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1.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804806

RESUMO

Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb- "peritoneal-like" macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large "peritoneal-like" macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.


Assuntos
Carga Bacteriana , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas Proto-Oncogênicas c-myb/deficiência , Sepse/etiologia , Sepse/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Contagem de Leucócitos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose/imunologia , Prognóstico , Ratos , Sepse/diagnóstico , Sepse/mortalidade , Índice de Gravidade de Doença
2.
Am J Respir Crit Care Med ; 203(10): 1266-1274, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33406012

RESUMO

Rationale: The physiological basis of lung protection and the impact of positive end-expiratory pressure (PEEP) during pronation in acute respiratory distress syndrome are not fully elucidated. Objectives: To compare pleural pressure (Ppl) gradient, ventilation distribution, and regional compliance between dependent and nondependent lungs, and investigate the effect of PEEP during supination and pronation. Methods: We used a two-hit model of lung injury (saline lavage and high-volume ventilation) in 14 mechanically ventilated pigs and studied supine and prone positions. Global and regional lung mechanics including Ppl and distribution of ventilation (electrical impedance tomography) were analyzed across PEEP steps from 20 to 3 cm H2O. Two pigs underwent computed tomography scans: tidal recruitment and hyperinflation were calculated. Measurements and Main Results: Pronation improved oxygenation, increased Ppl, thus decreasing transpulmonary pressure for any PEEP, and reduced the dorsal-ventral pleural pressure gradient at PEEP < 10 cm H2O. The distribution of ventilation was homogenized between dependent and nondependent while prone and was less dependent on the PEEP level than while supine. The highest regional compliance was achieved at different PEEP levels in dependent and nondependent regions in supine position (15 and 8 cm H2O), but for similar values in prone position (13 and 12 cm H2O). Tidal recruitment was more evenly distributed (dependent and nondependent), hyperinflation lower, and lungs cephalocaudally longer in the prone position. Conclusions: In this lung injury model, pronation reduces the vertical pleural pressure gradient and homogenizes regional ventilation and compliance between the dependent and nondependent regions. Homogenization is much less dependent on the PEEP level in prone than in supine positon.


Assuntos
Posicionamento do Paciente , Respiração com Pressão Positiva , Decúbito Ventral , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/terapia , Decúbito Dorsal , Animais , Modelos Animais de Doenças , Complacência Pulmonar/fisiologia , Lesão Pulmonar/complicações , Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Cavidade Pleural/fisiopatologia , Síndrome do Desconforto Respiratório/etiologia , Mecânica Respiratória/fisiologia , Suínos
3.
Am J Respir Crit Care Med ; 203(8): 969-976, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091317

RESUMO

Rationale: Asymmetrical lung injury is a frequent clinical presentation. Regional distribution of Vt and positive end-expiratory pressure (PEEP) could result in hyperinflation of the less-injured lung. The validity of esophageal pressure (Pes) is unknown.Objectives: To compare, in asymmetrical lung injury, Pes with directly measured pleural pressures (Ppl) of both sides and investigate how PEEP impacts ventilation distribution and the regional driving transpulmonary pressure (inspiratory - expiratory).Methods: Fourteen mechanically ventilated pigs with lung injury were studied. One lung was blocked while the contralateral one underwent surfactant lavage and injurious ventilation. Airway pressure and Pes were measured, as was Ppl in the dorsal and ventral pleural space adjacent to each lung. Distribution of ventilation was assessed by electrical impedance tomography. PEEP was studied through decremental steps.Measurements and Results: Ventral and dorsal Ppl were similar between the injured and the noninjured lung across all PEEP levels. Dorsal Ppl and Pes were similar. The driving transpulmonary pressure was similar in the two lungs. Vt distribution between lungs was different at zero end-expiratory pressure (≈70% of Vt going in noninjured lung) owing to different respiratory system compliance (8.3 ml/cm H2O noninjured lung vs. 3.7 ml/cm H2O injured lung). PEEP at 10 cm H2O with transpulmonary pressure around zero homogenized Vt distribution opening the lungs. PEEP ≥16 cm H2O equalized distribution of Vt but with overdistension for both lungs.Conclusions: Despite asymmetrical lung injury, Ppl between injured and noninjured lungs is equalized and esophageal pressure is a reliable estimate of dorsal Ppl. Driving transpulmonary pressure is similar for both lungs. Vt distribution results from regional respiratory system compliance. Moderate PEEP homogenizes Vt distribution between lungs without generating hyperinflation.


Assuntos
Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Respiração com Pressão Positiva/métodos , Respiração Artificial/métodos , Mecânica Respiratória/fisiologia , Suínos , Animais , Modelos Animais
5.
Anesthesiology ; 132(1): 140-154, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31764154

RESUMO

BACKGROUND: Mesenchymal stromal cells have therapeutic potential in sepsis, but the mechanism of action is unclear. We tested the effects, dose-response, and mechanisms of action of cryopreserved, xenogeneic-free human umbilical cord mesenchymal stromal cells in a rat model of fecal peritonitis, and examined the role of heme oxygenase-1 in protection. METHODS: Separate in vivo experiments evaluated mesenchymal stromal cells in fecal sepsis, established dose response (2, 5, and 10 million cells/kg), and the role of heme oxygenase-1 in mediating human umbilical cord-derived mesenchymal stromal/stem cell effects. Ex vivo studies utilized pharmacologic blockers and small inhibitory RNAs to evaluate mechanisms of mesenchymal stromal cell enhanced function in (rodent, healthy and septic human) macrophages. RESULTS: Human umbilical cord mesenchymal stromal cells reduced injury and increased survival (from 48%, 12 of 25 to 88%, 14 of 16, P = 0.0033) in fecal sepsis, with dose response studies demonstrating that 10 million cells/kg was the most effective dose. Mesenchymal stromal cells reduced bacterial load and peritoneal leukocyte infiltration (from 9.9 ± 3.1 × 10/ml to 6.2 ± 1.8 × 10/ml, N = 8 to 10 per group, P < 0.0001), and increased heme oxygenase-1 expression in peritoneal macrophages, liver, and spleen. Heme oxygenase-1 blockade abolished the effects of mesenchymal stromal cells (N = 7 or 8 per group). Mesenchymal stromal cells also increased heme oxygenase-1 expression in macrophages from healthy donors and septic patients. Direct ex vivo upregulation of macrophage heme oxygenase-1 enhanced macrophage function (phagocytosis, reactive oxygen species production, bacterial killing). Blockade of lipoxin A4 production in mesenchymal stromal cells, and of prostaglandin E2 synthesis in mesenchymal stromal cell/macrophage cocultures, prevented upregulation of heme oxygenase-1 in macrophages (from 9.6 ± 5.5-fold to 2.3 ± 1.3 and 2.4 ± 2.3 respectively, P = 0.004). Knockdown of heme oxygenase-1 production in macrophages ablated mesenchymal stromal cell enhancement of macrophage phagocytosis. CONCLUSIONS: Human umbilical cord mesenchymal stromal cells attenuate systemic sepsis by enhancing peritoneal macrophage bacterial killing, mediated partly via upregulation of peritoneal macrophage heme oxygenase-1. Lipoxin A4 and prostaglandin E2 play key roles in the mesenchymal stromal cell and macrophage interaction.


Assuntos
Heme Oxigenase-1/metabolismo , Macrófagos Peritoneais/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Sepse/terapia , Cordão Umbilical , Animais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
7.
Anesthesiology ; 131(3): 594-604, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31335543

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Higher driving pressure during controlled mechanical ventilation is known to be associated with increased mortality in patients with acute respiratory distress syndrome.Whereas patients with acute respiratory distress syndrome are initially managed with controlled mechanical ventilation, as they improve, they are transitioned to assisted ventilation. Whether higher driving pressure assessed during pressure support (assisted) ventilation can be reliably assessed and whether higher driving pressure is associated with worse outcomes in patients with acute respiratory distress syndrome has not been well studied. WHAT THIS ARTICLE TELLS US THAT IS NEW: This study shows that in the majority of adult patients with acute respiratory distress syndrome, both driving pressure and respiratory system compliance can be reliably measured during pressure support (assisted) ventilation.Higher driving pressure measured during pressure support (assisted) ventilation significantly associates with increased intensive care unit mortality, whereas peak inspiratory pressure does not.Lower respiratory system compliance also significantly associates with increased intensive care unit mortality. BACKGROUND: Driving pressure, the difference between plateau pressure and positive end-expiratory pressure (PEEP), is closely associated with increased mortality in patients with acute respiratory distress syndrome (ARDS). Although this relationship has been demonstrated during controlled mechanical ventilation, plateau pressure is often not measured during spontaneous breathing because of concerns about validity. The objective of the present study is to verify whether driving pressure and respiratory system compliance are independently associated with increased mortality during assisted ventilation (i.e., pressure support ventilation). METHODS: This is a retrospective cohort study conducted on 154 patients with ARDS in whom plateau pressure during the first three days of assisted ventilation was available. Associations between driving pressure, respiratory system compliance, and survival were assessed by univariable and multivariable analysis. In patients who underwent a computed tomography scan (n = 23) during the stage of assisted ventilation, the quantity of aerated lung was compared with respiratory system compliance measured on the same date. RESULTS: In contrast to controlled mechanical ventilation, plateau pressure during assisted ventilation was higher than the sum of PEEP and pressure support (peak pressure). Driving pressure was higher (11 [9-14] vs. 10 [8-11] cm H2O; P = 0.004); compliance was lower (40 [30-50] vs. 51 [42-61] ml · cm H2O; P < 0.001); and peak pressure was similar, in nonsurvivors versus survivors. Lower respiratory system compliance (odds ratio, 0.92 [0.88-0.96]) and higher driving pressure (odds ratio, 1.34 [1.12-1.61]) were each independently associated with increased risk of death. Respiratory system compliance was correlated with the aerated lung volume (n = 23, r = 0.69, P < 0.0001). CONCLUSIONS: In patients with ARDS, plateau pressure, driving pressure, and respiratory system compliance can be measured during assisted ventilation, and both higher driving pressure and lower compliance are associated with increased mortality.


Assuntos
Avaliação de Resultados da Assistência ao Paciente , Respiração com Pressão Positiva/mortalidade , Respiração com Pressão Positiva/métodos , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Idoso , Estudos de Coortes , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Complacência Pulmonar , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume de Ventilação Pulmonar , Tomografia Computadorizada por Raios X
9.
J Clin Med ; 8(6)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200579

RESUMO

Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0-3.0) × 109 Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naïve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 × 107 cells/kg). Lung injury severity, cellular infiltration, and E. coli colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and naïve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs-but not naïve UC-MSCs-significantly decreased the alveolar arterial gradient (455 93 and 520 81, mmHg, respectively) compared to that of vehicle animals (544 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naïve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naïve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naïve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in E. coli pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS).

10.
Curr Opin Crit Care ; 25(2): 192-198, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30720482

RESUMO

PURPOSE OF REVIEW: Facilitating spontaneous breathing has been traditionally recommended during mechanical ventilation in acute respiratory distress syndrome (ARDS). However, early, short-term use of neuromuscular blockade appears to improve survival, and spontaneous effort has been shown to potentiate lung injury in animal and clinical studies. The purpose of this review is to describe the beneficial and deleterious effects of spontaneous breathing in ARDS, explain potential mechanisms for harm, and provide contemporary suggestions for clinical management. RECENT FINDINGS: Gentle spontaneous effort can improve lung function and prevent diaphragm atrophy. However, accumulating evidence indicates that spontaneous effort may cause or worsen lung and diaphragm injury, especially if the ARDS is severe or spontaneous effort is vigorous. Recently, such effort-dependent lung injury has been termed patient self-inflicted lung injury (P-SILI). Finally, several approaches to minimize P-SILI while maintaining some diaphragm activity (e.g. partial neuromuscular blockade, high PEEP) appear promising. SUMMARY: We update and summarize the role of spontaneous breathing during mechanical ventilation in ARDS, which can be beneficial or deleterious, depending on the strength of spontaneous activity and severity of lung injury. Future studies are needed to determine ventilator strategies that minimize injury but maintaining some diaphragm activity.


Assuntos
Lesão Pulmonar , Respiração Artificial , Síndrome do Desconforto Respiratório , Animais , Diafragma/fisiopatologia , Humanos , Pulmão/fisiopatologia
11.
Crit Care Med ; 47(2): 254-263, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30653472

RESUMO

OBJECTIVES: A narrative review of the pathophysiology linking altered airway pressure and intracranial pressure and cerebral oxygenation. DATA SOURCES: Online search of PubMed and manual review of articles (laboratory and patient studies) of the altered airway pressure on intracranial pressure, cerebral perfusion, or cerebral oxygenation. STUDY SELECTION: Randomized trials, observational and physiologic studies. DATA EXTRACTION: Our group determined by consensus which resources would best inform this review. DATA SYNTHESIS: In the normal brain, positive-pressure ventilation does not significantly alter intracranial pressure, cerebral oxygenation, or perfusion. In injured brains, the impact of airway pressure on intracranial pressure is variable and determined by several factors; a cerebral venous Starling resistor explains much of the variability. Negative-pressure ventilation can improve cerebral perfusion and oxygenation and reduce intracranial pressure in experimental models, but data are limited, and mechanisms and clinical benefit remain uncertain. CONCLUSIONS: The effects of airway pressure and ventilation on cerebral perfusion and oxygenation are increasingly understood, especially in the setting of brain injury. In the face of competing mechanisms and priorities, multimodal monitoring and individualized titration will increasingly be required to optimize care.


Assuntos
Encéfalo/irrigação sanguínea , Pressão Intracraniana , Respiração com Pressão Positiva , Circulação Cerebrovascular/fisiologia , Humanos , Pressão Intracraniana/fisiologia
12.
Anesthesiology ; 131(3): 716-749, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30664057

RESUMO

Acute respiratory distress syndrome (ARDS) consists of acute hypoxemic respiratory failure characterized by massive and heterogeneously distributed loss of lung aeration caused by diffuse inflammation and edema present in interstitial and alveolar spaces. It is defined by consensus criteria, which include diffuse infiltrates on chest imaging-either plain radiography or computed tomography. This review will summarize how imaging sciences can inform modern respiratory management of ARDS and continue to increase the understanding of the acutely injured lung. This review also describes newer imaging methodologies that are likely to inform future clinical decision-making and potentially improve outcome. For each imaging modality, this review systematically describes the underlying principles, technology involved, measurements obtained, insights gained by the technique, emerging approaches, limitations, and future developments. Finally, integrated approaches are considered whereby multimodal imaging may impact management of ARDS.


Assuntos
Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia
13.
Lancet Respir Med ; 7(1): 90-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455078

RESUMO

Several mechanisms of diaphragm muscle injury (myotrauma) can result in ventilator-induced diaphragm dysfunction, including ventilator over-assistance, under-assistance, eccentric contractions, and end-expiratory shortening. In this Personal View, we summarise the evidence for the clinical relevance of these mechanisms, and present new data based on mediation analysis supporting the hypothesis that myotrauma due to ventilator over-assistance and under-assistance contribute, in part, to the effect of mechanical ventilation on clinical outcomes. The concept of diaphragmatic myotrauma has important implications for research and clinical practice.


Assuntos
Diafragma/lesões , Respiração Artificial/efeitos adversos , Estado Terminal , Diafragma/fisiopatologia , Humanos , Pulmão/fisiopatologia , Insuficiência Respiratória/terapia
14.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L1-L5, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407864

RESUMO

Vitamin E (VitE) has important antioxidant and anti-inflammatory effects and is necessary for normal physiological function. α-Tocopherol (α-T), the predominant form of VitE in human tissues, has been extensively studied. Other VitE forms, particularly γ-tocopherol (γ-T), are also potent bioactive molecules. The effects are complex, involving both reactive oxygen and nitrogen species, but trials of VitE have been generally negative. We propose that a nanoparticle approach to delivery of VitE might provide effective delivery and therapeutic effect.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/uso terapêutico , Nanotecnologia , Vitamina E/uso terapêutico , Animais , Humanos , Vitamina E/farmacocinética
19.
Am J Respir Crit Care Med ; 198(9): 1165-1176, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29902384

RESUMO

RATIONALE: Ventilator management in acute respiratory distress syndrome usually focuses on setting parameters, but events occurring at ventilator disconnection are not well understood. OBJECTIVES: To determine if abrupt deflation after sustained inflation causes lung injury. METHODS: Male Sprague-Dawley rats were ventilated (low Vt, 6 ml/kg) and randomized to control (n = 6; positive end-expiratory pressure [PEEP], 3 cm H2O; 100 min) or intervention (n = 6; PEEP, 3-11 cm H2O over 70 min; abrupt deflation to zero PEEP; ventilation for 30 min). Lung function and injury was assessed, scanning electron microscopy performed, and microvascular leak timed by Evans blue dye (n = 4/group at 0, 2, 5, 10, and 20 min after deflation). Hemodynamic assessment included systemic arterial pressure (n = 6), echocardiography (n = 4), and right (n = 6) and left ventricular pressures (n = 6). MEASUREMENTS AND MAIN RESULTS: Abrupt deflation after sustained inflation (vs. control) caused acute lung dysfunction (compliance 0.48 ± 1.0 vs. 0.82 ± 0.2 m/cm H2O, oxygen saturation as measured by pulse oximetry 67 ± 23.5 vs. 91 ± 4.4%; P < 0.05) and injury (wet/dry ratio 6.1 ± 0.6 vs. 4.6 ± 0.4; P < 0.01). Vascular leak was absent before deflation and maximal 5-10 minutes thereafter; injury was predominantly endothelial. At deflation, left ventricular preload, systemic blood pressure, and left ventricular end-diastolic pressure increased precipitously in proportion to the degree of injury. Injury caused later right ventricular failure. Sodium nitroprusside prevented the increase in systemic blood pressure and left ventricular end-diastolic pressure associated with deflation, and prevented injury. Injury did not occur with gradual deflation. CONCLUSIONS: Abrupt deflation after sustained inflation can cause acute lung injury. It seems to be mediated by acute left ventricular decompensation (caused by increased left ventricular preload and afterload) that elevates pulmonary microvascular pressure; this directly injures the endothelium and causes edema, which is potentiated by the surge in pulmonary perfusion.


Assuntos
Lesão Pulmonar/etiologia , Lesão Pulmonar/fisiopatologia , Respiração com Pressão Positiva , Suspensão de Tratamento , Animais , Modelos Animais de Doenças , Pulmão/fisiopatologia , Masculino , Oximetria , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória
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