deleterious effects of high ROS levels induced by fluoroquinolones. Importantly, S. pneumoniae develops persistence during infection, and is dependent on the oxidative stress status of the host cells, indicating that its transient intracellular life contributes to this mechanism. Furthermore, our findings suggest persistence may influence the outcome of antibiotic therapy and be part of a multistep mechanism in the evolution of fluoroquinolone resistance. IMPORTANCE In S. pneumoniae, different mechanisms that counteract antibiotic effects have been described, such as vancomycin tolerance, heteroresistance to penicillin and fluoroquinolone resistance, which critically affect the therapeutic efficacy. Antibiotic persistence is a type of antibiotic tolerance that allows a bacterial subpopulation to survive lethal antimicrobial concentrations. In this work, we used a host-cell infection model to reveal fluoroquinolone persistence in S. pneumoniae. This mechanism is induced by oxidative stress that the pneumococcus must overcome to survive in host cells. Many fluoroquinolones, such as levofloxacin and moxifloxacin, have a broad spectrum of activity against bacterial pathogens of community-acquired pneumonia, and they are used to treat pneumococcal diseases. However, the emergence of fluoroquinolone-resistant strains complicates antibiotic treatment of invasive infections. Consequently, antibiotic persistence in S. pneumoniae is clinically relevant due to prolonged exposure to fluoroquinolones likely favors the acquisition of mutations that generate antibiotic resistance in persisters. In addition, this work contributes to the knowledge of antibiotic persistence mechanisms in bacteria.
Assuntos
Fluoroquinolonas , Streptococcus pneumoniae , Streptococcus pneumoniae/genética , Fluoroquinolonas/farmacologia , Peróxido de Hidrogênio/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Levofloxacino/farmacologia , Bactérias , Testes de Sensibilidade MicrobianaRESUMO
AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.
Assuntos
Células Epiteliais Alveolares/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Sistema Renina-Angiotensina/fisiologia , Serina Endopeptidases/metabolismo , Adulto , Fatores Etários , Idoso , Células Epiteliais Alveolares/química , Células Epiteliais Alveolares/efeitos dos fármacos , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/análise , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Feminino , Humanos , Pulmão/química , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , Serina Endopeptidases/análise , Fumar/metabolismo , Fumar/patologiaRESUMO
Introduction: the severe acute respiratory syndrome coronavirus 2 (SARS Cov-2), leads to a diffuse alveolar deterioration due infection of type II pneumocytes. The type II pneumocytes are involved in synthesis and secretion of pulmonary surfactant in pulmonary alveoli. Objective: the purpose of this study is to discuss the indication of surfactant replacement as a potential adjunctive treatment modality for SARS CoV-2, similarly treatment to neonatal respiratory distress syndrome. Methodology: we argue that SARS can be triggered by surfactant deficiency secondary to production deficiency determined by type 2 pneumocyte injuries. In this sense, we carried out a bibliographic review. Conclusion: thus, the replacement of human surfactant could be a potential treatment modality for SARS CoV-2, in the same way that it is indicated for the treatment of neonatal respiratory distress syndrome.
Introdução: a síndrome respiratória aguda grave coronavírus 2 (SARS Cov-2), leva a uma deterioração alveolar difusa devido à infecção do pneumócitos tipo II. Os pneumócitos tipo II estão envolvidos na síntese e secreção de surfactante pulmonar nos alvéolos pulmonares. Objetivo: o objetivo deste estudo é discutir a indicação de reposição de surfactante como uma potencial modalidade de tratamento adjuvante para SARS CoV-2, similarmente ao tratamento da síndrome do desconforto respiratório neonatal. Metodologia: argumentamos que a SARS pode ser desencadeada pela deficiência de surfactante, secundária à deficiência da sua produção determinada por lesões de pneumócitos tipo 2. Nesse sentido, realizamos uma revisão bibliográfica. Conclusão: o uso de surfactante humana pode ser uma potencial modalidade de tratamento para a SARS CoV-2, da mesma forma que é indicada para o tratamento da síndrome do desconforto respiratório neonatal.
Assuntos
Surfactantes Pulmonares , Síndrome Respiratória Aguda Grave , Células Epiteliais Alveolares , SARS-CoV-2 , Revisão , Relatório AnualRESUMO
Among prematurity complications, the most important disorder is structural immaturity and inadequate production of pulmonary surfactant. Betamethasone is the drug of choice to artificially improve pulmonary capacity, thus we aimed to verify the effect of prenatal maternal treatment on lung development of premature puppies. Pregnant bitches were allocated in Term Group (n = 7), Preterm-Treated Group (interrupted pregnancies with maternal administration of betamethasone; n = 7), Preterm-Control Group (untreated interrupted pregnancies; n = 7), Extremely-Preterm Group (interrupted pregnancies at 55d; n = 6). Puppies were subjected to chest radiographic at birth, morphometric description of pulmonary structures and immunohistochemical analysis of surfactant protein B, proliferating cell nuclear antigen and cytokeratin were performed. In Preterm-Treated Group it was possible to more clearly identify cardiac silhouette and lung parenchyma by X-Ray. Saccular formation was higher in Preterm Groups, while Term Group had higher subsaccular development. Lung septation was higher in Treated and Term Groups. Term Group had higher number of cells marked for SP-B, whereas higher proliferation was observed in Extreme-Preterm and Preterm-Control Groups. Preterm Treated and Term Groups had higher tissue differentiation. In conclusion, antenatal maternal corticotherapy in dogs acted by increasing lung morphology and development of areas of gas exchange, regulate metabolism of pulmonary fluids rather than stimulate surfactant production.
Assuntos
Betametasona/uso terapêutico , Pneumopatias/veterinária , Pulmão/efeitos dos fármacos , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Cães , Feminino , Imuno-Histoquímica , Pulmão/patologia , Pneumopatias/prevenção & controle , Gravidez , Nascimento Prematuro , Radiografia Torácica/veterináriaRESUMO
Interstitial lung diseases are a group of diffuse parenchymal lung diseases that include interstitial lung fibrosis. The aim of this study is to characterize the clinical and pathological findings of idiopathic pulmonary fibrosis in three cats and to investigate possible etiological agents through bacteriological and mycological exams and immunohistochemistry. All three cats were female and aged from 10 to 14 years old, they presented with a clinical history of weight loss and dyspnea. The radiographic changes were similar in all cats and included increased pulmonary radiopacity with a mixed bronchointerstitial pattern progressing to an alveolar pattern. Two cats died during lung biopsy procedures. At necropsy, the lesions were limited to the pulmonary parenchyma and were firm, hypocrepitant with a multinodular appearance on the pleural surface; they failed to completely collapse when the thorax was opened. In the pleural region, there were multifocal star-shaped scarring lesions, with parenchymal retraction. Microscopically, all three cats had multifocal-to-coalescing fibrosis, type II pneumocyte hyperplasia, hypertrophy or hyperplasia of the smooth muscle tissue of terminal bronchioles and an accumulation of macrophages within the alveolar spaces. There was no growth on bacteriological or mycological cultures, and the immunohistochemical evaluations for the presence of viral etiological agents (FIV, FeLV, FCoV, FCV and FHV-1) were also negative.(AU)
As enfermidades pulmonares intersticiais são um grupo de doenças difusas do parênquima pulmonar, nas quais a fibrose pulmonar está incluída. O objetivo deste trabalho é caracterizar os achados clínicos e patológicos da fibrose pulmonar idiopática em três gatas, e avaliar possíveis agentes etiológicos através dos exames bacteriológicos, micológicos e imuno-histoquímicos. As três gatas tinham entre 10 e 14 anos de idade e histórico clínico de emagrecimento e dispneia. As alterações radiográficas observadas foram similares, com aumento de radiopacidade difuso dos campos pulmonares de padrão misto broncointersticial e eventualmente alveolar. Dois felinos morreram durante procedimento de biópsia pulmonar. No exame de necropsia as lesões eram exclusivas no parênquima pulmonar os quais estavam firmes, hipocreptantes, com aspecto levemente multinodular em superfície pleural e não colapsaram após a abertura da cavidade torácica. Em região pleural havia lesões cicatriciais de aspecto estrelar multifocais, com retração do parênquima. Microscopicamente, todos os gatos apresentaram fibrose multifocal a coalescente, hiperplasia dos pneumócitos do tipo II e hiperplasia e hipertrofia do músculo liso de bronquíolos terminais e acúmulo de macrófagos no interior de espaços alveolares. Não houve crescimento nas culturas bacteriana e micológica, e os exames de imuno-histoquímica para avaliação de possíveis agentes virais (FIV, FeLV, FCoV, FCV e FHV-1) foram negativos em todos os felinos.(AU)
Assuntos
Animais , Gatos , Gatos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/veterinária , Toracoscopia/veterinária , Fibrose Pulmonar Idiopática/sangueRESUMO
Interstitial lung diseases are a group of diffuse parenchymal lung diseases that include interstitial lung fibrosis. The aim of this study is to characterize the clinical and pathological findings of idiopathic pulmonary fibrosis in three cats and to investigate possible etiological agents through bacteriological and mycological exams and immunohistochemistry. All three cats were female and aged from 10 to 14 years old, they presented with a clinical history of weight loss and dyspnea. The radiographic changes were similar in all cats and included increased pulmonary radiopacity with a mixed bronchointerstitial pattern progressing to an alveolar pattern. Two cats died during lung biopsy procedures. At necropsy, the lesions were limited to the pulmonary parenchyma and were firm, hypocrepitant with a multinodular appearance on the pleural surface; they failed to completely collapse when the thorax was opened. In the pleural region, there were multifocal star-shaped scarring lesions, with parenchymal retraction. Microscopically, all three cats had multifocal-to-coalescing fibrosis, type II pneumocyte hyperplasia, hypertrophy or hyperplasia of the smooth muscle tissue of terminal bronchioles and an accumulation of macrophages within the alveolar spaces. There was no growth on bacteriological or mycological cultures, and the immunohistochemical evaluations for the presence of viral etiological agents (FIV, FeLV, FCoV, FCV and FHV-1) were also negative.(AU)
As enfermidades pulmonares intersticiais são um grupo de doenças difusas do parênquima pulmonar, nas quais a fibrose pulmonar está incluída. O objetivo deste trabalho é caracterizar os achados clínicos e patológicos da fibrose pulmonar idiopática em três gatas, e avaliar possíveis agentes etiológicos através dos exames bacteriológicos, micológicos e imuno-histoquímicos. As três gatas tinham entre 10 e 14 anos de idade e histórico clínico de emagrecimento e dispneia. As alterações radiográficas observadas foram similares, com aumento de radiopacidade difuso dos campos pulmonares de padrão misto broncointersticial e eventualmente alveolar. Dois felinos morreram durante procedimento de biópsia pulmonar. No exame de necropsia as lesões eram exclusivas no parênquima pulmonar os quais estavam firmes, hipocreptantes, com aspecto levemente multinodular em superfície pleural e não colapsaram após a abertura da cavidade torácica. Em região pleural havia lesões cicatriciais de aspecto estrelar multifocais, com retração do parênquima. Microscopicamente, todos os gatos apresentaram fibrose multifocal a coalescente, hiperplasia dos pneumócitos do tipo II e hiperplasia e hipertrofia do músculo liso de bronquíolos terminais e acúmulo de macrófagos no interior de espaços alveolares. Não houve crescimento nas culturas bacteriana e micológica, e os exames de imuno-histoquímica para avaliação de possíveis agentes virais (FIV, FeLV, FCoV, FCV e FHV-1) foram negativos em todos os felinos.(AU)
Assuntos
Animais , Gatos , Gatos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/veterinária , Toracoscopia/veterinária , Fibrose Pulmonar Idiopática/sangueRESUMO
The Paracoccidioides brasiliensis strain downregulated the expression of adhesin Pb14-3-3 (Pb14-3-3 aRNA) was evaluated in a murine model of paracoccidioidomycosis (PCM). Pb14-3-3 aRNA displays attenuated virulence and triggered the formation of fewer granulomas by lowering the fungal burden in the lungs. Additionally, the Pb14-3-3 aRNA showed more elongated yeast cells and less ability to induce pneumocytes apoptosis in vitro. Our results show that 14-3-3 is an important virulence factor in P. brasiliensis-induced pulmonary infection.
Assuntos
Proteínas 14-3-3/genética , Proteínas Fúngicas/genética , Paracoccidioides/genética , Paracoccidioides/patogenicidade , Fatores de Virulência/genética , Células Epiteliais Alveolares/microbiologia , Células Epiteliais Alveolares/patologia , Animais , Apoptose/genética , Modelos Animais de Doenças , Expressão Gênica , Pulmão/citologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Paracoccidioidomicose/microbiologiaRESUMO
As doenças pulmonares intersticiais constituem um grupo de doenças difusas do parênquima pulmonar, no qual a fibrose pulmonar intersticial está incluída. Histologicamente, esta se caracteriza por hiperplasia de pneumócitos tipo II, hiperplasia ou hipertrofia de músculo liso e fibrose. Embora a patogenia da fibrose pulmonar intersticial não esteja bem elucidada, devido às semelhanças microscópicas encontradas nos pneumócitos tipo II em felinos e na forma familiar da doença em humanos, acredita-se que haja caráter genético para o seu desenvolvimento. Os sinais clínicos frequentemente relatados incluem desconforto respiratório, cianose, letargia e perda de peso. Devido ao caráter progressivo e à ausência de tratamento específico, a doença apresenta prognóstico desfavorável. Foi atendida uma gata de 12 anos de idade, com histórico de dispneia há 20 dias. Ao exame clínico, o animal apresentou dispneia expiratória restritiva, crepitação à ausculta torácica e foi visualizado padrão intersticial ao exame radiográfico do tórax. A paciente foi submetida à punção com agulha fina de tecido pulmonar e veio a óbito algumas horas após o procedimento, apresentando insuficiência respiratória aguda. No exame histológico do tecido pulmonar, foi verificada a ocorrência de fibrose pulmonar idiopática. O objetivo do presente trabalho é relatar um caso de dispneia expiratória restritiva em um felino doméstico devido à fibrose pulmonar idiopática, já que, segundo o conhecimento dos autores, não há nenhum relato da ocorrência da doença no país.(AU)
Interstitial lung diseases are a group of diffuse parenchymal lung diseases in which interstitial lung fibrosis is included. Histologically, it is characterized by type II pneumocyte hyperplasia, hypertrophy or hyperplasia of smooth tissue and fibrosis. Although the pathogenesis of interstitial lung fibrosis has not been elucidated, due to the microscopic similarities found in type II pneumocytes in cats and familial form of the disease in humans, it is believed that there is a genetic trait for development. The frequently reported clinical signs include respiratory distress, cyanosis, lethargy, and weight loss. Due to the progressive nature and the absence of specific treatment, the disease has a poor prognosis. A 12-year-old cat with dyspnea for 20 days was assisted. The animal underwent fine needle aspiration of lung tissue and died few hours after the procedure, with acute respiratory failure. Upon histological examination of lung tissue, the occurrence of idiopathic pulmonary fibrosis was found. The aim of this study is to report a case of restrictive expiratory dyspnea in a domestic feline due to idiopathic pulmonary fibrosis, because, according to our knowledge, there is no report on the occurrence of the disease in our country.(AU)
Assuntos
Animais , Gatos , Dispneia/veterinária , Fibrose Pulmonar Idiopática/veterinária , Doenças Pulmonares Intersticiais/veterinária , Células Epiteliais AlveolaresRESUMO
As doenças pulmonares intersticiais constituem um grupo de doenças difusas do parênquima pulmonar, no qual a fibrose pulmonar intersticial está incluída. Histologicamente, esta se caracteriza por hiperplasia de pneumócitos tipo II, hiperplasia ou hipertrofia de músculo liso e fibrose. Embora a patogenia da fibrose pulmonar intersticial não esteja bem elucidada, devido às semelhanças microscópicas encontradas nos pneumócitos tipo II em felinos e na forma familiar da doença em humanos, acredita-se que haja caráter genético para o seu desenvolvimento. Os sinais clínicos frequentemente relatados incluem desconforto respiratório, cianose, letargia e perda de peso. Devido ao caráter progressivo e à ausência de tratamento específico, a doença apresenta prognóstico desfavorável. Foi atendida uma gata de 12 anos de idade, com histórico de dispneia há 20 dias. Ao exame clínico, o animal apresentou dispneia expiratória restritiva, crepitação à ausculta torácica e foi visualizado padrão intersticial ao exame radiográfico do tórax. A paciente foi submetida à punção com agulha fina de tecido pulmonar e veio a óbito algumas horas após o procedimento, apresentando insuficiência respiratória aguda. No exame histológico do tecido pulmonar, foi verificada a ocorrência de fibrose pulmonar idiopática. O objetivo do presente trabalho é relatar um caso de dispneia expiratória restritiva em um felino doméstico devido à fibrose pulmonar idiopática, já que, segundo o conhecimento dos autores, não há nenhum relato da ocorrência da doença no país.(AU)
Interstitial lung diseases are a group of diffuse parenchymal lung diseases in which interstitial lung fibrosis is included. Histologically, it is characterized by type II pneumocyte hyperplasia, hypertrophy or hyperplasia of smooth tissue and fibrosis. Although the pathogenesis of interstitial lung fibrosis has not been elucidated, due to the microscopic similarities found in type II pneumocytes in cats and familial form of the disease in humans, it is believed that there is a genetic trait for development. The frequently reported clinical signs include respiratory distress, cyanosis, lethargy, and weight loss. Due to the progressive nature and the absence of specific treatment, the disease has a poor prognosis. A 12-year-old cat with dyspnea for 20 days was assisted. The animal underwent fine needle aspiration of lung tissue and died few hours after the procedure, with acute respiratory failure. Upon histological examination of lung tissue, the occurrence of idiopathic pulmonary fibrosis was found. The aim of this study is to report a case of restrictive expiratory dyspnea in a domestic feline due to idiopathic pulmonary fibrosis, because, according to our knowledge, there is no report on the occurrence of the disease in our country.(AU)
Assuntos
Animais , Gatos , Dispneia/veterinária , Fibrose Pulmonar Idiopática/veterinária , Células Epiteliais Alveolares , Doenças Pulmonares Intersticiais/veterináriaRESUMO
During the influenza pandemic of 2009, the number of viral pneumonia cases showed a marked increase in comparison with seasonal influenza viruses. Mutations at amino acid 222 (D222G mutations) in the virus hemagglutinin (HA) molecule, known to alter the receptor-recognition properties of the virus, were detected in a number of the more severely-affected patients in the early phases of the pandemic. To understand the background for the emergence of the mutant amino acid D222G in human lungs, we conducted histological examinations on lung specimens of patients from Mexico who had succumbed in the pandemic. Prominent regenerative and hyperplastic changes in the alveolar type II pneumocytes, which express avian-type sialoglycan receptors in the respiratory tract of severely affected individuals, were observed in the Mexican patients. An infection model utilizing guinea pigs, which was chosen in order to best simulate the sialic acid distribution of severe pneumonia in human patients, demonstrated an increase of D222G mutants and a delay in the diminution of mutants in the lower respiratory tract in comparison to the upper respiratory tract. Our data suggests that the predominance of avian-type sialoglycan receptors in the pneumonic lungs may contribute to the emergence of viral HA mutants. This data comprehensively illustrates the mechanisms for the emergence of mutants in the clinical samples.