Distinct effects of intravenous bone marrow-derived mesenchymal stem cell therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury.

BACKGROUND: The preclinical efficacy of mesenchymal stem cell (MSC) therapy after intravenous infusion has been promising, but clinical studies have yielded only modest results. Although most preclinical studies have focused solely on the ischemic lung, it is crucial to evaluate both lungs after ischemia-reperfusion injury, considering the various mechanisms involved. This study aimed to bridge this gap by assessing the acute effects of bone marrow MSC(BM) infusion before ischemic insult and evaluating both ischemic and non-ischemic lungs after reperfusion. METHODS: Eighteen male Wistar rats (403 ± 23 g) were anesthetized and mechanically ventilated using a protective strategy. After baseline data collection, the animals were randomized to 3 groups (n = 6/group): (1) SHAM; (2) ischemia-reperfusion (IR), and (3) intravenous MSC(BM) infusion followed by IR. Ischemia was induced by complete clamping of the left hilum, followed by 1 h of reperfusion after clamp removal. At the end of the experiment, the right and left lungs (non-ischemic and ischemic, respectively) were collected for immunohistochemistry and molecular biology analysis. RESULTS: MSC(BM)s reduced endothelial cell damage and apoptosis markers and improved markers associated with endothelial cell integrity in both lungs. In addition, gene expression of catalase and nuclear factor erythroid 2-related factor 2 increased after MSC(BM) therapy. In the ischemic lung, MSC(BM) therapy mitigated endothelial cell damage and apoptosis and increased gene expression associated with endothelial cell integrity. Conversely, in the non-ischemic lung, apoptosis gene expression increased in the IR group but not after MSC(BM) therapy. CONCLUSION: This study demonstrates distinct effects of MSC(BM) therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. The findings underscore the importance of evaluating both lung types in ischemia-reperfusion studies, offering insights into the therapeutic potential of MSC(BM) therapy in the context of lung injury.

GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and pre-clinical evaluation in ARDS treatment.

BACKGROUND AIMS: Extracellular vesicles (EVs) represent a new axis of intercellular communication that can be harnessed for therapeutic purposes, as cell-free therapies. The clinical application of mesenchymal stromal cell (MSC)-derived EVs, however, is still in its infancy and faces many challenges. The heterogeneity inherent to MSCs, differences among donors, tissue sources, and variations in manufacturing conditions may influence the release of EVs and their cargo, thus potentially affecting the quality and consistency of the final product. We investigated the influence of cell culture and conditioned medium harvesting conditions on the physicochemical and proteomic profile of human umbilical cord MSC-derived EVs (hUCMSC-EVs) produced under current good manufacturing practice (cGMP) standards. We also evaluated the efficiency of the protocol in terms of yield, purity, productivity, and expression of surface markers, and assessed the biodistribution, toxicity and potential efficacy of hUCMSC-EVs in pre-clinical studies using the LPS-induced acute lung injury model. METHODS: hUCMSCs were isolated from a cord tissue, cultured, cryopreserved, and characterized at a cGMP facility. The conditioned medium was harvested at 24, 48, and 72 h after the addition of EV collection medium. Three conventional methods (nanoparticle tracking analysis, transmission electron microscopy, and nanoflow cytometry) and mass spectrometry were used to characterize hUCMSC-EVs. Safety (toxicity of single and repeated doses) and biodistribution were evaluated in naive mice after intravenous administration of the product. Efficacy was evaluated in an LPS-induced acute lung injury model. RESULTS: hUCMSC-EVs were successfully isolated using a cGMP-compliant protocol. Comparison of hUCMSC-EVs purified from multiple harvests revealed progressive EV productivity and slight changes in the proteomic profile, presenting higher homogeneity at later timepoints of conditioned medium harvesting. Pooled hUCMSC-EVs showed a non-toxic profile after single and repeated intravenous administration to naive mice. Biodistribution studies demonstrated a major concentration in liver, spleen and lungs. HUCMSC-EVs reduced lung damage and inflammation in a model of LPS-induced acute lung injury. CONCLUSIONS: hUCMSC-EVs were successfully obtained following a cGMP-compliant protocol, with consistent characteristics and pre-clinical safety profile, supporting their future clinical development as cell-free therapies.

The Role of Ultrasonography in the Process of Weaning from Mechanical Ventilation in Critically Ill Patients.

Weaning patients from mechanical ventilation (MV) is a complex process that may result in either success or failure. The use of ultrasound at the bedside to assess organs may help to identify the underlying mechanisms that could lead to weaning failure and enable proactive measures to minimize extubation failure. Moreover, ultrasound could be used to accurately identify pulmonary diseases, which may be responsive to respiratory physiotherapy, as well as monitor the effectiveness of physiotherapists' interventions. This article provides a comprehensive review of the role of ultrasonography during the weaning process in critically ill patients.

Comparison between high-flow nasal oxygen (HFNO) alternated with non-invasive ventilation (NIV) and HFNO and NIV alone in patients with COVID-19: a retrospective cohort study.

BACKGROUND: Non-invasive respiratory support (conventional oxygen therapy [COT], non-invasive ventilation [NIV], high-flow nasal oxygen [HFNO], and NIV alternated with HFNO [NIV + HFNO] may reduce the need for invasive mechanical ventilation (IMV) in patients with COVID-19. The outcome of patients treated non-invasively depends on clinical severity at admission. We assessed the need for IMV according to NIV, HFNO, and NIV + HFNO in patients with COVID-19 according to disease severity and evaluated in-hospital survival rates and hospital and intensive care unit (ICU) lengths of stay. METHODS: This cohort study was conducted using data collected between March 2020 and July 2021. Patients ≥ 18 years admitted to the ICU with a diagnosis of COVID-19 were included. Patients hospitalized for < 3 days, receiving therapy (COT, NIV, HFNO, or NIV + HFNO) for < 48 h, pregnant, and with no primary outcome data were excluded. The COT group was used as reference for multivariate Cox regression model adjustment. RESULTS: Of 1371 patients screened, 958 were eligible: 692 (72.2%) on COT, 92 (9.6%) on NIV, 31 (3.2%) on HFNO, and 143 (14.9%) on NIV + HFNO. The results for the patients in each group were as follows: median age (interquartile range): NIV (64 [49-79] years), HFNO (62 [55-70] years), NIV + HFNO (62 [48-72] years) (p = 0.615); heart failure: NIV (54.5%), HFNO (36.3%), NIV + HFNO (9%) (p = 0.003); diabetes mellitus: HFNO (17.6%), NIV + HFNO (44.7%) (p = 0.048). > 50% lung damage on chest computed tomography (CT): NIV (13.3%), HFNO (15%), NIV + HFNO (71.6%) (p = 0.038); SpO2/FiO2: NIV (271 [118-365] mmHg), HFNO (317 [254-420] mmHg), NIV + HFNO (229 [102-317] mmHg) (p = 0.001); rate of IMV: NIV (26.1%, p = 0.002), HFNO (22.6%, p = 0.023), NIV + HFNO (46.8%); survival rate: HFNO (83.9%), NIV + HFNO (63.6%) (p = 0.027); ICU length of stay: NIV (8.5 [5-14] days), NIV + HFNO (15 [10-25] days (p < 0.001); hospital length of stay: NIV (13 [10-21] days), NIV + HFNO (20 [15-30] days) (p < 0.001). After adjusting for comorbidities, chest CT score and SpO2/FiO2, the risk of IMV in patients on NIV + HFNO remained high (hazard ratio, 1.88; 95% confidence interval, 1.17-3.04). CONCLUSIONS: In patients with COVID-19, NIV alternating with HFNO was associated with a higher rate of IMV independent of the presence of comorbidities, chest CT score and SpO2/FiO2. Trial registration ClinicalTrials.gov identifier: NCT05579080.

Derivation and external validation of predictive models for invasive mechanical ventilation in intensive care unit patients with COVID-19.

BACKGROUND: This study aimed to develop prognostic models for predicting the need for invasive mechanical ventilation (IMV) in intensive care unit (ICU) patients with COVID-19 and compare their performance with the Respiratory rate-OXygenation (ROX) index. METHODS: A retrospective cohort study was conducted using data collected between March 2020 and August 2021 at three hospitals in Rio de Janeiro, Brazil. ICU patients aged 18 years and older with a diagnosis of COVID-19 were screened. The exclusion criteria were patients who received IMV within the first 24 h of ICU admission, pregnancy, clinical decision for minimal end-of-life care and missing primary outcome data. Clinical and laboratory variables were collected. Multiple logistic regression analysis was performed to select predictor variables. Models were based on the lowest Akaike Information Criteria (AIC) and lowest AIC with significant p values. Assessment of predictive performance was done for discrimination and calibration. Areas under the curves (AUC)s were compared using DeLong's algorithm. Models were validated externally using an international database. RESULTS: Of 656 patients screened, 346 patients were included; 155 required IMV (44.8%), 191 did not (55.2%), and 207 patients were male (59.8%). According to the lowest AIC, arterial hypertension, diabetes mellitus, obesity, Sequential Organ Failure Assessment (SOFA) score, heart rate, respiratory rate, peripheral oxygen saturation (SpO2), temperature, respiratory effort signals, and leukocytes were identified as predictors of IMV at hospital admission. According to AIC with significant p values, SOFA score, SpO2, and respiratory effort signals were the best predictors of IMV; odds ratios (95% confidence interval): 1.46 (1.07-2.05), 0.81 (0.72-0.90), 9.13 (3.29-28.67), respectively. The ROX index at admission was lower in the IMV group than in the non-IMV group (7.3 [5.2-9.8] versus 9.6 [6.8-12.9], p < 0.001, respectively). In the external validation population, the area under the curve (AUC) of the ROX index was 0.683 (accuracy 63%), the AIC model showed an AUC of 0.703 (accuracy 69%), and the lowest AIC model with significant p values had an AUC of 0.725 (accuracy 79%). CONCLUSIONS: In the development population of ICU patients with COVID-19, SOFA score, SpO2, and respiratory effort signals predicted the need for IMV better than the ROX index. In the external validation population, although the AUCs did not differ significantly, the accuracy was higher when using SOFA score, SpO2, and respiratory effort signals compared to the ROX index. This suggests that these variables may be more useful in predicting the need for IMV in ICU patients with COVID-19. GOV IDENTIFIER: NCT05663528.

Justificativa e limitações da SpO2/FiO2 como possível substituta da PaO2/FiO2 em diferentes cenários pré-clínicos e clínicos / Rationale and limitations of the SpO2/FiO2 as a possible substitute for PaO2/FiO2 in different preclinical and clinical scenarios

RESUMO Embora a PaO2/FiO2 derivada da gasometria arterial continue sendo o padrão-ouro do diagnóstico de insuficiência respiratória aguda, a SpO2/FiO2 tem sido investigada como potencial substituta. Esta revisão narrativa apresenta o estado da literatura pré-clínica e clínica sobre a SpO2/FiO2 como possível substituta da PaO2/FiO2 e para uso como marcador diagnóstico e prognóstico; ainda, é fornecida uma visão geral da oximetria de pulso e suas limitações, além da avaliação da utilidade da SpO2/ FiO2 como substituta da PaO2/FiO2 em pacientes com COVID-19. Ao todo, foram encontrados 49 estudos comparando SpO2/FiO2 e PaO2/ FiO2 com base em uma estratégia de pesquisa mínima. A maioria dos estudos foi realizada em recémnascidos, alguns foram realizados em adultos com síndrome do desconforto respiratório agudo, e outros foram realizados em outros cenários clínicos (incluindo poucos em pacientes com COVID-19). Há certa evidência de que os critérios de SpO2/FiO2 podem substituir a PaO2/FiO2 em diferentes cenários clínicos. Isso é reforçado pelo fato de que devem ser evitados procedimentos invasivos desnecessários em pacientes com insuficiência respiratória aguda. É inegável que os oxímetros de pulso estão cada vez mais difundidos e podem proporcionar um monitoramento sem custos. Portanto, substituir a PaO2/FiO2 pela SpO2/FiO2 pode permitir que instalações com recursos limitados diagnostiquem a insuficiência respiratória aguda de maneira objetiva.

ABSTRACT Although the PaO 2/FiO 2 derived from arterial blood gas analysis remains the gold standard for the diagnosis of acute respiratory failure, the SpO2/FiO2 has been investigated as a potential substitute. The current narrative review presents the state of the preclinical and clinical literature on the SpO2/FiO2 as a possible substitute for PaO2/FiO2 and for use as a diagnostic and prognostic marker; provides an overview of pulse oximetry and its limitations, and assesses the utility of SpO2/ FiO2 as a surrogate for PaO2/FiO2 in COVID-19 patients. Overall, 49 studies comparing SpO2/FiO2 and PaO2/FiO2 were found according to a minimal search strategy. Most were conducted on neonates, some were conducted on adults with acute respiratory distress syndrome, and a few were conducted in other clinical scenarios (including a very few on COVID-19 patients). There is some evidence that the SpO2/ FiO2 criteria can be a surrogate for PaO2/FiO2 in different clinical scenarios. This is reinforced by the fact that unnecessary invasive procedures should be avoided in patients with acute respiratory failure. It is undeniable that pulse oximeters are becoming increasingly widespread and can provide costless monitoring. Hence, replacing PaO2/FiO2 with SpO2/FiO2may allow resourcelimited facilities to objectively diagnose acute respiratory failure.

Development of different degrees of elastase-induced emphysema in mice: a randomized controlled experimental study

Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity. Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined. Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase. Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes.

Desenvolvimento de um novo modelo experimental de síndrome do compartimento abdominal / Developing a new experimental model of abdominal compartment syndrome

OBJETIVO: Este artigo objetiva descrever um modelo experimental, inédito, que mimetiza a síndrome do compartimento abdominal (SCA). MÉTODOS: Foram utilizados 20 ratos distribuídos aleatoriamente em quatro grupos. Para simular a SCA foi induzida hipertensão intra-abdominal (HIA) através da inserção de curativo cirúrgico algodoado (Zobec®) de 15x15cm (pressão intra-abdominal constante e igual a 12mmHg) associada à hipovolemia induzida através da retirada de sangue, mantendo-se a pressão arterial média (PAM) em torno de 60mmHg (HIPO). Para dissociar os efeitos da HIA daqueles induzidos pela hipovolemia per se, dois outros grupos foram analisados: aquele com somente HIA e outro com hipovolemia. O grupo Simulação (sham) foi submetido ao mesmo procedimento cirúrgico anteriormente realizado; entretanto, os níveis de pressão intra-abdominal e PAM se mantiveram iguais a 3mmHg e 90mmHg, respectivamente. RESULTADOS: Ao analisar o impacto da HIA sobre o intestino delgado, constataram-se necrose das vilosidades, congestão e infiltração neutrofílica. A hipovolemia induziu somente inflamação e edema do vilo. Entretanto, a associação de HIA e HIPO induziu, além de piora dos parâmetros supracitados, ao infarto hemorrágico. CONCLUSÃO: O presente modelo foi eficiente em induzir SCA expressa pelas repercussões encontradas no intestino delgado.

OBJECTIVE: To describe an experimental, unprecedented model that mimics the abdominal compartment syndrome (ACS). METHODS: twenty rats were randomly divided into four groups. To simulate ACS intra-abdominal hypertension (IAH) was induced by inserting cotton surgical dressing (Zobec ®), 15x15cm (intra-abdominal pressure constant and equal to 12 mmHg) associated with hypovolemia induced by withdrawing blood, keeping mean arterial pressure (MAP) around 60 mmHg (HYPO). To dissociate the effects of those IAH-induced hypovolemia per se, two other groups were analyzed: one with only with IAH and another with only hypovolemia. The simulation group (sham) underwent the same surgical procedure performed earlier, however, the levels of intra-abdominal pressure and MAP were kept in 3 mmHg and 90 mmHg, respectively. RESULTS: By analyzing the impact of IAH on the small intestine, we observed necrosis of the villi, congestion, and neutrophilic infiltration. Hypovolemia induced only inflammation and edema of the villi. However, the association of IAH and HYPO led to hemorrhagic infarction, besides worsening of the aforementioned parameters. CONCLUSION: This model was effective in inducing ACS expressed by the effects found in the small intestine.

Uso de corticosteroide na síndrome do desconforto respiratório agudo em pacientes pediátricos / Corticosteroids therapy in pediatric acute respiratory distress syndrome

A terapia com corticosteroide na lesão pulmonar aguda e na síndrome do desconforto respiratório agudo é um dos temas mais controversos na literatura. Apesar de o corticosteroide ser amplamente utilizado na faixa etária pediátrica, os estudos com corticosteroide na lesão pulmonar aguda/síndrome do desconforto respiratório agudo são restritos a adultos. Esse artigo realiza uma revisão crítica dos estudos experimentais e clínicos sobre a utilização de corticosteroide na síndrome do desconforto respiratório agudo, procurando apontar os prováveis riscos e benefícios da sua utilização em pediatria. Para tal, foi realizada ampla revisão da literatura, de 1980 a 2010, incluindo artigos experimentais e clínicos, bem como metanálises, usando-se o banco de dados do Medline, Registro Central da Cochrane de ensaios clínicos controlados, banco de dados de revisões sistemáticas da Cochrane, SciELO, LILACS e BIREME. As palavras chaves utilizadas foram: lesão pulmonar aguda, síndrome do desconforto respiratório agudo, corticosteroides, criança, ensaios clínicos, metanálises, revisões e relato de casos. A corticoterapia na lesão pulmonar aguda/síndrome do desconforto respiratório agudo foi associada à redução da resposta inflamatória sistêmica, melhora da oxigenação e da disfunção orgânica múltipla, diminuição do tempo de ventilação mecânica e dos dias de internação nas unidades de terapia intensiva. Sugere-se, para pacientes pediátricos, o uso precoce (nas primeiras 72h) e prolongado (por 14 dias) de metilprednisolona na lesão pulmonar aguda/síndrome do desconforto respiratório agudo, com dose de 1 mg/kg/dia sob infusão contínua para evitar variabilidade glicêmica e recomenda-se controle rígido da existência de infecção. Propõe-se a adequação de alguns aspectos do diagnóstico, da intervenção e da seleção de desfechos para viabilizar os estudos em pediatria. É fundamental a realização de mais pesquisas para elucidar a segurança e eficácia da administração de metilprednisolona na lesão pulmonar aguda/síndrome do desconforto respiratório agudo em crianças, bem como estabelecer os melhores parâmetros a serem utilizados no diagnóstico e acompanhamento da doença, na monitorização das complicações da corticoterapia, bem como os desfechos primários mais adequados.

The use of corticosteroids in acute lung injury and acute respiratory distress syndrome is one of the most controversial issues in the literature. However, acute lung injury/acute respiratory distress syndrome studies are restricted to adults, despite the widespread use of corticosteroid for hyper-reactive respiratory airway diseases in children. This review aimed to describe experimental and clinical evidence for corticosteroid therapy in acute lung injury/acute respiratory distress syndrome and to point out the risks and benefits of its use in pediatrics. For this purpose, an extensive review of the literature was performed from 1980 to 2010 including both experimental and clinical papers, as well as reviews and meta-analysis, using Medline, Cochrane Central Register of Controlled Trials, Cochrane database of systematic reviews, SciELO, Lilacs and Bireme databases. The search terms were: acute lung injury, acute respiratory distress syndrome, steroids, child, clinical trials, meta-analyses, reviews, and case reports. Most studies showed that the corticosteroids-induced down-regulation of systemic inflammatory response is associated with oxygenation improvement, reduction of multiple organ dysfunctions, mechanical ventilation time, and intensive care units length of stay. Based on the literature, the authors suggest early and prolonged methylprednisolone administration for acute lung injury/acute respiratory distress syndrome, using continuous 1 mg/kg/day infusion to prevent glycemic variability, associated with strict infection surveillance. In addition, they recommend some diagnostic parameters, interventions and choices of endpoint variables to be adjusted to improve pediatric trials feasibility. Therefore, more research is required to establish the safety and efficacy of methylprednisolone in pediatric patients with acute lung injury/acute respiratory distress syndrome , as well as to determine the best parameters for monitoring steroid side effects and outcomes.

Controvérsias acerca da acidose hipercápnica na síndrome do desconforto respiratório agudo / Controversies involving hypercapnic acidosis in acute respiratory distress syndrome

A síndrome do desconforto respiratório agudo é caracterizada por uma reação inflamatória difusa do parênquima pulmonar induzida por um insulto direto ao epitélio alveolar (síndrome do desconforto respiratório agudo pulmonar) ou indireto por meio do endotélio vascular (síndrome do desconforto respiratório agudo extrapulmonar). A principal estratégia terapêutica da síndrome do desconforto respiratório agudo é o suporte ventilatório. Entretanto, a ventilação mecânica pode agravar a lesão pulmonar. Nesse contexto, uma estratégia ventilatória protetora com baixo volume corrente foi proposta. Tal estratégia reduziu a taxa de mortalidade dos pacientes com síndrome do desconforto respiratório agudo, porém acarretou acidose hipercápnica. O presente artigo apresenta uma revisão da literatura acerca dos efeitos da acidose hipercápnica na síndrome do desconforto respiratório agudo. Para tal, realizou-se uma revisão sistemática da literatura científica conforme critérios já estabelecidos para análise documental incluindo artigos experimentais e clínicos sobre o tema, usando-se como bases de dados MedLine, LILACS, SciElo, PubMed, Cochrane. A acidose hipercápnica é defendida por alguns autores como moduladora do processo inflamatório da síndrome do desconforto respiratório agudo. Entretanto, estudos clínicos e experimentais acerca dos efeitos da acidose hipercápnica têm demonstrado resultados controversos. Logo, é fundamental a realização de mais pesquisas para elucidar o papel da acidose hipercápnica na síndrome do desconforto respiratório agudo.

Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate of acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a review of literature on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as data bases MedLine, LILACS, SciELO, PubMed, Cochrane. Hypercapnic acidosis has been considered by some authors as a modulator of the inflammatory process of acute respiratory distress syndrome. However, clinical and experimental studies on the effects of hypercapnic acidosis have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome.

BCG como modulador do processo inflamatório na asma / BCG as an inflammatory modulator in asthma

A aplicação da vacina do bacilo de Calmette-Guérin (BCG) tem sido bastante estudada, no que concerne ao tratamento/prevenção do processo alérgico da asma. Nesse artigo, será realizada uma revisão crítica dos efeitos do BCG na asma, abordando as conseqüências respiratórias relacionadas a diferentes doses, momentos de aplicação e vias de administração da BCG. O BCG parece aumentar a resposta Th1, contra balançando a resposta alérgica Th2, de modo a reduzir a eosinofilia nos pulmões e a hiperreatividade brônquica, bem como promover maiores níveis de IL-12 e menores níveis de IL-4, com conseqüente melhora da função pulmonar. Entretanto, o papel do BCG na asma ainda é pouco entendido e controverso, estando diversas questões acerca de dose e momento de aplicação do BCG ainda sem respostas. Portanto, mais estudos precisam ser realizados nesta área, para que a terapia com BCG possa vir a ser utilizada de maneira segura e eficaz em humanos.

The application of the vaccine of the bacillus Calmette-Guérin (BCG) has been studied regarding the treatment/prevention of the allergic asthma process. In this article, a review will be conducted on the effects of BCG in asthma addressing the respiratoryconsequences related to different doses, time of application and BCG administration routes. The BCG appears to increase the Th1 response, balancing the allergic Th2 response in order to reduce lung eosinophilia and bronchial hyperreactivity, and promote higher levels of IL-2 and lower levels of IL-4, with consequent improvement in lung function. However, the role of BCG in asthma is still poorly understood and controversial, with several questions related to its dosage and time of application. Therefore, more studies need to be performed in this area, enabling a safe and effective therapy in humans.

Terapia com células-tronco na síndrome do desconforto respiratório agudo / Stem cell therapy in acute respiratory distress syndrome

A síndrome do desconforto respiratório agudo é caracterizada por uma reação inflamatória difusa do parênquima pulmonar, podendo ser induzida por um insulto direto ao epitélio alveolar (síndrome do desconforto respiratório agudo pulmonar) ou indireto através do endotélio vascular (síndrome do desconforto respiratório agudo extrapulmonar). Acredita-se que uma terapia eficaz para o tratamento da síndrome do desconforto respiratório agudo deva atenuar a resposta inflamatória e promover adequado reparo da lesão pulmonar. O presente artigo apresenta uma breve revisão acerca do potencial terapêutico das células-tronco na síndrome do desconforto respiratório agudo. Essa revisão bibliográfica baseou-se em uma pesquisa sistemática de artigos experimentais e clínicos sobre terapia celular na síndrome do desconforto respiratório agudo incluídos nas bases de dados MedLine e SciELO nos últimos 10 anos. O transplante de células-tronco promove melhora da lesão inflamatória pulmonar e do conseqüente processo fibrótico, induzindo adequado reparo tecidual. Dentre os mecanismos envolvidos, podemos citar: diferenciação em células do epitélio alveolar e redução na liberação de mediadores inflamatórios e sistêmicos e fatores de crescimento. A terapia com células-tronco derivadas da medula óssea pode vir a ser uma opção eficaz e segura no tratamento da síndrome do desconforto respiratório agudo por acelerar o processo de reparo e atenuar a resposta inflamatória. Entretanto, os mecanismos relacionados à atividade antiinflamatória e antifibrogênica de tais células necessitam ser mais bem elucidados, limitando, assim, o seu uso clínico imediato.

Acute respiratory distress syndrome is characterized by an acute pulmonary inflammatory process induced by the presence of a direct (pulmonary) insult that affects lung parenchyma, or an indirect (extrapulmonary) insult that results from an acute systemic inflammatory response. It is believed that an efficient therapy for the acute respiratory distress syndrome should attenuate inflammatory response and promote adequate repair of the lung injury. This article presents a brief review on the use of stem cells and their potential therapeutic effect on the acute respiratory distress syndrome. This systematic review was based upon clinical and experimental acute respiratory distress syndrome studies included in the MedLine and SciElO database during the last 10 years. Stem cell transplant lead to an improvement in lung injury and fibrotic process by inducing adequate tissue repair. This includes alveolar epithelial cell differentiation,and also reduces pulmonary and systemic inflammatory mediators and secretion of growth factors. Stem cells could be a potential therapy for acute respiratory distress syndrome promoting lung repair and attenuating the inflammatory response. However, mechanisms involving their anti-inflammatory and antifibrinogenic effects require better elucidation, limiting their immediate clinical use in acute respiratory distress syndrome.

Terapia com surfactante na síndrome do desconforto respiratório agudo: prós e contras / Surfactant therapy in acute respiratory distress syndrome: pros and cons

A síndrome do desconforto respiratório agudo (SDRA) acarreta disfunção quantitativa e qualitativa do sistema de surfactante pulmonar endógeno, levando à disfunção respiratória. Nesse contexto, a administração de surfactante pode vir a ser uma opção de terapêutica na SDRA, com importante impacto sobre a função pulmonar e a oxigenação. O presente artigo apresenta uma breve revisão acerca do potencial terapêutico do surfactante na SDRA. Para tal, foi realizada uma revisão sistemática da literatura, através das bases de dados MedLine, Scielo e Lilacs, onde foram incluídos artigos dos últimos anos, referentes ao assunto. Os artigos incluídos abordaram a terapêutica de reposição do surfactante em estudos experimentais e clínicos, assim como revisões sistemáticas sobre aspectos bioquímicos e fisiológicos do surfactante e da SDRA. Apesar de diversos estudos experimentais terem evidenciado efeitos benéficos com o uso do surfactante exógeno na SDRA, proporcionando melhora da função pulmonar, os trabalhos clínicos vêm apresentando resultados controversos. Entretanto, a administração de novos surfactantes exógenos tem apresentado resultados promissores. Concluindo, o uso do surfactante exógeno pode vir a fazer parte do tratamento dos pacientes portadores de SDRA.

Acute respiratory distress syndrome (ARDS) causes changes in pulmonary surfactant leading to respiratory dysfunction. In this context, the administration of surfactant may become a therapeutic option for ARDS with significant impact on lung function and oxygenation. This article presents a brief review regarding the potential of surfactant therapy in acute respiratorydistress syndrome. We performed a systematic review of the literature using the following databases: MedLine,SciELO and Lilacs. Experimental and clinical studies related to surfactant therapy in ARDS as well as systematic reviews of the biochemical and physiological aspects of surfactant were included in the present manuscript. Despite several experimental studies have shown beneficial effects with the use of surfactant in ARDS, leading to improvement in lung function, clinicalstudies have shown controversial results. However, the use of new surfactants has providing promising results. Therefore, use of surfactant can become part of ARDS patient treatment.

Entendendo a fisiopatologia da silicose / Understanding the pathophysiology of silicosis

A silicose é uma doença fibrogênica, progressiva e irreversível, que resulta em falência respiratória, por alterações da ventilação pulmonar e das trocas gasosas. As alterações patológicas são representadas pela presença de granulomas, ou nódulos inflamatórios de células mononucleares, nos locais onde as partículas de sílica se acumulam. A silicose é uma pneumoconiose de alta prevalência, atribuída à inalação de sílica ou dióxido de silício (SiO2). Na maioria das vezes, a silicose ocorre devido à intensa exposição ocupacional à partícula de sílica, estando a sua ocorrência fora do ambiente de trabalho restrita a situações climáticas e geológicas específicas. Logo, a silicose é passível de prevenção, porém não dispõe de um tratamento eficaz. Esse artigo realizará uma revisão crítica dos estudos experimentais e clínicos que vêm sendo realizados na tentativa deelucidar os mecanismos pelos quais a silicose se desenvolve, para assim elaborar uma terapia específica e eficaz.

Silicosis is a fibrogenic, progressive and irreversible disease, which results in pulmonary insufficiency by altering lung ventilation and gas exchange. Pathologically, it is characterized by the development of nodules of mononuclear cell inflammation at sites of mineral particle accumulation. It is an important occupational lung disease with high prevalence that results from the chronic inhalation of silica or silicon dioxide (SiO2). The occurrence of silicosis outside the workplace is restricted to specific climatic and geological situations. Therefore, silicosis may be prevented; however, there is no specific therapy so far. This article critically reviews experimental and clinical studies that are being developed to elucidate the mechanisms in order toelaborate a specific and effective therapy.

Terapia celular nas doenças respiratórias / Cell therapy for respiratory diseases

As células-tronco são definidas como células indiferenciadas, com capacidade de se dividir por período indefinido, em cultura, e se diferenciar em diversos tipos celulares especializados, dependendo do estímulo ao qual são submetidas. Nesse artigo, será realizada uma revisão crítica dos efeitos da terapia com células-tronco em algumas doenças respiratórias tais como: síndrome do desconforto respiratório agudo, fibrose pulmonar, asma e enfisema. Estudos recentes têm mostrado os efeitos benéficos da administração de células-tronco endógenas e exógenas no desenvolvimento, reparo e remodelamento do pulmão em diversas doenças respiratórias. Entretanto, a biologia das células-tronco ainda é pouco entendida devido às limitações técnicas atuais, estando diversas questões ainda sem respostas. Portanto, mais estudos são necessários para ummelhor entendimento dos mecanismos que controlam a divisão e diferenciação dessas células, para que, assim, a terapia celular possa ser utilizada de maneira segura e eficaz em humanos.

Stem cells are defined as undifferentiated progenitors that can self-renew ad infinitum and differentiate into various specialized cell types depending on the stimulus to which they are submitted. In this article, we will perform a critical review of the effects of cell therapy in respiratory diseases such as: acute respiratory distress syndrome, pulmonary fibrosis, asthma,and emphysema. Recent studies have shown the beneficial effects of endogenous and exogenous stem cells in lung development, repair and remodeling in re spiratory diseases. However, the biology of stem cells remains poorly understood due to technical limitations, and some important questions need to be answered. More studies should be performed to better understand the mechanisms that control cell division and differentiation, therefore enabling the use of cell therapy in humanrespiratory diseases.

Stem cells and respiratory diseases

Stem cells have a multitude of clinical implications in the lung. This article is a critical review that includes clinical and experimental studies of MedLine and SciElo database in the last 10 years, where we highlight the effects of stem cell therapy in acute respiratory distress syndrome or more chronic disorders such as lung fibrosis and emphysema. Although, many studies have shown the beneficial effects of stem cells in lung development, repair and remodeling; some important questions need to be answered to better understand the mechanisms that control cell division and differentiation, therefore enabling the use of cell therapy in human respiratory diseases.

As células-tronco têm uma infinidade de implicações clínicas no pulmão. Este artigo é uma revisão crítica que inclui estudos clínicos e experimentais advindos do banco de dados do MEDLINE e SciElo nos últimos 10 anos, onde foram destacados os efeitos da terapia celular na síndrome do desconforto respiratório agudo ou doenças mais crônicas, como fibrose pulmonar e enfisema. Apesar de muitos estudos demonstrarem os efeitos benéficos das células-tronco no desenvolvimento, reparo e remodelamento pulmonar; algumas questões ainda precisam ser respondidas para um melhor entendimento dos mecanismos que controlam a divisão celular e diferenciação, permitindo o uso da terapia celular nas doenças respiratórias.

Cirurgia para controle do dano: uma revisão / Damage control surgery: a review

Damage control surgery is one of the major advances in surgical practice in the last 20 years. The indications for damage control surgery are: the need to terminate a laparotomy rapidly in an exsanguinating, hypothermic patient who had developed a coagulopathy and who is about to die on the operating table; inability to control bleeding by direct hemostasis; and inability to close the abdomen without tension because of massive visceral edema and a tense abdominal wall. Damage control surgery has three phases: 1) laparotomy to control hemorrhage by packing, shunting, or balloon tamponade, or both; control of intestinal spillage by resection or ligation of damaged bowel, or both; 2) physiological resuscitation to correct hypothermia, metabolic acidosis, and coagulopathy. 3) planned reoperation for definitive repair. Damage control surgery is appropriate in a small number of critically ill patients who are likely to require substantial hospital resources. However, there are many questions that need to be answered. Who is the patient elected for this surgery? When is the ideal time to make the decision? Which are the parameters that indicate to the surgeons the moment to re-operate the patient? How to treat the long-term complications? In the present review we described some historical aspects, indications, technical aspects, advantages and disadvantages of this procedure, as well as its physiological consequences and morbidity and mortality rates of damage control surgery. Damage control surgery offers a simple effective alternative to the traditional surgical management of complex or multiple injuries in critically injured patients.

Sistemas de inalação na asma: vantagens e desvantagens / Inhalation systems for asthma: advantages and disadvantages

A administração de medicamentos por inalação possibilita grandes concentrações da droga diretamente nas vias aéreas, reduzindo os efeitos sistêmicos adversos. Há muitos inaladores disponíveis no mercado, cada um com suas vantagens e desvantagens. O inalador do simetrado pressurizado (pMDI) constitui o sistema de inalação mais usado, porém necessita de treinamento para assegurar uma adequada coordenação em seu uso. O inalador de pó seco (DPI) é mais fácil de usar do que o pMDI, mas sua eficácia pode variar de acordo com o fluxo inspiratório. Os nebulizadores dispensam uma manobra respiratória coordenada ou um grande esforço respiratório, mas são pesados e seu uso requer algum tempo. Como há evidências fisiopatológicas sugerindo que o processo inflamatório da asma acomete não somente as vias aéreas centrais, como, também, as vias aéreas periféricas e o parênquima pulmonar, estão sendo desenvolvidos novos inaladores para administrar medicamentos às vias aéreas mais distais.

Fisiopatologia e manejo clínico da ventilação seletiva / Physiopathology and clinical management of one-lung ventilation

A ventilação seletiva consiste em ventilar um pulmão mecanicamente enquanto o outro é ocluído ou exposto ao ar ambiente. Essa técnica permite visualizar as estruturas intratorácicas e, assim, fornecer excelentes condições cirúrgicas. Todo o volume corrente é administrado apenas para um único pulmão. Entretanto, este procedimento está associado à redução da pressão parcial arterial de oxigênio, principalmente em pacientes com comprometimento pulmonar prévio, por diminuição na superfície da área de troca gasosa e perda da auto-regulação pulmonar normal. Sendo assim, a manutenção da oxigenação e a eliminação de gás carbônico adequadas representam o maior desafio durante o manejo da ventilação seletiva. Preconiza-se que o pulmão dependente seja ventilado com um volume corrente similar àquele utilizado para ventilar ambos os pulmões na ventilação mecânica convencional, além de altas frações inspiradas de oxigênio. Entretanto, vários outros métodos vêm sendo propostos a fim de minimizar a hipoxemia durante a ventilação seletiva: conferir o correto posicionamento do tubo de duplo-lúmen, uso de pressão positiva ao final da expiração, pressão contínua nas vias aéreas, uso de óxido nítrico, ventilação de alta freqüência e recrutamento alveolar. O manejo da ventilação seletiva continua sendo um desafio à prática clínica.

Lung tissue remodeling in the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro¡liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patientÆs prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.