RESUMO
Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Tratamento Farmacológico da COVID-19 , Hidrogênio/farmacologia , Substâncias Protetoras/farmacologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Humanos , Sepse/tratamento farmacológico , Sepse/fisiopatologiaRESUMO
Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.
Assuntos
Lesão Pulmonar Aguda/etiologia , Interleucina-18/metabolismo , Transplante de Pulmão/efeitos adversos , Obesidade/complicações , Disfunção Primária do Enxerto/etiologia , Traumatismo por Reperfusão/etiologia , Linfócitos T Reguladores/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Obesos , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/fisiopatologia , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Acute lung injury (ALI) is an acute inflammatory process arises from a wide range of lung insults. A major cause of ALI is dysfunction of the pulmonary vascular endothelial barrier but the mechanisms involved are incompletely understood. The therapeutic potential of histone deacetylase (HDAC) inhibitors for the treatment of cardiovascular and inflammatory diseases is increasingly apparent, but the mechanisms by which HDACs regulate pulmonary vascular barrier function remain to be resolved. We found that specific Class IIa HDACs inhibitor, TMP269, significantly attenuated the lipopolysaccharide (LPS)-induced human lung microvascular endothelial cells (HLMVEC) barrier compromise in vitro and improved vascular barrier integrity and lung function in murine model of ALI in vivo. TMP269 decreased LPS-induced myosin light chain phosphorylation suggesting the role for Class IIa HDACs in LPS-induced cytoskeleton reorganization. TMP269 did not affect microtubule structure and tubulin acetylation in contrast to the HDAC6-specific inhibitor, Tubastatin A suggesting that Class IIa HDACs and HDAC6 (Class IIb) regulate endothelial cytoskeleton and permeability via different mechanisms. Furthermore, LPS increased the expression of ArgBP2 which has recently been attributed to HDAC-mediated activation of Rho. Depletion of ArgBP2 abolished the ability of LPS to disrupt barrier function in HLMVEC and both TMP269 and Tubastatin A decreased the level of ArgBP2 expression after LPS stimulation suggesting that both Class IIa and IIb HDACs regulate endothelial permeability via ArgBP2-dependent mechanism. Collectively, our data strongly suggest that Class IIa HDACs are involved in LPS-induced ALI in vitro and in vivo via specific mechanism which involved contractile responses, but not microtubule reorganization.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/enzimologia , Histona Desacetilases/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotoxinas , Frequência Cardíaca/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Microvasos/patologia , Modelos Biológicos , Oxigênio/metabolismo , Pneumonia/complicações , Pneumonia/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
To develop a dynamic in vivo near-infrared (NIR) fluorescence imaging assay to quantify sequential changes in lung vascular permeability-surface area product (PS) in rodents. Dynamic NIR imaging methods for determining lung vascular permeability-surface area product were developed and tested on non-irradiated and 13 Gy irradiated rats with/without treatment with lisinopril, a radiation mitigator. A physiologically-based pharmacokinetic (PBPK) model of indocyanine green (ICG) pulmonary disposition was applied to in vivo imaging data and PS was estimated. In vivo results were validated by five accepted assays: ex vivo perfused lung imaging, endothelial filtration coefficient (Kf) measurement, pulmonary vascular resistance measurement, Evan's blue dye uptake, and histopathology. A PBPK model-derived measure of lung vascular permeability-surface area product increased from 2.60 ± 0.40 [CL: 2.42-2.78] mL/min in the non-irradiated group to 6.94 ± 8.25 [CL: 3.56-10.31] mL/min in 13 Gy group after 42 days. Lisinopril treatment lowered PS in the 13 Gy group to 4.76 ± 6.17 [CL: 2.12-7.40] mL/min. A much higher up to 5× change in PS values was observed in rats exhibiting severe radiation injury. Ex vivo Kf (mL/min/cm H2O/g dry lung weight), a measure of pulmonary vascular permeability, showed similar trends in lungs of irradiated rats (0.164 ± 0.081 [CL: 0.11-0.22]) as compared to non-irradiated controls (0.022 ± 0.003 [CL: 0.019-0.025]), with reduction to 0.070 ± 0.035 [CL: 0.045-0.096] for irradiated rats treated with lisinopril. Similar trends were observed for ex vivo pulmonary vascular resistance, Evan's blue uptake, and histopathology. Our results suggest that whole body dynamic NIR fluorescence imaging can replace current assays, which are all terminal. The imaging accurately tracks changes in PS and changes in lung interstitial transport in vivo in response to radiation injury.
Assuntos
Lesão Pulmonar Aguda , Permeabilidade Capilar/efeitos da radiação , Pulmão , Imagem Óptica , Lesões Experimentais por Radiação , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Feminino , Verde de Indocianina/farmacocinética , Verde de Indocianina/farmacologia , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pulmão/fisiopatologia , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/fisiopatologia , RatosRESUMO
Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.
Assuntos
Hemoglobinas/metabolismo , Pneumonia/metabolismo , Artéria Pulmonar/fisiopatologia , Choque Séptico/metabolismo , Infecções Estafilocócicas/metabolismo , Acidose/metabolismo , Acidose/fisiopatologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cães , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hemoglobinas/farmacologia , Ferro/metabolismo , Ácido Láctico/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/fisiopatologia , Óxido Nítrico/metabolismo , Pneumonia/fisiopatologia , Troca Gasosa Pulmonar , Distribuição Aleatória , Choque Séptico/fisiopatologia , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.
Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Comitês de Cuidado Animal/organização & administração , Bem-Estar do Animal/normas , Animais de Laboratório , Consenso , Animais , Biomarcadores , Humanos , Modelos Animais , Médicos Veterinários/normasRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has rapidly spread throughout the world since December 2019 to become a global public health emergency for the elevated deaths and hospitalizations in Intensive Care Units. The severity spectrum of SARS-CoV-2 pneumonia ranges from mild to severe clinical conditions. The clinical course of SARS-CoV-2 disease is correlated with multiple factors including host characteristics (genetics, immune status, age, and general health), viral load and, above all, the host distribution of the airways and lungs of the viral receptor cells. In this review, we will briefly summarize the current knowledge of the characteristics and management of coronavirus disease 2019-pneumonia. However, other studies are needed to better understand the pathogenetic mechanisms induced by SARS-Cov-2 infection, and to evaluate the long-term consequences of the virus on the lungs.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , COVID-19/patologia , COVID-19/fisiopatologia , Gerenciamento Clínico , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologiaRESUMO
BACKGROUND: Hypoxia induced injury of pulmonary microvascular endothelial barrier is closely related to the pathogenesis of acute lung injury after lung transplantation. VE-cadherin is an important structural molecule for pulmonary microvascular endothelial barrier. In this study, we aim to investigate the roles of VE-cadherin in hypoxia induced injury of pulmonary microvascular endothelial barrier. METHODS: Rat model of hypoxia and cultured pulmonary microvascular endothelial cells (PMVECs) were utilized. Determination of PMVECs apoptosis, skeleton combination was conducted to verify the effects of hypoxia on injury of pulmonary microvascular endothelial barrier. In addition, VE-cadherin expression was modulated by administration of siRNA in order to investigate the roles of VE-cadherin in hypoxia induced PMVECs apoptosis and skeleton recombination. RESULTS: Our data indicated that expression of VE-cadherin was down-regulated in hypoxia-exposed PMVECs. Whereas, in the cells treated using siRNA, down-regulation of VE-cadherin did not trigger PMVECs apoptosis, but it increased the sensitivity of PMVECs to the hypoxia induced apoptosis. In cases of hypoxia, the expression of VE-cadherin was significantly down-regulated, together with endothelial skeleton recombination and increase of permeability, which then triggered endothelial barrier dysfunction. CONCLUSIONS: These data verify that VE-cadherin expression played an important role in hypoxia induced PMVECs apoptosis and cellular skeletal recombination.
Assuntos
Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Antígenos CD/fisiologia , Caderinas/fisiologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Microcirculação , Circulação Pulmonar , Animais , Apoptose , Permeabilidade da Membrana Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Células Endoteliais/patologia , Hipóxia , Masculino , Ratos Sprague-DawleyRESUMO
Iron is typically the dominant metal in the ultrafine fraction of airborne particulate matter. Various studies have investigated the toxicity of inhaled nano-sized iron oxide particles (FeOxNPs) but their results have been contradictory, with some indicating no or minor effects and others finding effects including oxidative stress and inflammation. Most studies, however, did not use materials reflecting the characteristics of FeOxNPs present in the environment. We, therefore, analysed the potential toxicity of FeOxNPs of different forms (Fe3O4, α-Fe2O3 and γ-Fe2O3) reflecting the characteristics of high iron content nano-sized particles sampled from the environment, both individually and in a mixture (FeOx-mix). A preliminary in vitro study indicated Fe3O4 and FeOx-mix were more cytotoxic than either form of Fe2O3 in human bronchial epithelial cells (BEAS-2B). Follow-up in vitro (0.003, 0.03, 0.3 µg/mL, 24 h) and in vivo (Sprague-Dawley rats, nose-only exposure, 50 µg/m3 and 500 µg/m3, 3 h/d × 3 d) studies therefore focused on these materials. Experiments in vitro explored responses at the molecular level via multi-omics analyses at concentrations below those at which significant cytotoxicity was evident to avoid detection of responses secondary to toxicity. Inhalation experiments used aerosol concentrations chosen to produce similar levels of particle deposition on the airway surface as were delivered in vitro. These were markedly higher than environmental concentrations. No clinical signs of toxicity were seen nor effects on BALF cell counts or LDH levels. There were also no significant changes in transcriptomic or metabolomic responses in lung or BEAS-2B cells to suggest adverse effects.
Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Inflamação/fisiopatologia , Pulmão/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Aerossóis/química , Aerossóis/toxicidade , Poluentes Atmosféricos/toxicidade , Animais , Linhagem Celular , Humanos , Inflamação/induzido quimicamente , Exposição por Inalação , Pulmão/patologia , Material Particulado/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , COVID-19/metabolismo , COVID-19/fisiopatologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/fisiopatologia , Tratamento Farmacológico da COVID-19RESUMO
The most common cause of acute lung injury is ischemia-reperfusion injury (IRI), during which mitochondrial damage occurs. We have previously demonstrated that mitochondrial transplantation is an efficacious therapy to replace or augment mitochondria damaged by IRI, allowing for enhanced muscle viability and function in cardiac tissue. Here, we investigate the efficacy of mitochondrial transplantation in a murine lung IRI model using male C57BL/6J mice. Transient ischemia was induced by applying a microvascular clamp on the left hilum for 2 h. Upon reperfusion mice received either vehicle or vehicle-containing mitochondria either by vascular delivery (Mito V) through the pulmonary artery or by aerosol delivery (Mito Neb) via the trachea (nebulization). Sham control mice underwent thoracotomy without hilar clamping and were ventilated for 2 h before returning to the cage. After 24 h recovery, lung mechanics were assessed and lungs were collected for analysis. Our results demonstrated that at 24 h of reperfusion, dynamic compliance and inspiratory capacity were significantly increased and resistance, tissue damping, elastance, and peak inspiratory pressure (Mito V only) were significantly decreased (P < 0.05) in Mito groups as compared with their respective vehicle groups. Neutrophil infiltration, interstitial edema, and apoptosis were significantly decreased (P < 0.05) in Mito groups as compared with vehicles. No significant differences in cytokines and chemokines between groups were shown. All lung mechanics results in Mito groups except peak inspiratory pressure in Mito Neb showed no significant differences (P > 0.05) as compared with Sham. These results conclude that mitochondrial transplantation by vascular delivery or nebulization improves lung mechanics and decreases lung tissue injury.
Assuntos
Pulmão/fisiopatologia , Mitocôndrias/fisiologia , Traumatismo por Reperfusão/fisiopatologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , Apoptose/fisiologia , Líquido da Lavagem Broncoalveolar , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Infiltração de Neutrófilos/fisiologia , Traumatismo por Reperfusão/metabolismo , Testes de Função Respiratória/métodosRESUMO
Patients with COVID-19 present a broad spectrum of clinical presentation. Whereas hypoxaemia is the marker of severity, different strategies of management should be customised to five specific individual phenotypes. Many intubated patients present with phenotype 4, characterised by pulmonary hypoxic vasoconstriction, being associated with severe hypoxaemia with "normal" (>40â mL·cmH2O-1) lung compliance and likely representing pulmonary microvascular thrombosis. Phenotype 5 is often associated with high plasma procalcitonin and has low pulmonary compliance, Which is a result of co-infection or acute lung injury after noninvasive ventilation. Identifying these clinical phenotypes and applying a personalised approach would benefit the optimisation of therapies and improve outcomes.
Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Betacoronavirus/genética , Infecções por Coronavirus/genética , Fenótipo , Pneumonia Viral/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Lesão Pulmonar Aguda/terapia , Lesão Pulmonar Aguda/virologia , Biomarcadores/sangue , Pesquisa Biomédica , COVID-19 , Infecções por Coronavirus/terapia , Gerenciamento Clínico , Feminino , Humanos , Hipóxia/diagnóstico , Hipóxia/etiologia , Complacência Pulmonar/genética , Masculino , Pandemias , Pneumonia Viral/terapia , Pró-Calcitonina/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , SARS-CoV-2RESUMO
IMPORTANCE: Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV (RAAS-SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. OBSERVATIONS: This review discusses the role of the RAAS-SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS-SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited. CONCLUSION: Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV axis on acute lung injury in COVID-19.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Angiotensina II/metabolismo , Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/fisiologia , Lesão Pulmonar Aguda/fisiopatologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , COVID-19 , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Humanos , Pandemias , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
OBJECTIVES: Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures. DATA SOURCES: Online search of published scientific literature via Pubmed using the term "epigenetics" in combination with the terms "sepsis", "infection", "bacterial infection", "viral infection", "critical illness", "acute respiratory distress syndrome", and "acute lung injury". STUDY SELECTION: Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles. DATA EXTRACTION: Relevant data was extracted and synthesized for narrative review. DATA SYNTHESIS: Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1ß. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury. CONCLUSIONS: Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers.
Assuntos
Estado Terminal , Epigênese Genética/fisiologia , Sepse/genética , Sepse/fisiopatologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/fisiopatologia , Animais , Biomarcadores , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Expressão Gênica/fisiologia , Histonas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Insuficiência de Múltiplos Órgãos/genética , Insuficiência de Múltiplos Órgãos/fisiopatologia , RNA não Traduzido/metabolismo , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/fisiopatologiaRESUMO
Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by diffuse inflammation and edema formation. The main management strategy, low tidal volume ventilation, can be associated with the development of hypercapnic acidosis (HCA). Mesenchymal stem cells (MSCs) are a promising therapeutic candidate currently in early-phase clinical trials. The effects of HCA on the alveolar epithelium and capillary endothelium are not well established. The therapeutic efficacy of MSCs has never been reported in HCA. In the present study, we evaluated the effects of HCA on inflammatory response and reparative potential of the primary human small airway epithelial and lung microvasculature endothelial cells as well as on the capacity of bone marrow-derived MSCs to promote wound healing in vitro. We demonstrate that HCA attenuates the inflammatory response and reparative potential of primary human small airway epithelium and capillary endothelium and induces mitochondrial dysfunction. It was found that MSCs promote lung epithelial wound repair via the transfer of functional mitochondria; however, this proreparative effect of MSCs was lost in the setting of HCA. Therefore, HCA may adversely impact recovery from ARDS at the cellular level, whereas MSCs may not be therapeutically beneficial in patients with ARDS who develop HCA.-Fergie, N., Todd, N., McClements, L., McAuley, D., O'Kane, C., Krasnodembskaya, A. Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair.
Assuntos
Células Endoteliais/fisiologia , Pulmão/fisiopatologia , Células-Tronco Mesenquimais/fisiologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Mucosa Respiratória/fisiopatologia , Acidose , Lesão Pulmonar Aguda/fisiopatologia , Linhagem Celular , Humanos , Inflamação/fisiopatologiaRESUMO
BACKGROUND: Acute lung injury (ALI) is a frequent complication after severe trauma. Lung-protective ventilation strategies and damage control resuscitation have been proposed for the prevention of ALI; however, there are no clinical or laboratory parameters to predict who is at risk of developing ALI after trauma. In the present study, we explored pulmonary inflammatory markers as a potential predictor of ALI using a porcine model of hemorrhagic shock. MATERIALS AND METHODS: Female swine were randomized to mechanical ventilation with low tidal volume (VT) (6 mL/kg) or high VT (12 mL/kg). After equilibration, animals underwent pressure-controlled hemorrhage (mean arterial pressure [MAP] 35 ± 5 mmHg) for 1 h, followed by resuscitation with fresh whole blood or Hextend. They were maintained at MAP of 50 ± 5 mmHg for 3 h in the postresuscitation phase. Bronchoalveolar lavage fluids were collected hourly and analyzed for inflammatory markers. Lung samples were taken, and porcine neutrophil antibody staining was used to evaluate the presence of neutrophils. ELISA evaluated serum porcine surfactant protein D levels. Sham animals were used as negative controls. RESULTS: Pigs that underwent hemorrhagic shock had higher heart rates, lower cardiac output, lower MAPs, and worse acidosis compared with sham at the early time points (P < 0.05 each). There were no significant differences in central venous pressure or pulmonary capillary wedge pressure between groups. Pulmonary neutrophil infiltration, as defined by neutrophil antibody staining on lung samples, was greater in the shock groups regardless of resuscitation fluid (P < 0.05 each). Bronchoalveolar lavage fluid neutrophil levels were not different between groups. There were no differences in levels of porcine surfactant protein D between groups at any time points, and the levels did not change over time in each respective group. CONCLUSIONS: Our study demonstrates the reproducibility of a porcine model of hemorrhagic shock that is consistent with physiologic changes in humans in hemorrhagic shock. Pulmonary neutrophil infiltration may serve as an early marker for ALI; however, the practicality of this finding has yet to be determined.
Assuntos
Lesão Pulmonar Aguda/diagnóstico , Neutrófilos/imunologia , Choque Hemorrágico/complicações , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Transfusão de Sangue , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Débito Cardíaco/imunologia , Modelos Animais de Doenças , Feminino , Frequência Cardíaca/imunologia , Humanos , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Infiltração de Neutrófilos , Valor Preditivo dos Testes , Prognóstico , Proteína D Associada a Surfactante Pulmonar/análise , Proteína D Associada a Surfactante Pulmonar/imunologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Reprodutibilidade dos Testes , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Ressuscitação/métodos , Choque Hemorrágico/imunologia , Choque Hemorrágico/terapia , Sus scrofa , Fatores de TempoRESUMO
BACKGROUND: Acute liver injury (ALI) is associated with the oxidative stress and apoptosis in liver. Recent studies have shown that miR-195, a critical member of miR-15 family, has modulated the apoptosis in various organic diseases. However, it is elusive whether miR-195 regulation exert a hepatic ameliorative effect on ALI by the suppression of apoptosis and oxidative stress levels. We aimed to explore the regulated role of miR-195 in acute liver injury via the current study. METHODS: C57BL/6 J mice (male, seven-week, 18-20 g) were administrated intraperitoneal injection with tetrachloromethane (CCl4) to induce ALI. miR-195 inhibitor or mimics loaded in lentivirus vectors (miR-195 INH or MMC) and Pim-1 loaded in Adeno-associated viral vectors (AAV-Pim-1) were respectively delivered into mouse tail intravenous to establish silence or overexpression of miR-195 and overexpression of Pim-1. Western blotting, Reverse Transcription-Polymerase Chain Reaction (RT-PCR), enzyme linked immunosorbent assay (ELISA) technique, Immunohistochemistry (IHC) and Hematoxylin-eosin (H&E) staining were conducted to measure miR-195 and Pim-1 expression, apoptosis and oxidative stress levels, histological and functional change. RESULTS: We found that the expression of miR-195 markedly increased in CCl4-induced ALI. Besides, we demonstrated that the silence of miR-195 attenuated the apoptosis and oxidative stress via up-regulating Pim-1 in CCl4-induced ALI. Moreover, the inhibition of miR-195 protected the integrity and function of liver tissue. CONCLUSIONS: The above results showed that the suppression of miR-195 ameliorated ALI through inhibiting apoptosis and oxidative stress via targeting Pim-1. Our research provided a novel scheme that the miR-195 modulation in process of ALI may be an effective therapy method and verifies a promising target for diagnostic and therapeutic strategy of miRNAs.
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Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Apoptose , MicroRNAs/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Apoptose/genética , Sequência de Bases , Tetracloreto de Carbono , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Estresse Oxidativo/genética , Recuperação de Função FisiológicaRESUMO
This review summarizes current understanding of mitochondrial bioenergetic dysfunction applicable to mechanisms of lung diseases and outlines challenges and future directions in this rapidly emerging field. Although the role of mitochondria extends beyond the term of cellular "powerhouse", energy generation remains the most fundamental function of these organelles. It is not counterintuitive to propose that intact energy supply is important for favorable cellular fate following pulmonary insult. In this review, the discussion of mitochondrial dysfunction focuses on those molecular mechanisms that alter cellular bioenergetics in the lungs: (a) inhibition of mitochondrial respiratory chain, (b) mitochondrial leak and uncoupling, (c) alteration of mitochondrial Ca2+ handling, (d) mitochondrial production of reactive oxygen species and self-oxidation. The discussed lung diseases were selected according to their pathological nature and relevance to pediatrics: Acute lung injury (ALI), defined as acute parenchymal lung disease associated with cellular demise and inflammation (Acute Respiratory Distress Syndrome, ARDS, Pneumonia), alveolar developmental failure (Bronchopulmonary Dysplasia, BPD or chronic lung disease in premature infants), obstructive airway diseases (Bronchial asthma) and vascular remodeling affecting pulmonary circulation (Pulmonary Hypertension, PH). The analysis highlights primary mechanisms of mitochondrial bioenergetic dysfunction contributing to the disease-specific pulmonary insufficiency and proposes potential therapeutic targets.
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Metabolismo Energético , Pneumopatias/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Asma/metabolismo , Asma/fisiopatologia , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Cálcio/metabolismo , Respiração Celular , Transporte de Elétrons , Humanos , Hiperóxia/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Pneumopatias/fisiopatologia , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia , Remodelação VascularRESUMO
Electronic cigarettes (e-cigarettes) are noncombustible tobacco products that have been promoted as safer alternatives to conventional cigarettes and beneficial tools for smoking cessation. However, e-cigarettes have been shown to produce aerosols with high concentrations of propylene glycol, glycerol, volatile organic compounds, and free radicals, which can lead to lung damage. Furthermore, e-cigarettes can deliver nicotine at concentrations higher than traditional combustibles, making them highly addictive. As delivery devices became smaller, less expensive, and refillable, the use of e-cigarettes dramatically increased, especially among adolescents and young adults in the United States. This rise in popularity of noncombustible products led to an outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) in the fall of 2019. In this article, we review the history of e-cigarettes and its prevalence among American youth, the EVALI outbreak and clinical presentation of EVALI patients, and recent legislative efforts to regulate e-cigarette use.
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Lesão Pulmonar Aguda/epidemiologia , Vaping/epidemiologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Adolescente , Canabidiol/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Criança , Surtos de Doenças , Dronabinol/administração & dosagem , Vapor do Cigarro Eletrônico/efeitos adversos , Vapor do Cigarro Eletrônico/química , Sistemas Eletrônicos de Liberação de Nicotina , Humanos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Estados Unidos/epidemiologia , Vaping/efeitos adversos , Vaping/legislação & jurisprudência , Adulto JovemRESUMO
Since the initial description in 2019, the novel coronavirus SARS-Cov-2 infection (COVID-19) pandemic has swept the globe. The most severe form of the disease presents with fever and shortness of breath, which rapidly deteriorates to respiratory failure and acute lung injury (ALI). COVID-19 also presents with a severe coagulopathy with a high rate of venous thromboembiolism. In addition, autopsy studies have revealed co-localized thrombosis and inflammation, which is the signature of thromboinflammation, within the pulmonary capillary vasculature. While the majority of published data is on adult patients, there are parallels to pediatric patients. In our experience as a COVID-19 epicenter, children and young adults do develop both the coagulopathy and the ALI of COVID-19. This review will discuss COVID-19 ALI from a hematological perspective with discussion of the distinct aspects of coagulation that are apparent in COVID-19. Current and potential interventions targeting the multiple thromboinflammatory mechanisms will be discussed.