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1.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669167

RESUMO

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 , /metabolismo , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , /metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/fisiopatologia
2.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L436-L450, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33404364

RESUMO

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 , Ratos
3.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429876

RESUMO

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 , /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-Dawley
4.
F1000Res ; 9: 769, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32953091

RESUMO

Background: Numerous successful therapies developed for human medicine involve animal experimentation. Animal studies that are focused solely on translational potential, may not sufficiently document unexpected outcomes. Considerable amounts of data from such studies could be used to advance veterinary science. For example, sheep are increasingly being used as models of intensive care and therefore, data arising from such models must be published. In this study, the hypothesis is that there is little information describing cardiorespiratory physiological data from sheep models of intensive care and the author aimed to analyse such data to provide biological information that is currently not available for sheep that received extracorporeal life support (ECLS) following acute smoke-induced lung injury. Methods: Nineteen mechanically ventilated adult ewes undergoing intensive care during evaluation of a form of ECLS (treatment) for acute lung injury were used to collate clinical observations. Eight sheep were injured by acute smoke inhalation prior to treatment (injured/treated), while another eight were not injured but treated (uninjured/treated). Two sheep were injured but not treated (injured/untreated), while one received room air instead of smoke as the injury and was not treated (placebo/untreated). The data were then analysed for 11 physiological categories and compared between the two treated groups. Results: Compared with the baseline, treatment contributed to and exacerbated the deterioration of pulmonary pathology by reducing lung compliance and the arterial oxygen partial pressure to fractional inspired oxygen (PaO 2/FiO 2) ratio. The oxygen extraction index changes mirrored those of the PaO 2/FiO 2 ratio. Decreasing coronary perfusion pressure predicted the severity of cardiopulmonary injury. Conclusions: These novel observations could help in understanding similar pathology such as that which occurs in animal victims of smoke inhalation from house or bush fires, aspiration pneumonia secondary to tick paralysis and in the management of the severe coronavirus disease 2019 (COVID-19) in humans.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Oxigenação por Membrana Extracorpórea , Fumaça/efeitos adversos , Animais , Circulação Coronária , Feminino , Oxigênio/sangue , Pressão Parcial , Ovinos
5.
Paediatr Respir Rev ; 35: 20-24, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653469

RESUMO

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.


Assuntos
Lesão Pulmonar Aguda/sangue , Infecções por Coronavirus/sangue , Inflamação/sangue , Pneumonia Viral/sangue , Trombose/sangue , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/fisiopatologia , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Betacoronavirus , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Capilares/imunologia , Capilares/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Inibidores do Fator Xa/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Pandemias , Ativação Plaquetária , Inibidores da Agregação de Plaquetas/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Embolia Pulmonar/fisiopatologia , Trombina/imunologia , Trombina/metabolismo , Trombose/tratamento farmacológico , Trombose/imunologia , Trombose/fisiopatologia
7.
Nat Med ; 26(7): 1102-1113, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32661401

RESUMO

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.


Assuntos
Lesão Pulmonar Aguda/terapia , Transplante de Pulmão/métodos , Pulmão/irrigação sanguínea , Preservação de Órgãos/métodos , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/fisiopatologia , Animais , Circulação Extracorpórea/métodos , Humanos , Pulmão/fisiopatologia , Perfusão/métodos , Suínos , Doadores de Tecidos
10.
J Clin Pharmacol ; 60(7): 815-825, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32441805

RESUMO

Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID-19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome-coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra-alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add-on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti-inflammatory and anti-viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add-on therapy in ALI related to COVID-19 infection.


Assuntos
Lesão Pulmonar Aguda/etiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Escina/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/fisiopatologia , Quimioterapia Combinada , Escina/administração & dosagem , Escina/farmacologia , Humanos , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Pandemias , Pneumonia Viral/fisiopatologia
11.
Life Sci ; 256: 117851, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470454

RESUMO

AIMS: The aim of this study was to explore the role of miR-122-5p in acute lung injury. MATERIALS AND METHODS: Mice were subjected to intratracheal injection of lipopolysaccharide to establish an acute lung injury model. The mice also received miR-122-5p antagonist and mimic via injection to inhibit or overexpress miR-122-5p in the lung tissue, respectively. In an in vitro experiment, we isolated primary mouse lung microvascular endothelial cells and established a cell injury model via lipopolysaccharide treatment. KEY FINDINGS: Mice injected with an miR-122-5p antagonist exhibited reduced lung injury, inflammation and oxidative stress, while mice injected with a miR-122-5p mimic exhibited exaggerated lung injury, inflammation and oxidative stress. In an in vitro experiment, we found that the miR-122-5p antagonist suppressed lipopolysaccharide-induced inflammation, apoptosis and oxidative stress. Moreover, miR-122-5p regulated the promoter activity of DUSP4, which negatively regulated ERK1/2 signaling. The use of DUSP4 siRNA counteracted the effects of the miR-122-5p antagonist. SIGNIFICANCE: Taken together, these results show that miR-122-5p protected against acute lung injury via regulation of DUSP4/ERK signaling in pulmonary microvascular endothelial cells. MiR-122-5p antagonism may be a promising treatment method for acute lung injury.


Assuntos
Lesão Pulmonar Aguda/genética , Apoptose/genética , Inflamação/genética , MicroRNAs/genética , Estresse Oxidativo/genética , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Tirosina Fosfatases/genética , Transdução de Sinais/genética
12.
Exp Mol Pathol ; 115: 104438, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32277959

RESUMO

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.


Assuntos
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 Fisiológica
13.
Eur Respir J ; 56(1)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32341103

RESUMO

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 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , 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
14.
Eur Respir J ; 55(5)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341111

RESUMO

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" (>40 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 , Vírus da SARS/genética , Lesão Pulmonar Aguda/terapia , Lesão Pulmonar Aguda/virologia , Biomarcadores/sangue , Pesquisa Biomédica , Infecções por Coronavirus/terapia , Gerenciamento Clínico , Feminino , Humanos , Hipóxia/diagnóstico , Hipóxia/etiologia , Complacência Pulmonar/genética , Masculino , Pandemias , Pneumonia Viral/terapia , Pró-Calcitonina/metabolismo , Vírus da SARS/patogenicidade
15.
Sci Rep ; 10(1): 6722, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317734

RESUMO

Measuring respiratory resistance and elastance as a function of time, tidal volume, respiratory rate, and positive end-expiratory pressure can guide mechanical ventilation. However, current measurement techniques are limited since they are assessed intermittently at non-physiological frequencies or involve specialized equipment. To this end, we introduce ZVV, a practical approach to continuously track resistance and elastance during Variable Ventilation (VV), in which frequency and tidal volume vary from breath-to-breath. ZVV segments airway pressure and flow recordings into individual breaths, calculates resistance and elastance for each breath, bins them according to frequency or tidal volume and plots the results against bin means. ZVV's feasibility was assessed clinically in five human patients with acute lung injury, experimentally in five mice ventilated before and after lavage injury, and computationally using a viscoelastic respiratory model. ZVV provided continuous measurements in both settings, while the computational study revealed <2% estimation errors. Our findings support ZVV as a feasible technique to assess respiratory mechanics under physiological conditions. Additionally, in humans, ZVV detected a decrease in resistance and elastance with time by 12.8% and 6.2%, respectively, suggesting that VV can improve lung recruitment in some patients and can therefore potentially serve both as a dual diagnostic and therapeutic tool.


Assuntos
Ventilação Pulmonar/fisiologia , Mecânica Respiratória/fisiologia , Taxa Respiratória/fisiologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Simulação por Computador , Impedância Elétrica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos
16.
Mil Med ; 185(Suppl 1): 57-66, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-32074309

RESUMO

INTRODUCTION: Rapid aeromedical evacuation (AE) is standard of care in current conflicts. However, not much is known about possible effects of hypobaric conditions. We investigated possible effects of hypobaria on organ damage in a swine model of acute lung injury. METHODS: Lung injury was induced in anesthetized swine via intravenous oleic acid infusion. After a stabilization phase, animals were subjected to a 4 hour simulated AE at 8000 feet (HYPO). Control animals were kept at normobaria. After euthanasia and necropsy, organ damage was assessed by combined scores for hemorrhage, inflammation, edema, necrosis, and microatelectasis. RESULTS: Hemodynamic, neurological, or hematologic measurements were similar prior to transport. Hemodynamic instability became apparent during the last 2 hours of transport in the HYPO group. Histological injury scores in the HYPO group were higher for all organs (lung, kidney, liver, pancreas, and adrenal glands) except the brain, with the largest difference in the lungs (P < 0.001). CONCLUSIONS: Swine with mild acute lung injury subjected to a 4 hour simulated AE showed more injury to most organs and, in particular, to the lungs compared with ground transport. This may exacerbate otherwise subclinical pathology and, eventually, manifest as abnormalities in gas exchange or possibly end-organ function.


Assuntos
Lesão Pulmonar Aguda/etiologia , Insuficiência de Múltiplos Órgãos/patologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Medicina Aeroespacial/métodos , Animais , Modelos Animais de Doenças , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Ácido Oleico/efeitos adversos , Ácido Oleico/farmacologia , Suínos/lesões , Suínos/fisiologia
17.
J Ethnopharmacol ; 252: 112633, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32001275

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pequi fruit are obtained from the pequi tree (Caryocar coriaceum), from which the pulp and nut are used in order to extract an oil that is commonly used in popular medicine as an antiinflammatory agent, particularly for the treatment of colds, bronchitis and bronchopulmonary infections. Making use of the fixed oil of Caryocar coriaceum (FOCC), an attractive alternative for the treatment of diseases caused by exposure to environmental tobacco smoke. AIM OF THE STUDY: To evaluate whether oral intake FOCC provides beneficial effects in the respiratory system of rats submitted to a short-term secondhand smoke (SHS) exposure model. MATERIALS AND METHODS: The experiments were performed on Wistar rats divided into 4 groups; in the SHS + O and SHS + T groups, the animals were pretreated orally with 0.5 mL of FOCC (SHS + O) or vehicle (Tween-80 [1%] solution) (SHS + T). Immediately after pretreatment, the animals were submitted to the SHS exposure protocol, for a total period of 14 days. Exposures were performed 6 times per day, with a duration of 40 min per exposure (5 cigarettes per exposure), followed by a 1-h interval between subsequent exposures. In the AA + O and AA + T groups, animals were submitted to daily oral pretreatment with 0.5 mL of FOCC (AA + O) or vehicle (AA + T). These animals were then subjected to the aforementioned exposure protocol, but using ambient air. After the exposure period, we investigated the effects of FOCC in respiratory mechanics in vivo (Newtonian resistance -RN, tissue elastance -H, tissue resistance -G, static compliance -CST, inspiratory capacity -IC, PV loop area) histopathology and lung parenchymal morphometry in vitro (polymorphonuclear cells -PMN, mean alveolar diameter -Lm, bronchoconstriction index -BCI), temporal evolution of subjects' masses, and percent composition of the FOCC. RESULTS: Regarding the body mass of the animals, the results demonstrated an average body mass gain of 10.5 g for the animals in the AA + T group, and 15.5 g for those in the AA + O group. On the other hand, the body mass of animals in the SHS + T and SHS + O suffered an average loss of 14.4 and 4.75 g, respectively. Regarding respiratory system analyzes, our results demonstrated significant changes in all respiratory mechanics variables and lung parenchyma morphometry analyzed for the SHS + T group when compared to the AA + T group (p < 0,05), confirming the establishment of pulmonary injury induced by SHS exposure. We also observed that rats pretreated orally with FOCC (SHS + O) showed improvement in all variables when compared to the SHS + T group (p < 0,05), thus demonstrating the effectiveness of FOCC in preventing lung damage induced by short-term SHS exposure. CONCLUSION: In conclusion, our results demonstrate that FOCC was able to prevent lung injury in rats submitted to short-term SHS exposure.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Ericales , Óleos Vegetais/uso terapêutico , Mecânica Respiratória/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiologia , Masculino , Ratos Wistar , Sementes
19.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012801

RESUMO

Acute lung injury (ALI) is characterized by enhanced permeability of the air-blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (n = 10 per group). The control mice received saline alone (n = 7 per group). After 24 h, lung function was measured. The lungs were then excised for proteomics, cytokine, and stereological analysis to address inflammatory signaling and structural damage. LPS exposure induced ALI in both strains, however, only WT mice showed increased tissue resistance and septal thickening upon LPS treatment. Septal alterations due to LPS exposure in WT mice consisted of an increase in extracellular matrix (ECM), including collagen fibrils, elastic fibers, and amorphous ECM. Proteomics analysis revealed that the inflammatory response was dampened in miR-21 KO mice with reduced platelet and neutrophil activation compared with WT mice. The WT mice showed more functional and structural changes and inflammatory signaling in ALI than miR-21 KO mice, confirming the hypothesis that miR-21 KO reduces the development of pathological changes in ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Remodelação das Vias Aéreas/genética , MicroRNAs/genética , Alvéolos Pulmonares/metabolismo , Transdução de Sinais , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/ultraestrutura , Animais , Cromatografia Líquida , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Masculino , Espectrometria de Massas , Camundongos , Camundongos Knockout , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/ultraestrutura , Células RAW 264.7 , Testes de Função Respiratória
20.
BMC Pulm Med ; 20(1): 20, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964384

RESUMO

BACKGROUND: Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. METHODS: We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. RESULTS: Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. CONCLUSIONS: These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Inflamação/metabolismo , Mitocôndrias Musculares/metabolismo , Dinâmica Mitocondrial/genética , Mitofagia/fisiologia , Músculo Esquelético/metabolismo , Biogênese de Organelas , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/fisiopatologia , Animais , Inflamação/fisiopatologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Músculo Esquelético/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Transdução de Sinais
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