Recombinant thrombomodulin and recombinant antithrombin attenuate pulmonary endothelial glycocalyx degradation and neutrophil extracellular trap formation in ventilator-induced lung injury in the context of endotoxemia.

BACKGROUND: Vascular endothelial damage is involved in the development and exacerbation of ventilator-induced lung injury (VILI). Pulmonary endothelial glycocalyx and neutrophil extracellular traps (NETs) are endothelial protective and damaging factors, respectively; however, their dynamics in VILI and the effects of recombinant thrombomodulin and antithrombin on these dynamics remain unclear. We hypothesized that glycocalyx degradation and NETs are induced by VILI and suppressed by recombinant thrombomodulin, recombinant antithrombin, or their combination. METHODS: VILI was induced in male C57BL/6J mice by intraperitoneal lipopolysaccharide injection (20 mg/kg) and high tidal volume ventilation (20 mL/kg). In the intervention groups, recombinant thrombomodulin, recombinant antithrombin, or their combination was administered at the start of mechanical ventilation. Glycocalyx degradation was quantified by measuring serum syndecan-1, fluorescence-labeled lectin intensity, and glycocalyx-occupied area in the pulmonary vascular lumen. Double-stranded DNA in the bronchoalveolar fluid and fluorescent areas of citrullinated histone H3 and myeloperoxidase were quantified as NET formation. RESULTS: Serum syndecan-1 increased, and lectin fluorescence intensity decreased in VILI. Electron microscopy revealed decreases in glycocalyx-occupied areas within pulmonary microvessels in VILI. Double-stranded DNA levels in the bronchoalveolar lavage fluid and the fluorescent area of citrullinated histone H3 and myeloperoxidase in lung tissues increased in VILI. Recombinant thrombomodulin, recombinant antithrombin, and their combination reduced glycocalyx injury and NET marker levels. There was little difference in glycocalyx injury and NET makers between the intervention groups. CONCLUSION: VILI induced glycocalyx degradation and NET formation. Recombinant thrombomodulin and recombinant antithrombin attenuated glycocalyx degradation and NETs in our VILI model. The effect of their combination did not differ from that of either drug alone. Recombinant thrombomodulin and antithrombin have the potential to be therapeutic agents for biotrauma in VILI.

Understanding the mechanisms of ventilator-induced lung injury using animal models.

Mechanical ventilation is a life-saving therapy in several clinical situations, promoting gas exchange and providing rest to the respiratory muscles. However, mechanical ventilation may cause hemodynamic instability and pulmonary structural damage, which is known as ventilator-induced lung injury (VILI). The four main injury mechanisms associated with VILI are as follows: barotrauma/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; and biotrauma, the resulting biological response to tissue damage, which leads to lung and multi-organ failure. This narrative review elucidates the mechanisms underlying the pathogenesis, progression, and resolution of VILI and discusses the strategies that can mitigate VILI. Different static variables (peak, plateau, and driving pressures, positive end-expiratory pressure, and tidal volume) and dynamic variables (respiratory rate, airflow amplitude, and inspiratory time fraction) can contribute to VILI. Moreover, the potential for lung injury depends on tissue vulnerability, mechanical power (energy applied per unit of time), and the duration of that exposure. According to the current evidence based on models of acute respiratory distress syndrome and VILI, the following strategies are proposed to provide lung protection: keep the lungs partially collapsed (SaO2 > 88%), avoid opening and closing of collapsed alveoli, and gently ventilate aerated regions while keeping collapsed and consolidated areas at rest. Additional mechanisms, such as subject-ventilator asynchrony, cumulative power, and intensity, as well as the damaging threshold (stress-strain level at which tidal damage is initiated), are under experimental investigation and may enhance the understanding of VILI.

Research progress on mechanism of biotrauma caused by ventilation-induced lung injury / 中华危重病急救医学

Mechanical ventilation is an advanced life support treatment for patients with acute respiratory failure. While stabilizing respiratory function, it also acts as an injury factor to exacerbate or lead to lung injury, that is, ventilation-induced lung injury (VILI). There may be a more subtle form of damage to VILI known as "biotrauma". However, the mechanism of biotrauma in VILI is still unclear. This article intends to review the mechanism of biotrauma of VILI from the aspects of inflammatory response, oxidative stress and complement activation, in order to provide a new strategy for clinical prevention and treatment of biotrauma caused by VILI.

Ultra-lung-protective ventilation and biotrauma in severe ARDS patients on veno-venous extracorporeal membrane oxygenation: a randomized controlled study.

BACKGROUND: Ultra-lung-protective ventilation may be useful during veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe acute respiratory distress syndrome (ARDS) to minimize ventilator-induced lung injury and to facilitate lung recovery. The objective was to compare pulmonary and systemic biotrauma evaluated by numerous biomarkers of inflammation, epithelial, endothelial injuries, and lung repair according to two ventilator strategies on vv-ECMO. METHODS: This is a prospective randomized controlled study. Patients were randomized to receive during 48 h either ultra-lung-protective ventilation combining very low tidal volume (1-2 mL/kg of predicted body weight), low respiratory rate (5-10 cycles per minute), positive expiratory transpulmonary pressure, and 16 h of prone position or lung-protective-ventilation which followed the ECMO arm of the EOLIA trial (control group). RESULTS: The primary outcome was the alveolar concentrations of interleukin-1-beta, interleukin-6, interleukin-8, surfactant protein D, and blood concentrations of serum advanced glycation end products and angiopoietin-2 48 h after randomization. Enrollment was stopped for futility after the inclusion of 39 patients. Tidal volume, respiratory rate, minute ventilation, plateau pressure, and mechanical power were significantly lower in the ultra-lung-protective group. None of the concentrations of the pre-specified biomarkers differed between the two groups 48 h after randomization. However, a trend to higher 60-day mortality was observed in the ultra-lung-protective group compared to the control group (45 vs 17%, p = 0.06). CONCLUSIONS: Despite a significant reduction in the mechanical power, ultra-lung-protective ventilation during 48 h did not reduce biotrauma in patients with vv-ECMO-supported ARDS. The impact of this ventilation strategy on clinical outcomes warrants further investigation. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov ( NCT03918603 ). Registered 17 April 2019.

Ventilation-Induced Lung Injury (VILI) in Neonates: Evidence-Based Concepts and Lung-Protective Strategies.

Supportive care with mechanical ventilation continues to be an essential strategy for managing severe neonatal respiratory failure; however, it is well known to cause and accentuate neonatal lung injury. The pathogenesis of ventilator-induced lung injury (VILI) is multifactorial and complex, resulting predominantly from interactions between ventilator-related factors and patient-related factors. Importantly, VILI is a significant risk factor for developing bronchopulmonary dysplasia (BPD), the most common chronic respiratory morbidity of preterm infants that lacks specific therapies, causes life-long morbidities, and imposes psychosocial and economic burdens. Studies of older children and adults suggest that understanding how and why VILI occurs is essential to developing strategies for mitigating VILI and its consequences. This article reviews the preclinical and clinical evidence on the pathogenesis and pathophysiology of VILI in neonates. We also highlight the evidence behind various lung-protective strategies to guide clinicians in preventing and attenuating VILI and, by extension, BPD in neonates. Further, we provide a snapshot of future directions that may help minimize neonatal VILI.

Attenuation of ventilator-induced lung injury through suppressing the pro-inflammatory signaling pathways: A review on preclinical studies.

Mechanical ventilation (MV) is a relatively common medical intervention in ICU patients. The main side effect of MV is the so-called "ventilator-induced lung injury" (VILI). The pathogenesis of VILI is not completely understood; however, it has been reported that MV might be associated with up-regulation of various inflammatory mediators within the lung tissue and that these mediators might act as pathogenic factors in lung tissue injury. One potential mechanism for the generation of inflammatory mediators is through the release of endogenous molecules known as damage associated molecular patterns (DAMPs). These molecules are released from injured tissues and can bind to pattern recognition receptors (PRRs). PRR activation generally leads to the production and release of inflammation-related molecules including innate immune cytokines and chemokines. It has been suggested that blocking DAMP/PRR signaling pathways might diminish the progression of VILI. Herein, we review the latest findings with regard to the effects of DAMP/PRRs and their blockade, as well as the potential therapeutic targets and future research directions in VILI. Results of studies performed on human samples, animal models of disease, as well as relevant in vitro systems will be discussed.

The Renin-Angiotensin System as a Component of Biotrauma in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings.

Physiopathological mechanisms of diaphragmatic dysfunction associated with mechanical ventilation. / Mecanismos fisiopatológicos de la disfunción diafragmática asociada a ventilación mecánica.

Ventilator-induced diaphragm dysfunction (VIDD) is the loss of diaphragmatic muscle strength'related to of mechanical ventilation, noticed during the first day or 48hours after initiating controlled mechanical ventilation. This alteration has been related to disruption on the insulin growth factor/phosphoinositol 3-kinase/kinase B protein pathway (IGF/PI3K/AKT), in addition to an overexpression of FOXO, expression of NF-kB signaling, increase function of muscular ubiquitin ligase and activation of caspasa-3. VIDD has a negative impact on quality of life, duration of mechanical ventilation, and hospitalization stance and cost. More studies are necessary to understated the process and impact of VIDD. This is a narrative review of non-systematic literature, aiming to explain the molecular pathways involved in VIDD.

Ventilation-induced jet suggests biotrauma in reconstructed airways of the intubated neonate.

We investigate respiratory flow phenomena in a reconstructed upper airway model of an intubated neonate undergoing invasive mechanical ventilation, spanning conventional to high-frequency ventilation (HFV) modes. Using high-speed tomographic particle image velocimetry, we resolve transient, three-dimensional flow fields and observe a persistent jet flow exiting the endotracheal tube whose strength is directly modulated according to the ventilation protocol. We identify this synthetic jet as the dominating signature of convective flow under intubated ventilation. Concurrently, our in silico wall shear stress analysis reveals a hitherto overlooked source of ventilator-induced lung injury as a result of jet impingement on the tracheal carina, suggesting damage to the bronchial epithelium; this type of injury is known as biotrauma. We find HFV advantageous in mitigating the intensity of such impingement, which may contribute to its role as a lung protective method. Our findings may encourage the adoption of less invasive ventilation procedures currently used in neonatal intensive care units.

Recruitment maneuver leads to increased expression of pro-inflammatory cytokines in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a disease with high morbidity and mortality rates. The recruitment maneuver (RM) is one of the interventions used for ARDS patients suffering from severe hypoxemia. RM works by opening the atelectatic lungs using high transpulmonary pressure. RM has therefore been widely used for many years in patients with ARDS. However, because of the high transpulmonary pressure used in this intervention, there are concerns about both biotrauma and hemodynamic instability. To assess the effects of RM in ARDS, we conducted a study using three groups of pigs (n = 6 in each group): group I (control), group II (ARDS), and group III (ARDS with RM). After measuring the baseline values, ARDS was induced by deactivating the surfactant with 5% Tweens lavage. For pigs of group III, the RM protocol used was positive end-expiratory pressure (PEEP) of 25 cmH2O and peak pressure of 45 cmH2O. Gas exchange, hemodynamics, the expression of cytokines in serum, bronchoalveolar lavage fluid (BALF), and exhaled breath condensates (EBCs) were measured. The baseline measurements taken were similar across the three groups, and no significant difference was noted. After the induction of ARDS, PaO2 substantially decreased, while PaCO2, alveolar-arterial O2 gradient, pulmonary arterial pressure, lung water, level of cytokines in serum, EBCs, and BALF all increased. After RM, gas exchange and lung water level improved, but the level of cytokines in EBCs and BALF increased. Although RM led to an improvement in gas exchange, it may cause release of inflammatory cytokines in the EBCs and BALF.

Low tidal volume ventilation strategy and organ functions in patients with pre-existing systemic inflammatory response.

BACKGROUND AND AIMS: Ventilation can induce increase in inflammatory mediators that may contribute to systemic organ dysfunction. Ventilation-induced organ dysfunction is likely to be accentuated if there is a pre-existing systemic inflammatory response. MATERIAL AND METHODS: Adult patients suffering from intestinal perforation peritonitis-induced systemic inflammatory response syndrome and scheduled for emergency laparotomy were randomized to receive intraoperative ventilation with 10 ml.kg-1 tidal volume (Group H) versus lower tidal volume of 6 ml.kg-1 along with positive end-expiratory pressure (PEEP) of 10 cmH2O (Group L), (n = 45 each). The primary outcome was postoperative organ dysfunction evaluated using the aggregate Sepsis-related Organ Failure Assessment (SOFA) score. The secondary outcomes were, inflammatory mediators viz. interleukin-6, tumor necrosis factor-α, procalcitonin, and C-reactive protein, assessed prior to (basal) and 1 h after initiation of mechanical ventilation, and 18 h postoperatively. RESULTS: The aggregate SOFA score (3[1-3] vs. 1[1-3]); and that on the first postoperative day (2[1-3] vs. 1[0-3]) were higher for group L as compared to group H (P < 0.05). All inflammatory mediators were statistically similar between both groups at all time intervals (P > 0.05). CONCLUSIONS: Mechanical ventilation with low tidal volume of 6 ml/kg-1 along with PEEP of 10 cmH2O is associated with significantly worse postoperative organ functions as compared to high tidal volume of 10 ml.kg-1 in patients of perforation peritonitis-induced systemic inflammation undergoing emergency laparotomy.

Molecular Mechanisms of Ventilator-Induced Lung Injury.

OBJECTIVE: Mechanical ventilation (MV) has long been used as a life-sustaining approach for several decades. However, researchers realized that MV not only brings benefits to patients but also cause lung injury if used improperly, which is termed as ventilator-induced lung injury (VILI). This review aimed to discuss the pathogenesis of VILI and the underlying molecular mechanisms. DATA SOURCES: This review was based on articles in the PubMed database up to December 2017 using the following keywords: "ventilator-induced lung injury", "pathogenesis", "mechanism", and "biotrauma". STUDY SELECTION: Original articles and reviews pertaining to mechanisms of VILI were included and reviewed. RESULTS: The pathogenesis of VILI was defined gradually, from traditional pathological mechanisms (barotrauma, volutrauma, and atelectrauma) to biotrauma. High airway pressure and transpulmonary pressure or cyclic opening and collapse of alveoli were thought to be the mechanisms of barotraumas, volutrauma, and atelectrauma. In the past two decades, accumulating evidence have addressed the importance of biotrauma during VILI, the molecular mechanism underlying biotrauma included but not limited to proinflammatory cytokines release, reactive oxygen species production, complement activation as well as mechanotransduction. CONCLUSIONS: Barotrauma, volutrauma, atelectrauma, and biotrauma contribute to VILI, and the molecular mechanisms are being clarified gradually. More studies are warranted to figure out how to minimize lung injury induced by MV.

Molecular Mechanisms of Ventilator-Induced Lung Injury / 中华医学杂志(英文版)

<p><b>Objective</b>Mechanical ventilation (MV) has long been used as a life-sustaining approach for several decades. However, researchers realized that MV not only brings benefits to patients but also cause lung injury if used improperly, which is termed as ventilator-induced lung injury (VILI). This review aimed to discuss the pathogenesis of VILI and the underlying molecular mechanisms.</p><p><b>Data Sources</b>This review was based on articles in the PubMed database up to December 2017 using the following keywords: "ventilator-induced lung injury", "pathogenesis", "mechanism", and "biotrauma".</p><p><b>Study Selection</b>Original articles and reviews pertaining to mechanisms of VILI were included and reviewed.</p><p><b>Results</b>The pathogenesis of VILI was defined gradually, from traditional pathological mechanisms (barotrauma, volutrauma, and atelectrauma) to biotrauma. High airway pressure and transpulmonary pressure or cyclic opening and collapse of alveoli were thought to be the mechanisms of barotraumas, volutrauma, and atelectrauma. In the past two decades, accumulating evidence have addressed the importance of biotrauma during VILI, the molecular mechanism underlying biotrauma included but not limited to proinflammatory cytokines release, reactive oxygen species production, complement activation as well as mechanotransduction.</p><p><b>Conclusions</b>Barotrauma, volutrauma, atelectrauma, and biotrauma contribute to VILI, and the molecular mechanisms are being clarified gradually. More studies are warranted to figure out how to minimize lung injury induced by MV.</p>

An experiment on the pathogenesis of early biotrauma in ventilator-induced lung injury / 中华危重病急救医学

Objective To investigate the pathogenesis of early biotrauma in ventilator-induced lung injury (VILI).Methods Twenty-four 8-week-old male specific-pathogen-free Sprague-Dawley (SD) rats weighing 250-300 g were randomly divided into sham group (S group), conventional mechanical ventilation group (L group) and high tidal volume (VT) mechanical ventilation group (H group) with 8 rats in each group. All rats received tracheostomy after anesthesia. Rats in S group received no mechanical ventilation but breathe room air spontaneously. All other parameters of the ventilator were the same in both mechanical ventilation groups, and the fraction of oxygen was set to 0.21, the rats in L group received 7 mL/kg VT, and those in H group received 28 mL/kg VT. Four hours after ventilation all rats were sacrificed and the lung tissues were harvested for wet/dry (W/D) ratio. Pathological injury score was evaluated by hematoxylin and eosin (HE) staining. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling stain (TUNEL) was performed to count the apoptosis cell in lung epithelial. Western Blot was performed to evaluate hemi-channel protein Pannexin-1 expression in lung homogenate. Bronchoalveolar lavage fluid (BALF) was collected, and the concentration of lactate dehydrogenase (LDH), isoprostane, adenosine triphosphate (ATP) and white cell count in BALF were measured. Yo-pro-1/propidium iodide (PI) double stain was performed to evaluate early apoptosis cell in BALF.Results There was no significant difference in lung injury between S group and L group. Compared with S group and L group, rats in H group showed significant lung injury, represented as alveolar rupture, inflammatory cell infiltration, interstitial edema and airway epithelial exfoliation, and the lung W/D ratio was increased significantly (5.1±0.2 vs. 4.4±0.2, 4.3±0.4, bothP< 0.01), pathological score was significantly increased [4.00 (4.00, 8.00) vs. 1.00 (0, 4.00), 2.00 (0, 4.75), bothP< 0.01], the white cell in BALF was significantly increased (×106/L: 2.97±0.46 vs.1.03±0.26, 0.79±0.19, bothP< 0.01), the level of LDH was significantly increased (U/L: 148.6±38.2 vs. 34.4±13.5, 78.6±13.9, bothP< 0.01), and the expression of Pannexin-1 in lung homogenate was significantly increased (Pannexin-1/GAPDH: 0.89±0.21 vs. 0.48±0.25, 0.61±0.17, bothP< 0.01), the ATP concentration in BALF was also significantly increased (nmol/L: 456.84±148.72 vs. 19.23±13.34, 113.26±57.90, bothP< 0.01). There was no significant difference in the apoptosis cell in lung tissue or the apoptosis cell rate, isoprostane level in BALF among the three groups [apoptosis cell in lung (cells/HP): 4.00 (3.00, 5.00) vs. 5.00 (4.00, 6.00), 4.00 (3.25, 6.00); apoptosis cell rate in BALF: (0.57±0.20)％ vs. (0.42±0.16)％, (0.58±0.19)％; isoprostane in BALF (μg/L): 3.85±0.46 vs. 3.83±0.60, 3.59±0.69, allP > 0.05].Conclusion The early pathogenesis of biotrauma in VILI is related to the release of inflammation mediator via membrane channel after activating by pressure stress, but not apoptosis and lipid peroxidation.

Biotrauma and Ventilator-Induced Lung Injury: Clinical Implications.

The pathophysiological mechanisms by which mechanical ventilation can contribute to lung injury, termed "ventilator-induced lung injury" (VILI), is increasingly well understood. "Biotrauma" describes the release of mediators by injurious ventilatory strategies, which can lead to lung and distal organ injury. Insights from preclinical models demonstrating that traditional high tidal volumes drove the inflammatory response helped lead to clinical trials demonstrating lower mortality in patients who underwent ventilation with a lower-tidal-volume strategy. Other approaches that minimize VILI, such as higher positive end-expiratory pressure, prone positioning, and neuromuscular blockade have each been demonstrated to decrease indices of activation of the inflammatory response. This review examines the evolution of our understanding of the mechanisms underlying VILI, particularly regarding biotrauma. We will assess evidence that ventilatory and other "adjunctive" strategies that decrease biotrauma offer great potential to minimize the adverse consequences of VILI and to improve the outcomes of patients with respiratory failure.

New progress of pathogenesis in ventilator-induced lung injury / 中华危重病急救医学

Mechanical ventilation is not only an important treatment method of acute respiratory distress syndrome (ARDS),but also one of the basic treatments in the intensive care unit (ICU).However,mechanical ventilation itself can cause or aggravate acute lung injury,which is called ventilator-induced lung injury (VILI).Currently,clinical pathogenesis of VILI includes four categories such as barotrauma,volutrauma,atelectrauma and hiotrauma.The pathogenesis of mechanical injury has been widely accepted,but the biological injury pathogenesis is unclear.With further research,we found that in the late stage VILI patients occured proliferation of puhnonary fibrosis,which may be formed by partial epithelial-mesenchymal transdifferentiation (EMT).Further study of specific pathogenesis of biotrauma and ARDS pulmonary fibrosis proliferation could provide new ideas for the clinical treatment of VILI.