Exploring In Vitro and Ex Vivo Models as Pharmacological Tool for Acute Lung Injury

Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Medicine, Department of Epidemiology and Biostatistics, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA *See also p. 1731. The authors received funding from the National Institutes of Health.

To provide a comprehensive summary of the published data on cause of death in patients with acute respiratory distress syndrome (ARDS). PubMed (January 2015 to April 2024), bibliographies of relevant articles, and ARDS Network and Prevention & Early Treatment of Acute Lung Injury (PETAL) network websites. Observational studies and clinical trials that reported on cause of death in greater than or equal to 30 patients with ARDS, not obtained from death certificates. Animal studies, case reports, review articles, study protocols, and studies in pediatrics were excluded. Causes of death among ARDS patients who died were extracted and tabulated along with other pertinent study characteristics. We identified 15 observational studies (nine non-COVID ARDS, five COVID-related ARDS; one both) and five clinical trials (all non-COVID ARDS). Mutually exclusive prespecified categories were used for recording the cause of death in only eight studies although studies differed in the categories included and their definitions. When multiple organ failure was a predetermined category, it was the most common cause of death recorded (~50% of deaths), followed by respiratory causes with proportions varying from 16% to 42% depending on nomenclature (e.g., refractory hypoxemia, pulmonary causes) and definitions. However, the largest observational study in non-COVID ARDS (964 deaths), did not include multiple organ failure as a predetermined category, and found that pulmonary failure (42%) and cardiac failure (37%) were the most common causes of death. In COVID-related ARDS observational studies, pulmonary reasons were the most reported cause of death (up to 88%). Few studies have reported cause of death in patients with ARDS. In those that do, cause of death categories and definitions used are heterogeneous. Further research is needed to see whether a more rigorous and unified approach to assigning and reporting cause of death in ARDS would help identify more relevant endpoints for the assessment of targeted treatments in clinical trials.

Corticosteroids in ARDS: A Counterpoint

Advancing precision medicine for acute respiratory distress syndrome

EPO for stroke therapy - Is there a future for further clinical development?

COVID-19 acute respiratory distress syndrome: intriguing haemodynamics of an intriguing syndrome.

Background: Lung-protective ventilation (LPV) strategies have been beneficial in patients with acute respiratory distress syndrome (ARDS). As a vital part of LPV, positive end-expiratory pressure (PEEP) can enhance oxygenation. However, randomized clinical trials of different PEEP strategies seem to show no advantages in clinical outcomes in patients with ARDS. A potential reason is that diverse etiologies and phenotypes in patients with ARDS may account for different PEEP responses, resulting in variations in mortality. We consider hospital mortality to be associated with a more specific classification of ARDS, such as sepsis induced or not, and pulmonary or extrapulmonary one. Our study aimed to compare clinical outcomes in various patients with ARDS by etiologies using the China Critical Care Sepsis Trial (CCCST) database. This was a retrospective analysis of a prospective cohort of 2,138 patients with ARDS in the CCCST database. According to ARDS induced by sepsis or not and medical history, patients were stratified into different four groups. Differences among groups were assessed in hospital mortality, ventilation-free days, and other clinical features.Results: A total of 2,138 patients with ARDS were identified in the database, including 647 patients with sepsis-induced pulmonary ARDS (30.3%), 396 patients with sepsis-induced extrapulmonary ARDS (18.5%), 536 patients with non-sepsis pulmonary ARDS (25.1%), and 559 patients with non-sepsis extrapulmonary ARDS (26.1%). The pulmonary ARDS group had higher mortality compared with the extrapulmonary group (45.9 vs. 23.0%, p < 0.01), longer intensive care unit (ICU) and hospital stays (9 vs. 6 days, p < 0.01, 20 vs. 18 days, p = 0.01, respectively), and fewer ventilation-free days (5 vs. 9 days) in the presence of sepsis. However, the mortality in ARDS without sepsis was inverted compared with extrapulmonary ARDS (pulmonary 23.5% vs. extrapulmonary 29.2%, p = 0.04). After adjusting for the Acute Physiology and Chronic Health Evaluation II and sequential organ failure assessment scores and other clinical features, the sepsis-induced pulmonary condition was still a risk factor for death in patients with ARDS (hazard ratio 0.66, 95% CI, 0.54–0.82, p < 0.01) compared with sepsis-induced extrapulmonary ARDS and other subphenotypes.Conclusions: In the presence of sepsis, hospital mortality in pulmonary ARDS is higher compared with extrapulmonary ARDS; however, mortality is inverted in ARDS without sepsis. Sepsis-induced pulmonary ARDS should attract more attention from ICU physicians and be cautiously treated.Trial registration: ChiCTR-ECH-13003934. Registered August 3, 2013, http://www.chictr.org.cn.

BackgroundAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute respiratory failure with extremely high mortality and few effective treatments. Mesenchymal stem cells (MSCs) may reportedly contribute to tissue repair in ALI and ARDS. However, applications of MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced in pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form. Currently, there are no studies on the role of MSC SLP in ALI.MethodsIntratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was administered as a treatment. Histopathological assessment was performed by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively.ResultsWe found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited the interleukin 6–phosphorylated signal transducer and activator of transcription signaling pathway to activate tumor protein 63–jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and attenuate inflammatory responses.ConclusionsMSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and ARDS.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent need to find effective therapies. Preclinical studies have shown that inhaled halogenated agents may have beneficial effects in animal models of ARDS. The development of new devices to administer halogenated agents using modern intensive care unit (ICU) ventilators has significantly simplified the dispensing of halogenated agents to ICU patients. Because previous experimental and clinical research suggested potential benefits of halogenated volatiles, such as sevoflurane or isoflurane, for lung alveolar epithelial injury and inflammation, two pathophysiologic landmarks of diffuse alveolar damage during ARDS, we designed an animal model to understand the mechanisms of the effects of halogenated agents on lung injury and repair. After general anesthesia, tracheal intubation, and the initiation of mechanical ventilation, ARDS was induced in piglets via the intratracheal instillation of hydrochloric acid. Then, the piglets were sedated with inhaled sevoflurane or isoflurane using an ICU-type device, and the animals were ventilated with lung-protective mechanical ventilation during a 4 h period. During the study period, blood and alveolar samples were collected to evaluate arterial oxygenation, the permeability of the alveolar-capillary membrane, alveolar fluid clearance, and lung inflammation. Mechanical ventilation parameters were also collected throughout the experiment. Although this model induced a marked decrease in arterial oxygenation with altered alveolar-capillary permeability, it is reproducible and is characterized by a rapid onset, good stability over time, and no fatal complications. We have developed a piglet model of acid aspiration that reproduces most of the physiological, biological, and pathological features of clinical ARDS, and it will be helpful to further our understanding of the potential lung-protective effects of halogenated agents delivered through devices used for inhaled ICU sedation.

Nitric oxide: physiology and pharmacology.

Oxidative stress in clinical situations - fact or fiction?

Given the failure of pharmacological interventions in acute respiratory distress syndrome (ARDS), researchers have been actively pursuing novel strategies to treat this devastating, life-threatening condition commonly seen in the intensive care unit. There has been considerable research on harnessing the reparative properties of stem and progenitor cells to develop more effective therapeutic approaches for respiratory diseases with limited treatment options, such as ARDS. This review discusses the preclinical literature on the use of stem and progenitor cell therapy and cell-based gene therapy for the treatment of preclinical animal models of acute lung injury (ALI). A variety of cell types that have been used in preclinical models of ALI, such as mesenchymal stem cells, endothelial progenitor cells, and induced pluripotent stem cells, were evaluated. At present, two phase I trials have been completed and one phase I/II clinical trial is well underway in order to translate the therapeutic benefit gleaned from preclinical studies in complex animal models of ALI to patients with ARDS, paving the way for what could potentially develop into transformative therapy for critically ill patients. As we await the results of these early cell therapy trials, future success of stem cell therapy for ARDS will depend on selection of the most appropriate cell type, route and timing of cell delivery, enhancing effectiveness of cells (i.e., potency), and potentially combining beneficial cells and genes (cell-based gene therapy) to maximize therapeutic efficacy. The experimental models and scientific methods exploited to date have provided researchers with invaluable knowledge that will be leveraged to engineer cells with enhanced therapeutic capabilities for use in the next generation of clinical trials.

BackgroundChildren are susceptible to pulmonary injury, and acute lung injury (ALI) often results in a high mortality and financial cost in pediatric patients. Evidence has showed that oleic acid (OA) plays an important role in ALI. Therefore, it has special significance to study ALI in pediatric patients by using OA-induced animal models. Unfortunately, the animal model hs a high mortality due to hemodynamic instability. The aim of this study was to establish a novel hemodynamically stable OA-induced ALI model in piglets with two hits.Methods18 Chinese mini-piglets were randomized into three groups: group C (received saline-ethanol solution), group T (received OA-ethanol solution in routine administration manner) and group H (received OA-ethanol solution in two-hit manner). Hemodynamic and pulmonary function data were measured. Histopathological assessments were performed.ResultsTwo piglets in group T died of radical decline of systemic blood pressure. Group T showed more drastic hemodynamic changes than group H especially during the period of 5 to 30 minutes after OA administration. Both Group T and group H all produced severe lung injury, while group C had no significant pathologic changes. OA-induced hypotension might be caused by pulmonary hypertension rather than comprised left ventricular function.ConclusionOA leads to severe pulmonary hypertension which results in hemodynamic fluctuation in OA-induced ALI model. It is the first report on hemodynamic stable ALI animal model in piglets using two-hit method. The two-hit ALI animal model fulfils the ALI criteria and has the following characteristics: hemodynamic stability, stable damage to gas exchange and comparability with pediatric patients in body weight and corresponding age. The two-hit ALI animal model can be used to study the basic mechanism and the therapeutic strategies for pediatric ALI.

Acute lung injury is characterized by intense neutrophilic lung inflammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. There is an urgent need for effective therapies for acute lung injury. Zhang and colleagues tested the efficacy of adipose-derived stem cells in acute lung injury in mice. When adipose-derived stem cells were delivered to mice that had been challenged with lipopolysaccharide, they potently limited acute lung inflammation and injury in the mice, indicating that adipose-derived stem cells have therapeutic potential in acute lung injury in humans. Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury.

Purpose of ReviewTo summarize pathophysiology, key conflicts, and therapeutic approaches in managing concomitant severe acute brain injury (SABI) and acute respiratory distress syndrome (ARDS).Recent FindingsARDS is common in SABI and independently associated with worse outcomes in all SABI subtypes. Most landmark ARDS trials excluded patients with SABI, and evidence to guide decisions is limited in this population. Potential areas of conflict in the management of patients with both SABI and ARDS are (1) risk of intracranial pressure (ICP) elevation with high levels of positive end-expiratory pressure (PEEP), permissive hypercapnia due to lung protective ventilation (LPV), or prone ventilation; (2) balancing a conservative fluid management strategy with ensuring adequate cerebral perfusion, particularly in patients with symptomatic vasospasm or impaired cerebrovascular blood flow; and (3) uncertainty about the benefit and harm of corticosteroids in this population, with a mortality benefit in ARDS, increased mortality shown in TBI, and conflicting data in other SABI subtypes. Also, the widely adapted partial pressure of oxygen (PaO2) target of > 55 mmHg for ARDS may exacerbate secondary brain injury, and recent guidelines recommend higher goals of 80–120 mmHg in SABI. Distinct pathophysiology and trajectories among different SABI subtypes need to be considered.SummaryThe management of SABI with ARDS is highly complex, and conventional ARDS management strategies may result in increased ICP and decreased cerebral perfusion. A crucial aspect of concurrent management is to recognize the risk of secondary brain injury in the individual patient, monitor with vigilance, and adjust management during critical time windows. The care of these patients requires meticulous attention to oxygenation and ventilation, hemodynamics, temperature management, and the neurological exam. LPV and prone ventilation should be utilized, and supplemented with invasive ICP monitoring if there is concern for cerebral edema and increased ICP. PEEP titration should be deliberate, involving measures of hemodynamic, pulmonary, and brain physiology. Serial volume status assessments should be performed in SABI and ARDS, and fluid management should be individualized based on measures of brain perfusion, the neurological exam, and cardiopulmonary status. More research is needed to define risks and benefits in corticosteroids in this population.