Critical Illness Syndrome Research Articles

From Traditional Typing to Intelligent Insights: A Narrative Review of Directions Toward Targeted Therapies in Delirium.

Delirium is a heterogeneous syndrome characterized by an acute change in level of consciousness that is associated with inattention and disorganized thinking. Delirium affects most critically ill patients and is associated with poor patient-oriented outcomes such as increased mortality, longer ICU and hospital length of stay, and worse long-term cognitive outcomes. The concept of delirium and its subtypes has existed since nearly the beginning of recorded medical literature, yet robust therapies have yet to be identified. Analogous to other critical illness syndromes, we suspect the lack of identified therapies stems from patient heterogeneity and prior subtyping efforts that do not capture the underlying etiology of delirium. The time has come to leverage machine learning approaches, such as supervised and unsupervised clustering, to identify clinical and pathophysiological distinct clusters of delirium that will likely respond differently to various interventions. We use sedation in the ICU as an example of how precision therapies can be applied to critically ill patients, highlighting the fact that while for some patients a sedative drug may cause delirium, in another cohort sedation is the specific treatment. Finally, we conclude with a proposition to move away from the term delirium, and rather focus on the treatable traits that may allow precision therapies to be tested.

U-Shaped Association Between Carboxyhemoglobin and Mortality in Patients With Acute Respiratory Distress Syndrome on Venovenous Extracorporeal Membrane Oxygenation.

Carbon monoxide (CO) is an endogenous signaling molecule that activates cytoprotective programs implicated in the resolution of acute respiratory distress syndrome (ARDS) and survival of critical illness. Because CO levels can be measured in blood as carboxyhemoglobin, we hypothesized that carboxyhemoglobin percent (COHb%) may associate with mortality. To examine the relationship between COHb% and outcomes in patients with ARDS requiring venovenous extracorporeal membrane oxygenation (ECMO), a condition where elevated COHb% is commonly observed. Retrospective cohort study. Academic medical center ICU. Patients were included that had ARDS on venovenous ECMO. We examined the association between COHb% and mortality using a Cox proportional hazards model. Secondary outcomes including ECMO duration, ventilator weaning, and hospital and ICU length of stay were examined using both subdistribution and causal-specific hazard models for competing risks. We identified 109 consecutive patients for analysis. Mortality significantly decreased per 1 U increase in COHb% below 3.25% (hazard ratio [HR], 0.35; 95% CI, 0.15-0.80; p = 0.013) and increased per 1 U increase above 3.25% (HR, 4.7; 95% CI, 1.5-14.7; p = 0.007) reflecting a nonlinear association (p = 0.006). Each unit increase in COHb% was associated with reduced likelihood of liberation from ECMO and mechanical ventilation, and increased time to hospital and ICU discharge (all p < 0.05). COHb% was significantly associated with hemolysis but not with initiation of hemodialysis or blood transfusions. In patients with ARDS on venovenous ECMO, COHb% is a novel biomarker for mortality exhibiting a U-shaped pattern. Our findings suggest that too little CO (perhaps due to impaired host signaling) or excess CO (perhaps due to hemolysis) is associated with higher mortality. Patients with low COHb% may exhibit the most benefit from future therapies targeting anti-oxidant and anti-inflammatory pathways such as low-dose inhaled CO gas.

Are There Distinct Cardiovascular Subclasses in Acute Respiratory Distress Syndrome? Maybe.

Are There Distinct Cardiovascular Subclasses in Acute Respiratory Distress Syndrome? Maybe.

Effect of noradrenaline on propofol-induced mitochondrial dysfunction in human skeletal muscle cells

BackgroundMitochondrial dysfunction is a hallmark of both critical illness and propofol infusion syndrome and its severity seems to be proportional to the doses of noradrenaline, which patients are receiving. We comprehensively studied the effects of noradrenaline on cellular bioenergetics and mitochondrial biology in human skeletal muscle cells with and without propofol-induced mitochondrial dysfunction.MethodsHuman skeletal muscle cells were isolated from vastus lateralis biopsies from patients undergoing elective hip replacement surgery (n = 14) or healthy volunteers (n = 4). After long-term (96 h) exposure to propofol (10 µg/mL), noradrenaline (100 µM), or both, energy metabolism was assessed by extracellular flux analysis and substrate oxidation assays using [14C] palmitic and [14C(U)] lactic acid. Mitochondrial membrane potential, morphology and reactive oxygen species production were analysed by confocal laser scanning microscopy. Mitochondrial mass was assessed both spectrophotometrically and by confocal laser scanning microscopy.ResultsPropofol moderately reduced mitochondrial mass and induced bioenergetic dysfunction, such as a reduction of maximum electron transfer chain capacity, ATP synthesis and profound inhibition of exogenous fatty acid oxidation. Noradrenaline exposure increased mitochondrial network size and turnover in both propofol treated and untreated cells as apparent from increased co-localization with lysosomes. After adjustment to mitochondrial mass, noradrenaline did not affect mitochondrial functional parameters in naïve cells, but it significantly reduced the degree of mitochondrial dysfunction induced by propofol co-exposure. The fatty acid oxidation capacity was restored almost completely by noradrenaline co-exposure, most likely due to restoration of the capacity to transfer long-chain fatty acid to mitochondria. Both propofol and noradrenaline reduced mitochondrial membrane potential and increased reactive oxygen species production, but their effects were not additive.ConclusionsNoradrenaline prevents rather than aggravates propofol-induced impairment of mitochondrial functions in human skeletal muscle cells. Its effects on bioenergetic dysfunctions of other origins, such as sepsis, remain to be demonstrated.

Rethinking Acute Respiratory Distress Syndrome after COVID-19: If a "Better" Definition Is the Answer, What Is the Question?

The definition of acute respiratory distress syndrome (ARDS) has a somewhat controversial history, with some even questioning the need for the term "ARDS." This controversy has been amplified by the coronavirus disease (COVID-19) pandemic given the marked increase in the incidence of ARDS, the relatively new treatment modalities that do not fit neatly with the Berlin definition, and the difficulty of making the diagnosis in resource-limited settings. We propose that attempts to revise the definition of ARDS should apply the framework originally developed by psychologists and social scientists and used by other medical disciplines to generate and assess definitions of clinical syndromes that do not have gold standards. This framework is structured around measures of reliability, feasibility, and validity. Future revisions of the definition of ARDS should contain the purpose, the methodology, and the framework for empirically testing any proposed definition. Attempts to revise critical illness syndromes' definitions usually hope to make them "better"; our recommendation is that future attempts use the same criteria used by other fields in defining what "better" means.

GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr−/−) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr−/− mice survived longer than controls after LPS-induced lung injury. Ghsr−/− mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr−/− mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

Abstract 9123: Plasma Biomarkers Associated With PICU Mortality in Children With Cardiac Arrest and Acute Respiratory Distress Syndrome

Introduction: The post-cardiac arrest state is comprised of an ischemic and reperfusion syndrome, with inflammation similar to sepsis and acute respiratory distress syndrome (ARDS). However, it is unknown whether cardiac arrest has a distinct inflammatory profile relative to these other critical illness syndromes. Using plasma biomarkers of systemic inflammation measured in children with ARDS, we aimed to evaluate identify unique biomarkers in a sub-cohort with cardiac arrest, and the association of these biomarkers with mortality. Methods: This was a retrospective single-center cohort study of 17 biomarkers prospectively collected from pediatric subjects with ARDS between 2014-2019. Biomarkers were drawn within 24 hours after both ARDS diagnosis and cardiac arrest. Clinical characteristics and biomarkers were compared between those with ARDS and those with ARDS and cardiac arrest (ARDS+CA) using nonparametric tests. In ARDS+CA subjects, associations of biomarkers with mortality were tested with univariate and bivariate logistic regression. Results: Biomarkers were measured in 333 subjects: 301 with ARDS (median age 5.3 years, 55.5% male) and 32 ARDS+CA (median age 8 years, 53.1% male). Majority of arrests (68.7%) were out-of-hospital with median 11 minutes of CPR. ARDS+CA subjects were more likely to be immunosuppressed and present after aspiration or drowning than the ARDS cohort. ARDS severity, PRISM III score, vasoactive-ionotropic score and extra-pulmonary organ failure were worse in the ARDS+CA group (p&lt;0.05). Eight biomarkers were elevated in ARDS+CA compared to the ARDS cohort: sRAGE, nucleosomes, SP-D, CCL22, IL-6, HSP70, IL-8, and MIP-1b (p&lt;0.05). In the ARDS+CA cohort, 3 biomarkers were associated with mortality when controlling for markers of disease and cardiac arrest severity: sRAGE (unadjusted odds ratio 3.48 [IQR 1.35, 8.99], p=0.010), IL-6 (OR 1.75 [1.13, 2.71], p=0.012) and granzyme B (OR 3.74 [1.46, 9.57], p=0.006). Conclusion: sRAGE, IL-6 and granzyme B were independently associated with mortality after pediatric cardiac arrest in ARDS. This exploratory work suggests that cardiac arrest may induce a distinct inflammatory state that differs from other critical illness syndromes and further investigation is needed.

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS.

The severe respiratory consequences of the coronavirus disease 2019 (COVID-19) pandemic have prompted the urgent need for novel therapies. Cell-based therapies, primarily using mesenchymal stromal cells (MSCs), have demonstrated safety and potential efficacy in the treatment of critical illness, particularly sepsis and acute respiratory distress syndrome (ARDS). However, there are limited preclinical data for MSCs in COVID-19. Recent studies have shown that MSCs could decrease inflammation, improve lung permeability, enhance microbe and alveolar fluid clearance, and promote lung epithelial and endothelial repair. In addition, MSC-based therapy has shown promising effects in preclinical studies and phase 1 clinical trials in sepsis and ARDS. Here, we review recent advances related to MSC-based therapy in the context of sepsis and ARDS and evaluate the potential value of MSCs as a therapeutic strategy for COVID-19.

Deep learning to detect acute respiratory distress syndrome on chest radiographs: a retrospective study with external validation

SummaryBackgroundAcute respiratory distress syndrome (ARDS) is a common, but under-recognised, critical illness syndrome associated with high mortality. An important factor in its under-recognition is the variability in chest radiograph interpretation for ARDS. We sought to train a deep convolutional neural network (CNN) to detect ARDS findings on chest radiographs.MethodsCNNs were pretrained on 595 506 radiographs from two centres to identify common chest findings (eg, opacity and effusion), and then trained on 8072 radiographs annotated for ARDS by multiple physicians using various transfer learning approaches. The best performing CNN was tested on chest radiographs in an internal and external cohort, including a subset reviewed by six physicians, including a chest radiologist and physicians trained in intensive care medicine. Chest radiograph data were acquired from four US hospitals.FindingsIn an internal test set of 1560 chest radiographs from 455 patients with acute hypoxaemic respiratory failure, a CNN could detect ARDS with an area under the receiver operator characteristics curve (AUROC) of 0·92 (95% CI 0·89–0·94). In the subgroup of 413 images reviewed by at least six physicians, its AUROC was 0·93 (95% CI 0·88–0·96), sensitivity 83·0% (95% CI 74·0–91·1), and specificity 88·3% (95% CI 83·1–92·8). Among images with zero of six ARDS annotations (n=155), the median CNN probability was 11%, with six (4%) assigned a probability above 50%. Among images with six of six ARDS annotations (n=27), the median CNN probability was 91%, with two (7%) assigned a probability below 50%. In an external cohort of 958 chest radiographs from 431 patients with sepsis, the AUROC was 0·88 (95% CI 0·85–0·91). When radiographs annotated as equivocal were excluded, the AUROC was 0·93 (0·92–0·95).InterpretationA CNN can be trained to achieve expert physician-level performance in ARDS detection on chest radiographs. Further research is needed to evaluate the use of these algorithms to support real-time identification of ARDS patients to ensure fidelity with evidence-based care or to support ongoing ARDS research.FundingNational Institutes of Health, Department of Defense, and Department of Veterans Affairs.

Immunological Endotyping of Chronic Critical Illness After Severe Sepsis

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early “cytokine or genomic storm,” but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed.

The Emerging Role of Copeptin.

Direct measurement of the nonapeptide vasopressin has been limited by analyte instability ex vivo and in vivo rapid degradation, low serum concentrations requiring a sensitive assay and inherent secretory pulsatility. Copeptin is a 39 amino acid glycopeptide cleavage product of vasopressin synthesis with high stability, providing a marker of vasopressin secretion. Copeptin measurement has applications in diagnosis of diabetes insipidus and other diseases with altered vasopressin secretion. This review summarises our current understanding of serum copeptin measurement in diabetes insipidus and possible future applications of copeptin assays. As vasopressin is a stress hormone, there is emerging evidence on the use of copeptin for diagnosis and prognostication of disorders such as syndrome of inappropriate anti-diuretic hormone secretion, diabetes mellitus, critical illness, stroke, cardiovascular disease, respiratory disease, renal disease and thermal stress. Copeptin concentration measurement is likely to improve the diagnostic reliability of diabetes insipidus and, as a marker of stress, may have diagnostic or prognostic utility in specific clinical circumstances. Further studies are needed to determine if goal-directed therapy using plasma copeptin concentrations may improve patient outcomes.

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine.

A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients’ inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.

Human adaptation to hypoxia in critical illness.

The syndrome of critical illness is a complex physiological stressor that can be triggered by diverse pathologies. It is widely believed that organ dysfunction and death result from bioenergetic failure caused by inadequate cellular oxygen supply. Teleologically, life has evolved to survive in the face of stressors by undergoing a suite of adaptive changes. Adaptation not only comprises alterations in systemic physiology but also involves molecular reprogramming within cells. The concept of cellular adaptation in critically ill patients is a matter of contention in part because medical interventions mask underlying physiology, creating the artificial construct of "chronic critical illness," without which death would be imminent. Thus far, the intensive care armamentarium has not targeted cellular metabolism to preserve a temporary equilibrium but instead attempts to normalize global oxygen and substrate delivery. Here, we review adaptations to hypoxia that have been demonstrated in cellular models and in human conditions associated with hypoxia, including the hypobaric hypoxia of high altitude, the intrauterine low-oxygen environment, and adult myocardial hibernation. Common features include upregulation of glycolytic ATP production, enhancement of respiratory efficiency, downregulation of mitochondrial density, and suppression of energy-consuming processes. We argue that these innate cellular adaptations to hypoxia represent potential avenues for intervention that have thus far remained untapped by intensive care medicine.

Acute Uterine Torsion Mimicking Tumor Lysis Syndrome

Background: Non-gravid uterine torsion is rare and mostly diagnosed at surgery. This report describes a patient with a large abdominal mass, critical illness, and tumor lysis syndrome. Case: A female presented with acute abdominal pain. Physical exam showed a large abdominal mass and abdominal rigidity. Serial laboratory tests showed a drop in hemoglobin level, progressive renal failure and serum uric acid and phosphate concentrations compatible with tumor lysis syndrome. Computed tomography showed a 30 cm mass filling the pelvis and abdomen. At an emergency exploratory laparotomy, a 360 degrees torsion of the uterus was found. An uneventful total hysterectomy was done. After surgery renal function restored. Conclusion: Uterine torsion is rare and can be potentially life threatening when presenting as tumor lysis syndrome

Respiratory support for adult patients with COVID-19.

The COVID‐19 pandemic is creating unique strains on the healthcare system. While only a small percentage of patients require mechanical ventilation and ICU care, the enormous size of the populations affected means that these critical resources may become limited. A number of non‐invasive options exist to avert mechanical ventilation and ICU admission. This is a clinical review of these options and their applicability in adult COVID‐19 patients. Summary recommendations include: (1) Avoid nebulized therapies. Consider metered dose inhaler alternatives. (2) Provide supplemental oxygen following usual treatment principles for hypoxic respiratory failure. Maintain awareness of the aerosol‐generating potential of all devices, including nasal cannulas, simple face masks, and venturi masks. Use non‐rebreather masks when possible. Be attentive to aerosol generation and the use of personal protective equipment. (3) High flow nasal oxygen is preferred for patients with higher oxygen support requirements. Non‐invasive positive pressure ventilation may be associated with higher risk of nosocomial transmission. If used, measures special precautions should be used reduce aerosol formation. (4) Early intubation/mechanical ventilation may be prudent for patients deemed likely to progress to critical illness, multi‐organ failure, or acute respiratory distress syndrome (ARDS).

Time to stop randomized and large pragmatic trials for intensive care medicine syndromes: the case of sepsis and acute respiratory distress syndrome.

In this paper we discuss the limitations of large randomized controlled trials with mortality endpoints in patients with critical illness associated diagnoses such as sepsis. When patients with the same syndrome diagnosis do not share the pathways that lead to death (the attributable risk), any therapy can only lead to small effects in these populations. Using Monte Carlo simulations, we show how the syndrome-attributable risks of critical illness-associated diagnoses are likely overestimated using common statistical methods. This overestimation of syndrome-attributable risks leads to a corresponding overestimation of attainable treatment effects and an underestimation of required sample sizes. We demonstrate that larger and more 'pragmatic' randomized trials are not the solution because they decrease therapeutic and diagnostic precision, the therapeutic effect size and the probability of finding a beneficial effect. Finally, we argue that the most logical solution is a renewed focus on mechanistic research into the complexities of critical illness syndromes.

1059. Impact of a Syndrome-Based Antimicrobial Stewardship Intervention on Anti-Pseudomonal β-Lactam Use, C. difficile Rates and Cost in an Urban Community Hospital

BackgroundThe use of anti-Pseudomonal β-lactam (APBL) agents has significantly increased in the past decade, carrying higher costs and contributing to antimicrobial pressure. Antimicrobial stewardship (ASP) can promote evidence-based antimicrobial selection and mitigate excess APBL use. We implemented a comprehensive ASP with syndrome-based prospective audit and feedback (PAF) at an urban community hospital. The goal of this study is to assess the impact of syndrome-based PAF on APBL use, C. difficile rates and cost.MethodsASP with all CDC core elements was implemented at a 151-bed community hospital in October 2017. Syndrome-based guidelines and PAF was established and overseen via direct communication with an ID physician. Days of therapy (DOT), cost and C. difficile rates were assessed 12 months before and after ASP. DOT for APBL and non-APBL utilization was tabulated by unit and paired t-test performed.ResultsMost cases reviewed by PAF (51%) were represented in our syndrome-based treatment guidelines (Figure 1). Soft tissue (33%) and intra-abdominal (24%) infections were the most common syndromes. Change to guideline was the most common PAF intervention (62%) followed by de-escalation (30%). At 12 months, total DOT/1,000 increased (392.5 vs. 404) while the proportion of parenteral antimicrobials used decreased (71% vs. 65%). Antibiotic expenditures decreased by 23%, with a reduction in APBL of 20% and non-APBL of 10% (Table 1). Statistically significant reductions APBL use in non-ICU settings (P = 0.0139) and statistically significant increases in non-APBL in ICU settings occurred (P = 0.0001) (Figure 2 and 3). C difficile rates decreased from 21% (3.27 vs. 2.56).ConclusionSyndrome-based PAF was successfully implemented. A reduction in APBL use was seen in non-ICU settings, where evidence-based de-escalation may be more feasible. APBL use remained high in the ICU but was guideline consistent. A rise in non-APBL use also occurred. Certain critical illness syndromes warrant APBLs, but PAF may promote culture-directed and syndrome-specific treatments. ASP increased guideline-based therapy and contributed to decreased broad-spectrum antimicrobial use, antimicrobial expenditures and C difficile rates. Syndrome based PAF can be successfully implemented in community settings. Disclosures All authors: No reported disclosures.

Nonthyroidal illness in critically ill children.

This review summarizes recent literature on nonthyroidal illness syndrome (NTI) and outcome of pediatric critical illness, to provide insight in pathophysiology and therapeutic implications. NTI is typically characterized by lowered triiodothyronine levels without compensatory TSH rise. Although NTI severity is associated with poor outcome of pediatric critical illness, it remains unclear whether this association reflects an adaptive protective response or contributes to poor outcome. Recently, two metabolic interventions that improved outcome also altered NTI in critically ill children. These studies shed new light on the topic, as the results suggested that the peripheral NTI component, with inactivation of thyroid hormone, may represent a beneficial adaptation, whereas the central component, with suppressed TSH-driven thyroid hormone secretion, may be maladaptive. There is currently insufficient evidence for treatment of NTI in children. However, the recent findings raised the hypothesis that reactivation of the central NTI component could offer benefit, which should be tested in RCTs. NTI in critically ill children can be modified by metabolic interventions. The peripheral, but not the central, component of NTI may be a beneficial adaptive response. These findings open perspectives for the development of novel strategies to improve outcome of critical illness in children.

Dioscin attenuates Bleomycin-Induced acute lung injury via inhibiting the inflammatory response in mice

Aim: Acute lung injury (ALI), a critical illness syndrome with high morbidity and mortality, is characterized by a severe inflammatory response. Dioscin exerts protective effects against crystalline silica-induced pulmonary inflammation and fibrosis in mice. Bleomycin (BLM) is widely used to induce ALI and fibrosis in animal models. This study aims to investigate the effects of dioscin on BLM-induced ALI in mice. Methods: C57BL/6 mice were intratracheally injected with BLM to induce ALI. Lungs and bronchoalveolar lavage fluids were then harvested on day 7 for evaluation. Changes in tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-10 (IL-10) expression level were measured by RT-qPCR and ELISA. Protein expressions of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and high-mobility group box 1 (HMGB1) were measured by western blot. Results: Dioscin protects against BLM-induced ALI by decreasing the numbers of total and inflammatory cells, lung edema, myeloperoxidase activity, and malondialdehyde content. Moreover, dioscin significantly inhibited TNF-α, IL-1β, NF-κB, COX-2, and HMGB1 levels, and upregulated IL-10 levels. Conclusion: Our data indicate that dioscin attenuates oxidative stress, the lung inflammatory response, and acute lung injury in BLM-challenged mice.

Puerarin prevents LPS-induced acute lung injury via inhibiting inflammatory response

Acute lung injury (ALI) is a critical illness syndrome with high morbidity and mortality in patients. Inflammation has been known to be involved in the development of ALI. The purpose of this study was to investigate the effect of puerarin on lipopolysaccharide (LPS)-induced ALI in mice. The pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were determined by ELISA. Western blot analysis was used for detecting the expression of NF-κB, IκBα, and LXRα. And myeloperoxidase (MPO) activity, lung wet/dry (W/D) ratio, and histopathological examination were also detected in lung tissues. The results showed that puerarin significantly inhibited LPS-stimulated MPO activity in lung tissues. Meanwhile, puerarin attenuated lung histopathological changes and lung wet/dry (W/D) ratio. We also found that the expression of pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β were inhibited by puerarin. Puerarin also inhibited LPS-induced TNF-α in RAW264.7 cells and IL-8 in A549 cells. From the results of western blotting, puerarin significantly suppressed LPS-stimulated NF-κB activation. And the expression of LXRα was dose-dependently increased by treatment of puerarin. The inhibition of puerarin on TNF-α production in RAW264.7 cells and IL-8 production in A549 cells were blocked by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). These results suggested that puerarin attenuated ALI by activating LXRα, which subsequently inhibited LPS-induced inflammatory response.