Terapia celular em doenças pulmonares: existem perspectivas?

A terapia celular poderia ser conceituada de forma ampla e genérica como o emprego de células para tratamento de doenças. Apesar de um número não tão expressivo de relatos tendo o pulmão como objeto de estudo na terapia celular em pacientes humanos, há dados consistentes da literatura, tanto em humanos, quanto em modelos animais,que evidenciam a migração de células-tronco da medula óssea para o pulmão,em diferentes situações experimentais. Esses resultados forneceram o embasamento experimental para o emprego de células-tronco na regeneração do tecido pulmonar em modelos animais. em nosso laboratório, vários projetos de pesquisa têm sido conduzidos com a finalidade de avaliar a resposta pulmonar (morfológica e funcional) ao tratamento com células-tronco adultas em camundongos com doença pulmonar obstrutiva crônica (DPOC) induzida experimentalmente. Os resultados obtidos, aliados àqueles de outros grupos de pesquisa, permitem aventar a possibilidade de aplicação, a curto prazo, da terapia celular em pacientes com DPOC. em outra patologia pulmonar, fibrose cística (FC), cuja abordagem terapêutica com células-tronco apresenta aspectos particulares em relação às patologias pulmonares crônico-degenerativas, há avanços promissores e potencialmente interessantes; no entanto, os resultados podem ser considerados incipientes e deve-se assinalar, portanto, que a associação da terapia gênica e celular apresenta-se como uma alternativa possível, mas ainda muito distante quanto à sua consolidação e incorporação como opção terapêutica segura e eficaz em FC. Por outro lado, tendo por embasamento os resultados obtidos em modelos experimentais, é possível postular que a terapia celular com células-tronco hematopoéticas (ou de outras fontes) encerra perspectivas consistentes de aplicação em diversas outras patologias pulmonares humanas, especialmente em DPOC.

Paracoccidioidomicose pulmonar agressiva, endotraqueíte estenosante e cor-pulmonale subagudo: descrição de um caso

A paracoccidioidomicose (Pbmicose) atinge os pulmões pela via inalatória, onde se estabelece o complexo primário semelhante ao da tuberculose. A traquéia comprometida pela via tubohemolinfática desenvolveria reação inflamatória em processo granulomatoso levando à obstrução estenosante com asíixia. Acompanhou-se um doente, masculino, 32 anos, branco, natural de Sarutaiá (SP), lavrador, que há 8 meses desenvolveu tosse expectorativa branco-amarelada, diária, sem fatores de melhora ou piora e dispnéia inicial discreta. Há 4 meses, anorexia, fraqueza e astenia. Há 1 mês a dispneia se agravou. Perdeu 15 kg. Tabagista e etilista há 16 anos. Exame físico revelou: PA 10/7 mmHg, FR = 28 bpm, peso 31 kg, hipocratismo digital e hipotrofia muscular Tórax enfisematoso e síndrome obstrutivo aos testes de função pulmonar. Coração: P2 desdobrada e hiperfonética. Hepatesplenomegalia. Desenvolveu cor-pulmonale e insuficiência adrenal à internação, evoluindo após 45 dias para óbito em insuficiência respiratória aguda asfixiante, apesar da terapia antifúngica ter sido completa. A literatura médica revista não mostrou registro de caso semelhante de cor-pulmonale e insuficiência adrenal de evolução subaguda.

Primary Pulmonary Choriocarcinoma After Human Chorionic Gonadotropin Normalization Following Hydatidiform Mole A Report of Two Cases

BACKGROUND: Primary pulmonary choriocarcinoma (PPC) is rare and frequently leads to death.CASES: Two young patients presented with previous molar pregnancy and spontaneous serum human chorionic gonadotropin (hCG) normalization. Patient 1 was referred to our center after partial response to chemotherapy. Pulmonary lobectomy was performed, and hCG rapidly declined. During further chemotherapy, liver metastasis was detected by positron emission tomography. Right hepatectomy was performed, and hCG declined for 28 days, but increased again despite chemotherapy. This patient died from hepatic failure 3 years after diagnosis. Patient 2 presented with persistently high hCG, though the affected organ was not identified. Chemotherapy was unsuccessful. Patient reevaluation showed an isolated pulmonary mass. Pulmonary lobectomy was performed; 2 weeks later, hCG was normal and consolidation with 2 cycles of chemotherapy was administered. The patient has been in remission for 24 months. PPC was confirmed by histo pathology and immunohistochemistry in both cases. Gestational origin of the tumor was confirmed by molecular genetic analysis (polymorphic microsatellite markers).CONCLUSION: The possibility of choriocarcinoma cannot be overlooked in young women with an isolated pulmonary mass. Early diagnosis, prompt chemotherapy, and surgical resection in a specialized center improves the prognosis. (J Reprod Med 2010;55:311-316)

Induction of apoptosis in A549 pulmonary cells by two Paracoccidioides brasiliensis samples

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Dirofilariose: zoonose emergente negligenciada

A dirofilariose é uma zoonose pouco conhecida causada por Dirofilaria spp., nematódeo mais conhecido como verme do coração dos cães (Dirofilaria immitis), parasita do sistema circulatório desses animais, mas que também pode acometer gatos e o ser humano. Sua ocorrência está intimamente ligada à presença de mosquitos vetores (Aedes spp., Anopheles spp., Culex spp.), condições climáticas favoráveis, assim como trânsito entre regiões indenes e endêmicas/epidêmicas. O ser humano pode se infectar com D. immitis (pulmão), Dirofilaria repens (pulmão, subcutâneo) e Dirofilaria tenuis (subcutâneo). A fisiopatologia está intimamente ligada à morte do parasita onde, no cão, pode induzir a obstrução de vasos circulatórios e no ser humano produzir uma lesão nodular com intensa reação inflamatória no parênquima pulmonar com formato de moeda observada nas radiografias. Pode ser diagnosticada pelo exame físico, pela detecção de microfilárias na circulação sangüínea, imunoadsorção enzimático (ELISA), alterações radiográficas, ecocardiografia, ultrassonografia e necropsia. Há riscos no tratamento, sendo a prevenção com a utilização de drogas nos animais o método mais eficaz, principalmente em visitas a áreas endêmicas ou epidêmicas, diminuindo-se, assim, o risco para saúde pública devido à disseminação do parasita.

Study of pulmonary experimental paracoccidioidomycosis by analysis of bronchoalveolar lavage cells: Resistant vs. susceptible mice

Adult Swiss (susceptible) and BALB/c (non-susceptible) mice were inoculated by the intravenous route with 1 x 10(6) yeast cells of Paracoccidioides brasiliensis, strain 18. Immunologic parameters, histopathology and features of the bronchoalveolar lavage (BAL) were evaluated at week 2, 4, 8 and 16 post-infection. The pulmonary infection was progressive in Swiss mice and regressive in BALB/c mice. The numbers of total cells, lymphocytes and polymorphonuclear neutrophils increased in BAL, as well as the percentages of giant cells, and CD4 and CD8 positive cells. The ultrastructural study of BAL cells revealed a predominance of macrophages and a frequency of 13.2% of type II pneumocytes. As the infection progressed, the number of fungal cells and spreading macrophages, as well as the stimulated release of H2O2 by macrophages, increased. The animals exhibited an exacerbation of the humoral immune response and a depression of cellular immunity during the infection. There was a good correlation between the intensity and the pattern of the pulmonary histopathology and the cellular findings in the BAL. The present model reproduces some anatomoclinical patterns of the human disease and shows that BAL may be a useful tool in monitoring the pulmonary infection caused by P. brasiliensis.

A comparative-analysis of glycosaminoglycans from human umbilical arteries in normal subjects and in pathological conditions affecting pregnancy

BACKGROUND: Vascular cells express different phenotypes in adult and fetal vessels, and the extracellular matrix they synthesize should reflect these differences. Alterations of vascular proteoglycan/glycosaminoglycan is verified in disorders such as hypertension and diabetes, and when occurring during pregnancy, they bring about structural changes to fetal vessels that often lead to impaired fetus growth. Yet there is little data about the extracellular matrix of an important human fetal vessel, the umbilical artery.EXPERIMENTAL DESIGN: This study involved the biochemical characterization of the extracellular matrix of normal umbilical arteries, umbilical arteries from complicated pregnancies (maternal hypertension and diabetes and intrauterine growth retardation syndrome), and, for purpose of comparison, normal adult arteries (aorta and iliac and pulmonary arteries). Although the collagen types I:III ratio was determined in some cases, emphasis was placed on analysis of glycosaminoglycans.RESULTS: Normal umbilical arteries differ from normal adult arteries in that they contain greater concentrations of hyaluronic acid and lesser concentrations of heparan sulfate and chondroitin 4-and 6-sulfate. The umbilical artery also differs from adult arteries in the disaccharide composition of its chondroitin and heparan sulfates and in the molecular weight of this latter glycosaminoglycan. The glycosaminoglycan distribution in umbilical arteries derived from complicated pregnancies is roughly similar to that of controls. However, total glycosaminoglycan and collagen were significantly reduced, and the collagen I:III ratio was increased in the umbilical arteries from hypertension-complicated pregnancies.CONCLUSIONS: the glycosaminoglycan composition of the normal umbilical artery, a fully differentiated tissue, differs in many aspects from that of normal adult arteries. of the cases of complicated pregnancies studied, the extracellular matrix of umbilical arteries was altered only in maternal hypertension. The changes, notably a mild fibrosis, were not very pronounced and should not impair hemodynamic properties of the vessel.

Experimental Basis and New Insights for Cell Therapy in Chronic Obstructive Pulmonary Disease

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Sputum cytology in the diagnosis of pulmonary paracoccidioidomycosis

The presence of Paracoccidioides brasiliensis was determined in sputum samples from 50 patients with paracoccidioidomycosis using four different techniques: (a) cell-block preparations stained with silver methenamine, (b) direct microbiologie examination, (c) smears stained with Shorr, and (d) smears stained with silver methenamine. Overall, cell-block preparations and smears stained with silver methenamine proved to be the most sensitive techniques, followed by smears stained with Shorr and direct microbiologic examination in decreasing order of sensitivity. Sputum cytology tended to be less positive in patients with interstitial pulmonary lesions as determined by chest X-ray than in patients with alveolar lesions. In addition to its high sensitivity, cell-block preparation technique allows storage of blocks and slides for further studies. © 1991 Kluwer Academic Publishers.

Is chronic hypoxemia in patients with chronic obstructive pulmonary disease associated with more marked nutritional deficiency?: A study of the fat-free mass evaluated by anthropometry and bioelectrical impedance methods

In order to determine wheter blood gases abnormalities, specially hypoxemia, are associated with more marked changes in fat-free mass in patients with chronic obstructive pulmonary disease (CPOD), nutritional assessment was performed on 16 normoxemic (PaO 2 > 55 mm Hg) and 16 hypoxemic (PaO 2 < 55 mm Hg) COPD patients in stable clinical condition. Body weight was expressed as percentage of the ideal body weight. Fat-free mass was estimated by anthropometry (FFM-Anthr) and by bioelectrical impedance (FFM- BI). Handgrip-strength was assessed as a measure of peripheral skeletal muscle strength. Patients were age-matched and presented similar degree of airway obstruction. Malnutrition, defined as body weight less than 90% of the ideal, was observed in 19% of the normoxemic patients and in 25% of the hypoxemic patients (p>0,05). FFM values in hypoxemic patients, estimated by both methods, were not different from those observed in normoxemic patients. No significant difference was observed on handgrip values between the two groups. No correlation was found between nutritional indices and pulmonary function and gases exchange parameters. FFM correlated positively with values of peripheral muscle function in normoxemic and hypoxemic patients. These data add further evidence to the hypothesis that hypoxemia is not a primary cause of the nutritional deficiency observed in COPD patients.

Cytokines and dietary energy restriction in stable chronic obstructive pulmonary disease patients

Tumour necrosis factor (TNF)-α has been found to be increased in malnourished chronic obstructive pulmonary disease (COPD) patients; however, the main cause of this phenomenon remains undetermined. In normal subjects, TNF-α production may be induced by dietary energy deprivation. The aim of this study was to investigate if stable COPD patients present alterations of inflammatory mediators after 48 h of dietary energy restriction. Fourteen COPD patients were admitted to the hospital while receiving an experimental diet with an energy content of approximately one-third of their energy needs. Clinical evaluation, nutritional assessment and serum levels of interleukin (IL)-6, TNF-α and C-reactive protein, and secretion of TNF-α by peripheral blood monocytes were assessed on admission and after the experimental diet. For reference values of the laboratory parameters, blood was collected from 10 healthy, elderly subjects. COPD patients showed significantly higher serum concentrations of IL-6 than control subjects, however, the experimental diet was not associated with statistically significant changes in the inflammatory mediators. The findings of this study, although preliminary because of the limited degree and duration of the energy restriction, suggest that the elevated levels of tumour necrosis factor-α, previously described in undernourished or weight-losing chronic obstructive pulmonary disease patients, may not be linked to a decrease of dietary energy intake.

Sildenafil for pulmonary hypertension treatment after cardiac surgery

Objective: To report on the use of sildenafil for pulmonary hypertension treatment of a newborn patient after cardiac surgery. Description: A female, full term newborn infant with diagnosis of double outlet right ventricle, pulmonary hypoplasia and subaortic ventricular septal defect, was submitted to Blalock surgery in the first week of life. In postoperative the newborn had pulmonary hypertension and persistent hypoxia, without response to nitric oxide, but with improved oxygenation after continuous intravenous infusion of prostaglandin E1. After several failed attempts to discontinue prostaglandin E1, oral sildenafil was used. There was a decrease in pulmonary vascular resistance with consequent oxygenation improvement and 48 hours later it was possible to discontinue prostaglandin E1 infusion. Comments: Sildenafil can be an alternative therapy for pulmonary hypertension, especially when there is no response to conventional therapy. Copyright © 2005 by Sociedade Brasileira de Pediatria.

Echocardiographic Doppler estimation of pulmonary artery pressure in critically ill patients with severe hypoxemia

BACKGROUND: In spontaneously breathing cardiac patients, pulmonary artery pressure (PAP) can be accurately estimated from the transthoracic Doppler study of pulmonary artery and tricuspid regurgitation blood flows. In critically ill patients on mechanical ventilation for acute lung injury, the interposition of gas between the probe and the heart renders the transthoracic approach problematic. This study was aimed at determining whether the transesophageal approach could offer an alternative. METHODS: Fifty-one consecutive sedated and ventilated patients with severe hypoxemia (arterial oxygen tension/fraction of inspired oxygen < 300) were prospectively studied. Mean PAP measured from the pulmonary artery catheter was compared with several indices characterizing pulmonary artery blood flow assessed using transesophageal echocardiography: preejection time, acceleration time, ejection duration, preejection time on ejection duration ratio, and acceleration time on ejection duration ratio. In a subgroup of 20 patients, systolic PAP measured from the pulmonary artery catheter immediately before withdrawal was compared with Doppler study of regurgitation tricuspid flow performed immediately after pulmonary artery catheter withdrawal using either the transthoracic or the transesophageal approach. RESULTS: Weak and clinically irrelevant correlations were found between mean PAP and indices of pulmonary artery flow. A statistically significant and clinically relevant correlation was found between systolic PAP and regurgitation tricuspid flow. In 3 patients (14%), pulmonary artery pressure could not be assessed echocardiographically. CONCLUSIONS: In hypoxemic patients on mechanical ventilation, mean PAP cannot be reliably estimated from indices characterizing pulmonary artery blood flow. Systolic PAP can be estimated from regurgitation tricuspid flow using either transthoracic or transesophageal approach. © 2008 American Society of Anesthesiologists, Inc.