Pathogenesis of Acute Respiratory Distress Syndrome Huppert, Laura A; Matthay, Michael A; Ware, Lorraine B
Seminars in respiratory and critical care medicine,
02/2019, Letnik:
40, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure caused by noncardiogenic pulmonary edema. Despite five decades of basic and clinical research, there is still no ...effective pharmacotherapy for this condition and the treatment remains primarily supportive. It is critical to study the molecular and physiologic mechanisms that cause ARDS to improve our understanding of this syndrome and reduce mortality. The goal of this review is to describe our current understanding of the pathogenesis and pathophysiology of ARDS. First, we will describe how pulmonary edema fluid accumulates in ARDS due to lung inflammation and increased alveolar endothelial and epithelial permeabilities. Next, we will review how pulmonary edema fluid is normally cleared in the uninjured lung, and describe how these pathways are disrupted in ARDS. Finally, we will explain how clinical trials and preclinical studies of novel therapeutic agents have further refined our understanding of this condition, highlighting, in particular, the study of mesenchymal stromal cells in the treatment of ARDS.
Acute respiratory distress syndrome (ARDS) is a common clinical syndrome of acute respiratory failure as a result of diffuse lung inflammation and oedema. ARDS can be precipitated by a variety of ...causes. The pathophysiology of ARDS is complex and involves the activation and dysregulation of multiple overlapping and interacting pathways of injury, inflammation, and coagulation, both in the lung and systemically. Mechanical ventilation can contribute to a cycle of lung injury and inflammation. Resolution of inflammation is a coordinated process that requires downregulation of proinflammatory pathways and upregulation of anti-inflammatory pathways. The heterogeneity of the clinical syndrome, along with its biology, physiology, and radiology, has increasingly been recognised and incorporated into identification of phenotypes. A precision-medicine approach that improves the identification of more homogeneous ARDS phenotypes should lead to an improved understanding of its pathophysiological mechanisms and how they differ from patient to patient.
BACKGROUND ARDS is a heterogeneous syndrome that encompasses lung injury from both direct and indirect sources. Direct ARDS (pneumonia, aspiration) has been hypothesized to cause more severe lung ...epithelial injury than indirect ARDS (eg, nonpulmonary sepsis); however, this hypothesis has not been well studied in humans. METHODS We measured plasma biomarkers of lung epithelial and endothelial injury and inflammation in a single-center study of 100 patients with ARDS and severe sepsis and in a secondary analysis of 853 patients with ARDS drawn from a multicenter randomized controlled trial. Biomarker levels in patients with direct vs indirect ARDS were compared in both cohorts. RESULTS In both studies, patients with direct ARDS had significantly higher levels of a biomarker of lung epithelial injury (surfactant protein D) and significantly lower levels of a biomarker of endothelial injury (angiopoietin-2) than those with indirect ARDS. These associations were robust to adjustment for severity of illness and ARDS severity. In the multicenter study, patients with direct ARDS also had lower levels of von Willebrand factor antigen and IL-6 and IL-8, markers of endothelial injury and inflammation, respectively. The prognostic value of the biomarkers was similar in direct and indirect ARDS. CONCLUSIONS Direct lung injury in humans is characterized by a molecular phenotype consistent with more severe lung epithelial injury and less severe endothelial injury. The opposite pattern was identified in indirect lung injury. Clinical trials of novel therapies targeted specifically at the lung epithelium or endothelium may benefit from preferentially enrolling patients with direct and indirect ARDS, respectively.
The acute respiratory distress syndrome Matthay, Michael A; Ware, Lorraine B; Zimmerman, Guy A
The Journal of clinical investigation
122, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ...ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated ...with emergency department (ED) delirium duration.
We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 IL-6, IL-8, soluble tumor necrosis factor receptor I sTNFRI), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 PAI-1), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status.
A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed.
Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.
Ware discusses the impact of the SARS-CoV-2 pandemic on the future of the physician-scientist and the changing landscape of clinical investigation. The pandemic has had both positive and negative ...effects on the physician-scientist community. One positive impact has been to underscore the central role that a vibrant community of well-trained physician-scientists plays in advancing biomedical science and public health. Around the world, physician-scientists have been integral to every aspect of the scientific response to COVID-19. Many physician-scientists have played pivotal roles in efforts to understand, track, treat, and contain the pandemic. Physician-scientists have been at the forefront of studies of the fundamental biology of coronaviruses and in the development and testing of the novel mRNA and other vaccines that have shown unprecedented efficacy against this virus.
This year is the 50th anniversary of the first description of acute respiratory distress syndrome (ARDS). Since then, much has been learned about the pathogenesis of lung injury in ARDS, with an ...emphasis on the mechanisms of injury to the lung endothelium and the alveolar epithelium. In terms of treatment, major progress has been made in reducing mortality from ARDS with lung-protective ventilation, using a tidal volume of 6 mL per kg of predicted bodyweight and a plateau airway pressure of less than 30 cm H
O. In more severely hypoxaemic patients with ARDS, neuromuscular blockade and prone positioning have further reduced mortality, probably by extending the therapeutic effects of lung protective ventilation. Fluid-conservative therapy has also increased ventilator-free days in patients with ARDS. The lack of success of pharmacological therapies for ARDS, however, presents a continued challenge in the field. In addition to presenting a brief summary of previous experience with clinical trials in ARDS, we focus in this Review on future opportunities to improve clinical trial design to maximise the likelihood of identifying beneficial pharmacological therapies. In view of the heterogeneity in ARDS, both prognostic and predictive enrichment strategies are needed that target therapies toward specific subgroups of patients with ARDS on the basis of both severity and biology. Approaches to reducing heterogeneity in ARDS clinical trials include using physiological, radiographic, and biological criteria to select patients for both phase 2 and 3 trials. Additionally, interest is growing in the design of preventive clinical trials in ARDS and to initiate early treatment of patients with acute lung injury before the need for endotracheal intubation. We also present promising new approaches to treating ARDS, including combination therapies, cell-based therapies, and generic pharmacological compounds with low-risk profiles that are already in routine clinical use for other clinical indications.
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