Variable positive end-expiratory pressure in an experimental model of acute respiratory distress syndrome: an advanced ventilation modality.

Background: Introducing variability in tidal volume, ventilatory frequency, or both is beneficial during mechanical ventilation in acute respiratory distress syndrome (ARDS). We investigated whether applying cycle-by-cycle variability in the positive end-expiratory pressure (PEEP) exerts beneficial effect on lung function in a model of ARDS. Methods: Rabbits with lung injury were randomly allocated to receive mechanical ventilation for 6 h by applying a pressure-controlled mode with constant PEEP of 7 cm H2O (PC group: n=6) or variable PEEP (VEEP) with a coefficient of variation of 21.4%, range 4-10 cm H2O (PC-VEEP group; n=6). Lung oxygenation index (Pao2/FiO2) after 6 h of ventilation (H6) was the primary outcome and respiratory mechanics, lung volume, intrapulmonary shunt, and lung inflammatory markers were secondary outcomes. Results: After lung injury, both groups presented moderate-to-severe ARDS (Pao2/FiO2 <27 kPa). The Pao2/FiO2 was significantly higher in the PC-VEEP group than in the PC group at H6 (12.3 [sd 3.5] vs 19.2 [7.2] kPa, P=0.013) and a lower arterial partial pressure of CO2 at 1-3 h (P<0.02). The ventilation-induced increases in airway resistance and tissue elastance were prevented by PC-VEEP. There was no evidence for a difference in minute volume, driving pressure, end-tidal CO2, lung volumes, intrapulmonary shunt fraction, and cytokines between the ventilation modes. Conclusions: Prolonged mechanical ventilation with cycle-by-cycle VEEP prevents deterioration in gas exchange and respiratory mechanics in a model of ARDS, suggesting the benefit of this novel ventilation strategy to optimise gas exchange without increasing driving pressure and lung overdistension.

Transforming growth factor-ß1 is associated with inflammatory resolution via regulating macrophage polarization in lung injury model mice.

OBJECTIVE: Ventilation is the main respiratory support therapy for acute respiratory distress syndrome, which triggers acute lung injury (ALI). Macrophage polarization is vital for the resolution of inflammation and tissue injury. We hypothesized that transforming growth factor (TGF)-ß1 may attenuate inflammation and ventilator-induced ALI by promoting M2 macrophage polarization. METHODS: C57BL/6 mice received 4-hour ventilation and extubation to observe the resolution of lung injury and inflammation. Lung vascular permeability, inflammation, and histological changes in the lungs were evaluated by bronchoalveolar lavage analysis, enzyme linked immunosorbent assay, hematoxylin and eosin staining, as well as transmission electron microscope. TGF-ß1 cellular production and macrophage subsets were analyzed by flow cytometry. The relative expressions of targeted proteins and genes were measured by immunofuorescence staining, Western blot, and quantitative polymerase chain reaction. RESULTS: High tidal volume-induced injury and inflammation were resolved at 3 days of post-ventilation (PV3d) to PV10d, with increased elastic fibers, proteoglycans, and collagen content, as well as higher TGF-ß1 levels. M1 macrophages were increased in the acute phase, whereas M2a macrophages began to increase from PV1d to PV3d, as well as increased M2c macrophages from PV3d to PV7d. A single dose of rTGF-ß1 attenuated lung injury and inflammation at end of ventilation with polymorphonuclear leukocyte apoptosis, while nTAb pretreatment induced the abnormal elevation of TGF-ß1 that aggravated lung injury and inflammation due to the significant inhibition of M1 macrophages polarized to M2a, M2b, and M2c macrophages. CONCLUSIONS: Precise secretion of TGF-ß1-mediated macrophage polarization plays a crucial role in the resolution of ventilator-induced inflammatory lung injury.

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.

Remimazolam Alleviates Ventilator-Induced Lung Injury by Activating TSPO to Inhibit Macrophage Pyroptosis.

BACKGROUND: Macrophages are activated in ventilator-induced lung injury (VILI), accompanied by macrophage pyroptosis. Remimazolam (Re) plays a role in inhibiting macrophage activation. In this study, we aimed to investigate the mechanism of Re in VILI. METHODS: A VILI model (20 mL/kg mechanical ventilation) was created using C57BL/6 mice. Alveolar macrophages were isolated from bronchoalveolar lavage fluid (BALF) and received mechanical stretching to simulate the mechanical ventilation in vitro. VILI model mice were treated with Re (16 mg/kg) to assess the alveolar structure, wet/dry (W/D) weight ratio, endothelial barrier antigen (EBA) permeability index, BALF protein content, inflammatory factors, macrophage pyroptosis, pyroptosis-related factors, and translocator protein (TSPO) level using a series of biological experiments. Whether Re alleviated macrophage pyroptosis by regulating TSPO was determined by rescue experiments. RESULTS: Re alleviated VILI, as evidenced by improvement of abnormal morphology of lung tissues during VILI and decreases in the lung W/D weight ratio, lung EBA permeability index, and BALF protein content. Re attenuated pulmonary inflammation and macrophage pyroptosis during VILI via down-regulation of inflammatory factors (myeloperoxidase, malondialchehyche, 8-hydroxy-2 deoxyguanosine, interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2, interleukin-1ß, and interleukin-18), and pyroptosis factors (cleaved gasdermin D (GSDMD)/GSDMD value, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and caspase-1). Re activated TSPO in macrophages. TSPO overexpression rescued the cell stretch-inhibited macrophage viability and cell stretch-induced macrophage pyroptosis. CONCLUSION: Re alleviates VILI by activating TSPO to inhibit macrophage pyroptosis.

Positive end-expiratory pressure management in patients with severe ARDS: implications of prone positioning and extracorporeal membrane oxygenation.

The optimal strategy for positive end-expiratory pressure (PEEP) titration in the management of severe acute respiratory distress syndrome (ARDS) patients remains unclear. Current guidelines emphasize the importance of a careful risk-benefit assessment for PEEP titration in terms of cardiopulmonary function in these patients. Over the last few decades, the primary goal of PEEP usage has shifted from merely improving oxygenation to emphasizing lung protection, with a growing focus on the individual pattern of lung injury, lung and chest wall mechanics, and the hemodynamic consequences of PEEP. In moderate-to-severe ARDS patients, prone positioning (PP) is recommended as part of a lung protective ventilation strategy to reduce mortality. However, the physiologic changes in respiratory mechanics and hemodynamics during PP may require careful re-assessment of the ventilation strategy, including PEEP. For the most severe ARDS patients with refractory gas exchange impairment, where lung protective ventilation is not possible, veno-venous extracorporeal membrane oxygenation (V-V ECMO) facilitates gas exchange and allows for a "lung rest" strategy using "ultraprotective" ventilation. Consequently, the importance of lung recruitment to improve oxygenation and homogenize ventilation with adequate PEEP may differ in severe ARDS patients treated with V-V ECMO compared to those managed conservatively. This review discusses PEEP management in severe ARDS patients and the implications of management with PP or V-V ECMO with respect to respiratory mechanics and hemodynamic function.

The ventilator of the future: key principles and unmet needs.

Persistent shortcomings of invasive positive pressure ventilation make it less than an ideal intervention. Over the course of more than seven decades, clinical experience and scientific investigation have helped define its range of hazards and limitations. Apart from compromised airway clearance and lower airway contamination imposed by endotracheal intubation, the primary hazards inherent to positive pressure ventilation may be considered in three broad categories: hemodynamic impairment, potential for ventilation-induced lung injury, and impairment of the respiratory muscle pump. To optimize care delivery, it is crucial for monitoring and machine outputs to integrate information with the potential to impact the underlying requirements of the patient and/or responses of the cardiopulmonary system to ventilatory interventions. Trending analysis, timely interventions, and closer communication with the caregiver would limit adverse clinical trajectories. Judging from the rapid progress of recent years, we are encouraged to think that insights from physiologic research and emerging technological capability may eventually address important aspects of current deficiencies.

A machine-learning regional clustering approach to understand ventilator-induced lung injury: a proof-of-concept experimental study.

BACKGROUND: The spatiotemporal progression and patterns of tissue deformation in ventilator-induced lung injury (VILI) remain understudied. Our aim was to identify lung clusters based on their regional mechanical behavior over space and time in lungs subjected to VILI using machine-learning techniques. RESULTS: Ten anesthetized pigs (27 ± 2 kg) were studied. Eight subjects were analyzed. End-inspiratory and end-expiratory lung computed tomography scans were performed at the beginning and after 12 h of one-hit VILI model. Regional image-based biomechanical analysis was used to determine end-expiratory aeration, tidal recruitment, and volumetric strain for both early and late stages. Clustering analysis was performed using principal component analysis and K-Means algorithms. We identified three different clusters of lung tissue: Stable, Recruitable Unstable, and Non-Recruitable Unstable. End-expiratory aeration, tidal recruitment, and volumetric strain were significantly different between clusters at early stage. At late stage, we found a step loss of end-expiratory aeration among clusters, lowest in Stable, followed by Unstable Recruitable, and highest in the Unstable Non-Recruitable cluster. Volumetric strain remaining unchanged in the Stable cluster, with slight increases in the Recruitable cluster, and strong reduction in the Unstable Non-Recruitable cluster. CONCLUSIONS: VILI is a regional and dynamic phenomenon. Using unbiased machine-learning techniques we can identify the coexistence of three functional lung tissue compartments with different spatiotemporal regional biomechanical behavior.

Advancing ICU patient care with a Real-Time predictive model for mechanical Power to mitigate VILI.

BACKGROUND: Invasive Mechanical Ventilation (IMV) in Intensive Care Units (ICU) significantly increases the risk of Ventilator-Induced Lung Injury (VILI), necessitating careful management of mechanical power (MP). This study aims to develop a real-time predictive model of MP utilizing Artificial Intelligence to mitigate VILI. METHODOLOGY: A retrospective observational study was conducted, extracting patient data from Clinical Information Systems from 2018 to 2022. Patients over 18 years old with more than 6 h of IMV were selected. Continuous data on IMV variables, laboratory data, monitoring, procedures, demographic data, type of admission, reason for admission, and APACHE II at admission were extracted. The variables with the highest correlation to MP were used for prediction and IMV data was grouped in 15-minute intervals using the mean. A mixed neural network model was developed to forecast MP 15 min in advance, using IMV data from 6 h before the prediction and current patient status. The model's ability to predict future MP was analyzed and compared to a baseline model predicting the future value of MP as equal to the current value. RESULTS: The cohort consisted of 1967 patients after applying inclusion criteria, with a median age of 63 years and 66.9 % male. The deep learning model achieved a mean squared error of 2.79 in the test set, indicating a 20 % improvement over the baseline model. It demonstrated high accuracy (94 %) in predicting whether MP would exceed a critical threshold of 18 J/min, which correlates with increased mortality. The integration of this model into a web platform allows clinicians real-time access to MP predictions, facilitating timely adjustments to ventilation settings. CONCLUSIONS: The study successfully developed and integrated in clinical practice a predictive model for MP. This model will assist clinicians allowing for the adjustment of ventilatory parameters before lung damage occurs.

Stress-strain curve and elastic behavior of the fibrotic lung with usual interstitial pneumonia pattern during protective mechanical ventilation.

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress-strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO2/FiO2 ratio) during a PEEP trial performed within 24 h from intubation. Patient's stress-strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8-33.2] cmH2O versus 11.4 [10.3-14.6] cmH2O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress-strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Driving pressure decoded: Precision strategies in adult respiratory distress syndrome management.

Mechanical ventilation (MV) is an important strategy for improving the survival of patients with respiratory failure. However, MV is associated with aggravation of lung injury, with ventilator-induced lung injury (VILI) becoming a major concern. Thus, ventilation protection strategies have been developed to minimize complications from MV, with the goal of relieving excessive breathing workload, improving gas exchange, and minimizing VILI. By opting for lower tidal volumes, clinicians seek to strike a balance between providing adequate ventilation to support gas exchange and preventing overdistension of the alveoli, which can contribute to lung injury. Additionally, other factors play a role in optimizing lung protection during MV, including adequate positive end-expiratory pressure levels, to maintain alveolar recruitment and prevent atelectasis as well as careful consideration of plateau pressures to avoid excessive stress on the lung parenchyma.

A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology.

Introduction: Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes. Methods: Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events. Results: Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks. Conclusion: The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management.

Angiotensin II Type 2 Receptor Inhibits M1 Polarization and Apoptosis of Alveolar Macrophage and Protects Against Mechanical Ventilation-Induced Lung Injury.

Angiotensin II (Ang II) is associated with macrophage polarization and apoptosis, but the role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. However, the effect of AT2Rs on alveolar macrophages and mechanical ventilation-induced lung injury has not been determined. Mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats and LPS-stimulated rat alveolar macrophages (NR8383) were used to determine the effects of AT2Rs, selective AT2R agonists and selective AT1Rs or AT2R antagonists. Macrophage polarization, apoptosis, and related signaling pathways were assessed via western blotting, QPCR and flow cytometry. AT2R expression was decreased in LPS-stimulated rat alveolar macrophages (NR8383). Administration of the AT2R agonist CGP-42112 was associated with an increase in AT2R expression and M2 polarization, but no effect was observed upon administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan. In mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats, the administration of the AT2R agonist C21 was associated with attenuation of the pathological damage score, lung wet/dry weight, cell count and protein content in BALF. C21 can significantly reduce proinflammatory factor TNF-α, IL-1ß levels, increase anti-inflammatory factor IL-4, IL-10 levels in BALF, compared with the model group (p < 0.01). Similarly, compared with those at the same time points, the M1/M2 ratios in alveolar macrophages and apoptosis in peritoneal macrophages at 4 h, 6 h and 8 h in the mechanical ventilation models were lower after C21 administration. These findings indicated that the expression of AT2Rs in alveolar macrophages mediates M1 macrophage polarization and apoptosis and that AT2Rs play a protective role in mediating mechanical ventilation-induced lung injury.

Recent advances in cardiorespiratory monitoring in acute respiratory distress syndrome patients.

BACKGROUND: Recent advances on cardiorespiratory monitoring applied in ARDS patients undergoing invasive mechanical ventilation and noninvasive ventilatory support are available in the literature and may have potential prognostic implication in ARDS treatment. MAIN BODY: The measurement of oxygen saturation by pulse oximetry is a valid, low-cost, noninvasive alternative for assessing arterial oxygenation. Caution must be taken in patients with darker skin pigmentation, who may experience a greater incidence of occult hypoxemia. Dead space surrogates, which are easy to calculate, have important prognostic implications. The mechanical power, which can be automatically computed by intensive care ventilators, is an important parameter correlated with ventilator-induced lung injury and outcome. In patients undergoing noninvasive ventilatory support, the use of esophageal pressure can measure inspiratory effort, avoiding possible delays in endotracheal intubation. Fluid responsiveness can also be evaluated using dynamic indices in patients ventilated at low tidal volumes (< 8 mL/kg). In patients ventilated at high levels of positive end expiratory pressure (PEEP), the PEEP test represents a valid alternative to passive leg raising. There is growing evidence on alternative parameters for evaluating fluid responsiveness, such as central venous oxygen saturation variations, inferior vena cava diameter variations and capillary refill time. CONCLUSION: Careful cardiorespiratory monitoring in patients affected by ARDS is crucial to improve prognosis and to tailor treatment via mechanical ventilatory support.

Comparison of limited driving pressure ventilation and low tidal volume strategies in adults with acute respiratory failure on mechanical ventilation: a randomized controlled trial.

BACKGROUND: Ventilator-induced lung injury (VILI) presents a grave risk to acute respiratory failure patients undergoing mechanical ventilation. Low tidal volume (LTV) ventilation has been advocated as a protective strategy against VILI. However, the effectiveness of limited driving pressure (plateau pressure minus positive end-expiratory pressure) remains unclear. OBJECTIVES: This study evaluated the efficacy of LTV against limited driving pressure in preventing VILI in adults with respiratory failure. DESIGN: A single-centre, prospective, open-labelled, randomized controlled trial. METHODS: This study was executed in medical intensive care units at Siriraj Hospital, Mahidol University, Bangkok, Thailand. We enrolled acute respiratory failure patients undergoing intubation and mechanical ventilation. They were randomized in a 1:1 allocation to limited driving pressure (LDP; ⩽15 cmH2O) or LTV (⩽8 mL/kg of predicted body weight). The primary outcome was the acute lung injury (ALI) score 7 days post-enrolment. RESULTS: From July 2019 to December 2020, 126 patients participated, with 63 each in the LDP and LTV groups. The cohorts had the mean (standard deviation) ages of 60.5 (17.6) and 60.9 (17.9) years, respectively, and they exhibited comparable baseline characteristics. The primary reasons for intubation were acute hypoxic respiratory failure (LDP 49.2%, LTV 63.5%) and shock-related respiratory failure (LDP 39.7%, LTV 30.2%). No significant difference emerged in the primary outcome: the median (interquartile range) ALI scores for LDP and LTV were 1.75 (1.00-2.67) and 1.75 (1.25-2.25), respectively (p = 0.713). Twenty-eight-day mortality rates were comparable: LDP 34.9% (22/63), LTV 31.7% (20/63), relative risk (RR) 1.08, 95% confidence interval (CI) 0.74-1.57, p = 0.705. Incidences of newly developed acute respiratory distress syndrome also aligned: LDP 14.3% (9/63), LTV 20.6% (13/63), RR 0.81, 95% CI 0.55-1.22, p = 0.348. CONCLUSIONS: In adults with acute respiratory failure, the efficacy of LDP and LTV in averting lung injury 7 days post-mechanical ventilation was indistinguishable. CLINICAL TRIAL REGISTRATION: The study was registered with the ClinicalTrials.gov database (identification number NCT04035915).

Limited breathing pressure or low amount of air given to the lung; which one is better for adults who need breathing help by ventilator machineWe conducted this research at Siriraj Hospital in Bangkok, Thailand, aiming to compare two ways of helping patients with breathing problems. We studied 126 patients who were randomly put into two groups. One group received a method where the pressure during breathing was limited (limited driving pressure: LDP), and the other group got a method where the amount of air given to the lungs was kept low (low tidal volume: LTV). We checked how bad the lung injury was at seven days later. The results showed that there was no difference between the two methods. Both ways of helping patients breathe had similar outcomes, and neither was significantly better than the other in preventing lung problems. The study suggests that both approaches work about the same for patients who need help with breathing using a machine.

Effect of antibody-mediated connective tissue growth factor neutralization on lung edema in ventilator-induced lung injury in rats.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by alveolar edema that can progress to septal fibrosis. Mechanical ventilation can augment lung injury, termed ventilator-induced lung injury (VILI). Connective tissue growth factor (CTGF), a mediator of fibrosis, is increased in ARDS patients. Blocking CTGF inhibits fibrosis and possibly vascular leakage. This study investigated whether neutralizing CTGF reduces pulmonary edema in VILI. METHODS: Following LPS administration, rats were mechanically ventilated for 6 h with low (6 mL/kg; low VT) or moderate (10 mL/kg; mod VT) tidal volume and treated with a neutralizing CTGF antibody (FG-3154) or placebo lgG (vehicle). Control rats without LPS were ventilated for 6 h with low VT. Lung wet-to-dry weight ratio, FITC-labeled dextran permeability, histopathology, and soluble RAGE were determined. RESULTS: VILI was characterized by reduced PaO2/FiO2 ratio (low VT: 540 [381-661] vs. control: 693 [620-754], p < 0.05), increased wet-to-dry weight ratio (low VT: 4.8 [4.6-4.9] vs. control: 4.5 [4.4-4.6], p < 0.05), pneumonia (low VT: 30 [0-58] vs. control: 0 [0-0]%, p < 0.05) and interstitial inflammation (low VT: 2 [1-3] vs. control: 1 [0-1], p < 0.05). FG-3154 did not affect wet-to-dry weight ratio (mod VT + FG-3154: 4.8 [4.7-5.0] vs. mod VT + vehicle: 4.8 [4.8-5.0], p > 0.99), extravasated dextrans (mod VT + FG-3154: 0.06 [0.04-0.09] vs. mod VT + vehicle: 0.04 [0.03-0.09] µg/mg tissue, p > 0.99), sRAGE (mod VT + FG-3154: 1865 [1628-2252] vs. mod VT + vehicle: 1885 [1695-2159] pg/mL, p > 0.99) or histopathology. CONCLUSIONS: 'Double hit' VILI was characterized by inflammation, impaired oxygenation, pulmonary edema and histopathological lung injury. Blocking CTGF does not improve oxygenation nor reduce pulmonary edema in rats with VILI.

Effects of mechanical ventilation on the interstitial extracellular matrix in healthy lungs and lungs affected by acute respiratory distress syndrome: a narrative review.

BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.

Driving pressure in mechanical ventilation: A review.

Driving pressure (∆P) is a core therapeutic component of mechanical ventilation (MV). Varying levels of ∆P have been employed during MV depending on the type of underlying pathology and severity of injury. However, ∆P levels have also been shown to closely impact hard endpoints such as mortality. Considering this, conducting an in-depth review of ∆P as a unique, outcome-impacting therapeutic modality is extremely important. There is a need to understand the subtleties involved in making sure ∆P levels are optimized to enhance outcomes and minimize harm. We performed this narrative review to further explore the various uses of ∆P, the different parameters that can affect its use, and how outcomes vary in different patient populations at different pressure levels. To better utilize ∆P in MV-requiring patients, additional large-scale clinical studies are needed.

Rutin targets AKT to inhibit ferroptosis in ventilator-induced lung injury.

Our previous research confirmed that rutin reduced ventilator-induced lung injury (VILI) in mice. Ferroptosis has been reported to participate in the pathogenic process of VILI. We will explore whether rutin inhibits ferroptosis to alleviate VILI. A mouse model of VILI was constructed with or without rutin pretreatment to perform a multiomics analysis. Hematoxylin-eosin (HE) staining and transmission electron microscopy were used to evaluate lung injury in VILI mice. Dihydroethidium (DHE) staining and the malondialdehyde (MDA) and superoxide dismutase (SOD) levels were detected. Molecular docking was performed to determine the binding affinity between rutin and ferroptosis-related proteins. Western blot analysis, real-time PCR (RT-PCR) and immunohistochemical (IHC) staining were conducted to detect the expression levels of GPX4, XCT, ACSL4, FTH1, AKT and p-AKT in lung tissues. Microscale thermophoresis (MST) was used to evaluate the binding between rutin and AKT1. Transcriptomic and proteomic analyses showed that ferroptosis may play a key role in VILI mice. Metabolomic analysis demonstrated that rutin may affect ferroptosis via the AKT pathway. Molecular docking analysis indicated that rutin may regulate the expression of ferroptosis-related proteins. Moreover, rutin upregulated GPX4 expression and downregulated the expression of XCT, ACSL4 and FTH1 in the lung tissues. Rutin also increased the ratio of p-AKT/AKT and p-AKT expression. MST analysis showed that rutin binds to AKT1. Rutin binds to AKT to activate the AKT signaling pathway, contributing to inhibit ferroptosis, thus preventing VILI in mice. Our study elucidated a possible novel strategy of involving the use of rutin for preventing VILI.

Stress & strain in mechanically nonuniform alveoli using clinical input variables: a simple conceptual model.

Clinicians currently monitor pressure and volume at the airway opening, assuming that these observations relate closely to stresses and strains at the micro level. Indeed, this assumption forms the basis of current approaches to lung protective ventilation. Nonetheless, although the airway pressure applied under static conditions may be the same everywhere in healthy lungs, the stresses within a mechanically non-uniform ARDS lung are not. Estimating actual tissue stresses and strains that occur in a mechanically non-uniform environment must account for factors beyond the measurements from the ventilator circuit of airway pressures, tidal volume, and total mechanical power. A first conceptual step for the clinician to better define the VILI hazard requires consideration of lung unit tension, stress focusing, and intracycle power concentration. With reasonable approximations, better understanding of the value and limitations of presently used general guidelines for lung protection may eventually be developed from clinical inputs measured by the caregiver. The primary purpose of the present thought exercise is to extend our published model of a uniform, spherical lung unit to characterize the amplifications of stress (tension) and strain (area change) that occur under static conditions at interface boundaries between a sphere's surface segments having differing compliances. Together with measurable ventilating power, these are incorporated into our perspective of VILI risk. This conceptual exercise brings to light how variables that are seldom considered by the clinician but are both recognizable and measurable might help gauge the hazard for VILI of applied pressure and power.

Collagen Tubular Airway-on-Chip for Extended Epithelial Culture and Investigation of Ventilation Dynamics.

The lower respiratory tract is a hierarchical network of compliant tubular structures that are made from extracellular matrix proteins with a wall lined by an epithelium. While microfluidic airway-on-a-chip models incorporate the effects of shear and stretch on the epithelium, week-long air-liquid-interface culture at physiological shear stresses, the circular cross-section, and compliance of native airway walls have yet to be recapitulated. To overcome these limitations, a collagen tube-based airway model is presented. The lumen is lined with a confluent epithelium during two-week continuous perfusion with warm, humid air while presenting culture medium from the outside and compensating for evaporation. The model recapitulates human small airways in extracellular matrix composition and mechanical microenvironment, allowing for the first time dynamic studies of elastocapillary phenomena associated with regular breathing and mechanical ventilation, as well as their impacts on the epithelium. A case study reveales increasing damage to the epithelium during repetitive collapse and reopening cycles as opposed to overdistension, suggesting expiratory flow resistance to reduce atelectasis. The model is expected to promote systematic comparisons between different clinically used ventilation strategies and, more broadly, to enhance human organ-on-a-chip platforms for a variety of tubular tissues.