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Arteriosclerosis, Thrombosis, and... Nov 2023Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the...
BACKGROUND
Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the microvasculature, induced by uncontrolled inflammatory stimulation, causes pulmonary edema. Identifying the inflammatory mediators that induce human lung microvascular endothelial cell barrier dysfunction is essential to find the best anti-inflammatory treatments for critically ill acute respiratory distress syndrome patients.
METHODS
We have compared the responses of primary human lung microvascular endothelial cells to the main inflammatory mediators involved in cytokine storms induced by sepsis and SARS-CoV2 pulmonary infection and to sera from healthy donors and severely ill patients with sepsis. Endothelial barrier function was measured by electric cell-substrate impedance sensing, quantitative confocal microscopy, and Western blot.
RESULTS
The human lung microvascular endothelial cell barrier was completely disrupted by IL (interleukin)-6 conjugated with soluble IL-6R (IL-6 receptor) and by IL-1β (interleukin-1beta), moderately affected by TNF (tumor necrosis factor)-α and IFN (interferon)-γ and unaffected by other cytokines and chemokines, such as IL-6, IL-8, MCP (monocyte chemoattractant protein)-1 and MCP-3. The inhibition of IL-1 and IL-6R simultaneously, but not separately, significantly reduced endothelial hyperpermeability on exposing human lung microvascular endothelial cells to a cytokine storm consisting of 8 inflammatory mediators or to sera from patients with sepsis. Simultaneous inhibition of IL-1 and JAK (Janus kinase)-STAT (signal transducer and activator of transcription protein), a signaling node downstream IL-6 and IFN-γ, also prevented septic serum-induced endothelial barrier disruption.
CONCLUSIONS
These findings strongly suggest a major role for both IL-6 trans-signaling and IL-1β signaling in the pathological increase in permeability of the human lung microvasculature and reveal combinatorial strategies that enable the gradual control of pulmonary endothelial barrier function in response to a cytokine storm.
Topics: Humans; Interleukin-6; Cytokine Release Syndrome; Endothelial Cells; RNA, Viral; Lung; Interferon-gamma; Tumor Necrosis Factor-alpha; Respiratory Distress Syndrome; COVID-19; Sepsis; Interleukin-1
PubMed: 37732482
DOI: 10.1161/ATVBAHA.123.319695 -
Immunity, Inflammation and Disease Mar 2024Pyroptosis and polarization are significant contributors to the onset and development of many diseases. At present, the relationship between pyroptosis and polarization... (Review)
Review
BACKGROUND
Pyroptosis and polarization are significant contributors to the onset and development of many diseases. At present, the relationship between pyroptosis and polarization in acute lung injury (ALI) caused by sepsis remains unclear.
METHODS
The ALI model for sepsis was created in mice and categorized into the blank control, lipopolysaccharide (LPS) group, LPS + low-dose Belnacasan group, LPS + high-dose Belnacasan group, LPS + low-dose Wedelolactone group, LPS + high-dose Wedelolactone group, and positive control group. The wet-dry specific gravity was evaluated to compare pulmonary edema. Hematoxylin-eosin, Masson, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining techniques were conducted to observe and contrast the pathological changes in lung tissue. ELISA was utilized to identify M1 and M2 macrophages and correlated inflammatory factors. Immunohistochemical staining and flow cytometry were employed to identify markers of M1 and M2 macrophages in lung tissue. Propidium iodide staining, together with flow cytometry, was utilized to observe the degree and positive rate of pyroptosis of alveolar macrophages. Western blot analysis was conducted to detect the expression levels of Caspase 1, Caspase 11, GSDMD, and IL-18 in the lung tissues of each group. The real-time quantitative polymerase chain reaction method was used to ascertain relative expression levels of NLRP3, Caspase 1, Caspase 11, GSDMD, IL-18, iNOS, and Arg-1 in lung tissues of all groups.
RESULTS
In mice with sepsis-induced ALI, both classical and nonclassical pathways of pyroptosis are observed. Inhibiting pyroptosis has been found to ameliorate lung injury, pulmonary edema, and inflammation induced by LPS. Notably, the expression of NLRP3, Caspase 1, Caspase 11, GSDMD, IL-1β, IL-18, TGF-β, CD86, CD206, iNOS, and Arg-1 were all altered in this process. Additionally, alveolar macrophages were polarized along with pyroptosis in mice with ALI caused by sepsis.
CONCLUSION
Pyroptosis of alveolar macrophages in the context of ALI in mice infected with sepsis has been linked to the polarization of alveolar macrophages toward type M1.
Topics: Animals; Mice; Lipopolysaccharides; Interleukin-18; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Caspase 1; Macrophages; Acute Lung Injury; Caspases; Sepsis
PubMed: 38501547
DOI: 10.1002/iid3.1197 -
Journal of Hepatology Mar 2024The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been...
BACKGROUND & AIMS
The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice.
METHODS
We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy.
RESULTS
A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema.
CONCLUSIONS
The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy.
IMPACT AND IMPLICATIONS
The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice.
PubMed: 38479614
DOI: 10.1016/j.jhep.2024.03.006 -
Journal of Education & Teaching in... Apr 2024The target audiences for this team-based learning (TBL) activity are resident physicians and medical students.
AUDIENCE
The target audiences for this team-based learning (TBL) activity are resident physicians and medical students.
INTRODUCTION
According to the Centers for Disease Control and Prevention (CDC), nearly half of the adults in the United States have hypertension,1 which is a leading cause of cardiovascular disease and premature death.2 In extreme cases, patients may present in hypertensive emergencies, defined as an acute, marked elevation of systolic blood pressure >180mmHg or diastolic blood pressure >120mmHg with evidence of organ dysfunction.3,4 Patients presenting to the emergency department (ED) with symptoms of hypertensive emergencies must be promptly diagnosed and treated to prevent further morbidity and mortality. This TBL utilizes four clinical cases to educate resident physicians and medical students not only on the recognition of hypertensive emergencies, but also on the workup, management, and disposition of patients who present to the ED with hypertension.
EDUCATIONAL OBJECTIVES
By the end of this TBL session, learners should be able to: 1) define features of asymptomatic hypertension versus hypertensive emergency, 2) discuss which patients with elevated blood pressure may require further diagnostic workup and intervention, 3) identify a differential diagnosis for patients presenting with elevated blood pressures, 4) recognize the features of different types of end-organ damage, 5) review an algorithm for the pharmacologic management of hypertensive emergencies, 6) indicate dosing and routes of various anti-hypertensive medications, 7) choose the appropriate treatment for a patient who is hypertensive and presenting with flash pulmonary edema, 8) identify an aortic dissection on computed tomography (CT), 9) choose the appropriate treatment for a patient who is hypertensive and presenting with an aortic dissection, 10) identify intracranial hemorrhage on CT, 11) choose the appropriate treatment for a patient who is hypertensive and presenting with an intracranial hemorrhage, and 12) describe the intervention for warfarin reversal.
EDUCATIONAL METHODS
This is a classic TBL that includes an individual readiness assessment test (iRAT), a multiple-choice group readiness assessment test (gRAT), and a group application exercise (GAE).
RESEARCH METHODS
Learners and instructors were given the opportunity to provide verbal feedback after completion of the TBL. Learners included senior medical students and first-, second-, and third-year emergency-medicine residents. Learners were specifically asked if they felt the cases were educational, relevant, and useful to their training.
RESULTS
Six resident physicians and three medical students volunteered their verbal feedback, and agreed when they were specifically asked if the cases were educational, relevant, and useful to their training. The same learners also agreed when asked if they felt the TBL was a more enjoyable activity than a direct lecture to refresh their knowledge and skills. One instructor observed that interns and medical students were generally able to reach a correct diagnosis; however, they seemed to struggle more with describing appropriate pharmacologic interventions when compared to more senior learners.
DISCUSSION
Hypertension is a common complaint and incidental finding in patients presenting to the ED. Given its non-specific value, it can be a difficult topic for the novice healthcare provider to master. The differential diagnosis for a patient presenting with hypertension is vast, ranging from benign to emergent, and can sometimes necessitate minimal to substantial workups. Thus, this TBL is a useful, relevant, and effective exercise for residents-in-training to review and understand the management of hypertension.
TOPICS
Hypertension, hypertensive emergency, asymptomatic hypertension, flash pulmonary edema, aortic dissection, intracranial hemorrhage, warfarin reversal, team-based learning.
PubMed: 38707946
DOI: 10.21980/J8BP90 -
BMC Pulmonary Medicine Aug 2023Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a clinical syndrome with various causes. It is not uncommon that COPD patients presenting with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a clinical syndrome with various causes. It is not uncommon that COPD patients presenting with dyspnea have multiple causes for their symptoms including AECOPD, pneumonia, or congestive heart failure occurring concurrently.
METHODS
To identify clinical, radiographic, and laboratory characteristics that might help distinguish AECOPD from another dominant disease in patients with a history of COPD, we conducted a retrospective cohort study of hospitalized patients with admitting diagnosis of AECOPD who were screened for a prospective randomized controlled trial from Sep 2016 to Mar 2018. Clinical characteristics, course in hospital, and final diagnosis at discharge were reviewed and adjudicated by two authors. The final diagnosis of each patient was determined based on the synthesis of all presenting signs and symptoms, imaging, and laboratory results. We adhered to AECOPD diagnosis definitions based on the GOLD guidelines. Univariate and multivariate analyses were performed to identify any associated features of AECOPD with and without other acute processes contributing to dyspnea.
RESULTS
Three hundred fifteen hospitalized patients with admitting diagnosis of AECOPD were included. Mean age was 72.5 (SD 10.6) years. Two thirds (65.4%) had spirometry defined COPD. The most common presenting symptom was dyspnea (96.5%), followed by cough (67.9%), and increased sputum (57.5%). One hundred and eighty (57.1%) had a final diagnosis of AECOPD alone whereas 87 (27.6%) had AECOPD with other conditions and 48 (15.2%) did not have AECOPD after adjudication. Increased sputum purulence (OR 3.35, 95%CI 1.68-6.69) and elevated venous pCO2 (OR 1.04, 95%CI 1.01 - 1.07) were associated with a diagnosis of AECOPD but these were not associated with AECOPD alone without concomitant conditions. Radiographic evidence of pleural effusion (OR 0.26, 95%CI 0.12 - 0.58) was negatively associated with AECOPD with or without other conditions while radiographic evidence of pulmonary edema (OR 0.31; 95%CI 0.11 - 0.91) and lobar pneumonia (OR 0.13, 95%CI 0.07 - 0.25) suggested against the diagnosis of AECOPD alone.
CONCLUSION
The study highlighted the complexity and difficulty of AECOPD diagnosis. A more specific clinical tool to diagnose AECOPD is needed.
Topics: Humans; Aged; Prospective Studies; Retrospective Studies; Pulmonary Disease, Chronic Obstructive; Dyspnea; Cough; Disease Progression; Acute Disease
PubMed: 37580731
DOI: 10.1186/s12890-023-02587-1 -
Respiratory Research Jan 2024Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with... (Review)
Review
Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With the outbreak of coronavirus disease 19 worldwide, the mortality of ARDS has increased correspondingly. Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. To facilitate further understanding of its pathogenesis and exploring novel therapeutics, this review provides comprehensive information of ARDS from pathophysiology to molecular mechanisms and presents targeted therapeutics. We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. Next, we summarize the molecular mechanisms and signaling pathways related to the above four aspects of ARDS pathophysiology, along with the latest research progress. Finally, we discuss the emerging therapeutic strategies that show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies and mesenchymal stromal cell therapies, highlighting the pathophysiological basis and the influences on signal transduction pathways for their use.
Topics: Humans; Respiratory Distress Syndrome; Lung; MicroRNAs; Signal Transduction; Pulmonary Edema
PubMed: 38218783
DOI: 10.1186/s12931-024-02678-5 -
Biomolecules Jan 2024A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space.... (Review)
Review
A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.
Topics: Histone Deacetylases; Endothelial Cells; Epigenesis, Genetic; Zinc; Histone Deacetylase Inhibitors; Lung; Histones
PubMed: 38397377
DOI: 10.3390/biom14020140 -
The Journal of Venomous Animals and... 2023Venomous animals and their venom have always been of human interest because, despite species differences, coevolution has made them capable of targeting key...
Venomous animals and their venom have always been of human interest because, despite species differences, coevolution has made them capable of targeting key physiological components of our bodies. Respiratory failure from lung injury is one of the serious consequences of envenomation, and the underlying mechanisms are rarely discussed. This review aims to demonstrate how toxins affect the pulmonary system through various biological pathways. Herein, we propose the common underlying cellular mechanisms of toxin-induced lung injury: interference with normal cell function and integrity, disruption of normal vascular function, and provocation of excessive inflammation. Viperid snakebites are the leading cause of envenomation-induced lung injury, followed by other terrestrial venomous animals such as scorpions, spiders, and centipedes. Marine species, particularly jellyfish, can also inflict such injury. Common pulmonary manifestations include pulmonary edema, pulmonary hemorrhage, and exudative infiltration. Severe envenomation can result in acute respiratory distress syndrome. Pulmonary involvement suggests severe envenomation, thus recognizing these mechanisms and manifestations can aid physicians in providing appropriate treatment.
PubMed: 37727535
DOI: 10.1590/1678-9199-JVATITD-2023-0026 -
Journal of the American College of... Aug 2023Non-fatal drownings confer significant morbidity and mortality in the United States. Chest radiograph (CXR) is typically used as a screening modality for interstitial...
OBJECTIVES
Non-fatal drownings confer significant morbidity and mortality in the United States. Chest radiograph (CXR) is typically used as a screening modality for interstitial edema but lacks sensitivity early after submersion. No study has evaluated lung ultrasound in assessing for pulmonary edema after submersion events and we hypothesized that lung point-of-care (POC) ultrasound can identify interstitial edema in patients presenting after non-fatal drownings.
METHODS
Patients presenting to the emergency department after a submersion event were eligible if a CXR was obtained as part of their care. Emergency medicine residents performed a lung POC ultrasound and provided a "novice" interpretation of "normal" or "abnormal," which was independently reviewed by a blinded expert sonographer. Patients were contacted 2 weeks after presentation to assess for late sequela.
RESULTS
A prospective convenience sample of 59 patients included 21 adults (36%) and 38 children (64%) enrolled over 17 months with a median age of 6. Twenty-four (41%) patients had abnormalities on CXR. Of these, 20 patients had a positive ultrasound per novice interpretation. Compared to CXR, ultrasound had an overall sensitivity of 83% and a specificity of 66% for detecting pulmonary edema in non-fatal drownings. Notably, out of 35 subjects with a negative CXR, there were 12 (34%) cases with a positive lung ultrasound, 10 of which required hospital admission.
CONCLUSION
Lung POC ultrasound has a moderate sensitivity and specificity when performed by novice sonographers to detect pulmonary edema presenting to an ED setting after a non-fatal drowning event.
PubMed: 37492531
DOI: 10.1002/emp2.13010 -
International Journal of Molecular... Dec 2023This narrative review critically examines the role of albumin in sepsis management and compares it to its well-established application in liver cirrhosis. Albumin, a key... (Review)
Review
This narrative review critically examines the role of albumin in sepsis management and compares it to its well-established application in liver cirrhosis. Albumin, a key plasma protein, is effective in the management of fluid imbalance, circulatory dysfunction, and inflammation-related complications. However, its role in sepsis is more intricate and characterized by ongoing debate and varied results from clinical studies. In sepsis, the potential benefits of albumin include maintaining vascular integrity and modulating inflammation, yet its consistent clinical efficacy is not as definitive as that in cirrhosis. This review evaluated various clinical trials and evidence, highlighting their limitations and providing practical insights for clinicians. It emphasizes identifying sepsis patient subgroups that are most likely to benefit from albumin therapy, particularly exploring the correction of hypoalbuminemia. This condition, which is significantly corrected in patients with cirrhosis, may have similar therapeutic advantages in sepsis. The potential effectiveness of albumin in the low-volume resuscitation and deresuscitation phases of sepsis management was noted. Given the safety concerns observed in cirrhosis, such as pulmonary edema and hypervolemia associated with albumin therapy, cautious integration of albumin into sepsis treatment is mandatory. Personalized albumin therapy is advocated for tailoring strategies to the specific needs of each patient, based on their clinical presentation and underlying conditions. The need for further research to delineate the role of albumin in sepsis pathophysiology is underscored. The review emphasizes the importance of conducting trials to assess the effectiveness of albumin in correcting hypoalbuminemia in sepsis, its impact on patient outcomes, and the establishment of appropriate dosing and administration methods. This approach to albumin use in sepsis management is posited as a way to potentially improve patient outcomes in this complex clinical scenario while being mindful of the lessons learned from its use in cirrhosis.
Topics: Humans; Hypoalbuminemia; Albumins; Sepsis; Liver Cirrhosis; Water-Electrolyte Imbalance; Inflammation
PubMed: 38139434
DOI: 10.3390/ijms242417606