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95-414: It is often impossible to distinguish TRALI from acute respiratory distress syndrome (ARDS). The typical presentation of TRALI is the sudden development of shortness of breath , severe hypoxemia (O 2 saturation <90% in room air), low blood pressure , and fever that develop within 6 hours after transfusion and usually resolve with supportive care within 48 to 96 hours. Although low blood pressure

190-829: A low oxygen level in the blood due to abnormal ventilation. Other common symptoms include muscle fatigue and general weakness, low blood pressure, a dry, hacking cough, and fever. Complications may include the following: Other complications that are typically associated with ARDS include: There are direct and indirect causes of ARDS depending whether the lungs are initially affected. Direct causes include pneumonia (including bacterial and viral), aspiration, inhalational lung injury, lung contusion, chest trauma, and near-drowning. Indirect causes include sepsis , shock , pancreatitis , trauma (e.g. fat embolism), cardiopulmonary bypass , TRALI , burns, increased intracranial pressure . Fewer cases of ARDS are linked to large volumes of fluid used during post-trauma resuscitation. ARDS

285-500: A biological matrix (such as a complex fluid or tissue) so that the uniquely EV components can be analyzed. Many approaches have been used, including differential ultracentrifugation, density gradient ultracentrifugation, size exclusion chromatography, ultrafiltration, capillary electrophoresis, asymmetric-flow field-flow fractionation, and affinity/immunoaffinity capture methods. Each method has its own recovery and purity outcomes: that is, what percentage of input EVs are obtained, and

380-699: A continuous population, some of which can be recruited with minimal PEEP, and others can only be recruited with high levels of PEEP. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. PEEP can be harmful; high PEEP necessarily increases mean airway pressure and alveolar pressure, which can damage normal alveoli by overdistension resulting in DAD. A compromise between

475-546: A functional role for this EV in mitochondrial homeostasis. Enveloped viruses are a type of EV produced under the influence of viral infection. That is, the virion is composed of cellular membranes but contains proteins and nucleic acids produced from the viral genome. Some enveloped viruses can infect other cells even without a functional virion, when genomic material is transferred via EVs. Certain non-enveloped viruses may also reproduce with assistance from EVs. Studying EVs and their cargo typically requires separation from

570-563: A high distending pressure before restoring previous ventilation. The final PEEP level should be the one just before the drop in Pa O 2 or peripheral blood oxygen saturation during a step-down trial. A large randomized controlled trial of patients with ARDS found that lung recruitment maneuvers and PEEP titration was associated with high rates of barotrauma and pneumothorax and increased mortality. Intrinsic PEEP (iPEEP) or auto-PEEP—first described by John Marini of St. Paul Regions Hospital—is

665-472: A historically heterogenous nomenclature including terms like exosomes and ectosomes . Numerous functions of EVs have been established or postulated. The first evidence for the existence of EVs was enabled by the ultracentrifuge , the electron microscope , and functional studies of coagulation in the mid-20th century. A sharp increase in interest in EVs occurred in the first decade of the 21st century following

760-525: A metastatic niche; betray the presence of specific cancers; or be used as a therapy to target cancer cells. Meanwhile, strides were made in the understanding of vesicle biogenesis and subtypes. Rapid growth of the EV research community in the early 2000s led to the creation of the International Society for Extracellular Vesicles (ISEV), which has led efforts for rigor and standardization in

855-530: A mild form of ARDS. However, the criteria for the diagnosis of ARDS in the Berlin definition excludes many children, and a new definition for children was termed pediatric acute respiratory distress syndrome (PARDS); this is known as the PALICC definition (2015). There is ongoing research on the treatment of ARDS by interferon (IFN) beta-1a to aid in preventing leakage of vascular beds. Traumakine (FP-1201-lyo)

950-500: A mortality benefit of 26% compared to supine ventilation. However, attention should be paid to avoid the SIDS in the management of the respiratory distressed infants by continuous careful monitoring of their cardiovascular system. Several studies have shown that pulmonary function and outcome are better in people with ARDS who lost weight or whose pulmonary wedge pressure was lowered by diuresis or fluid restriction. As of 2019, it

1045-400: A mortality of 6–9%. Acute respiratory distress syndrome Acute respiratory distress syndrome ( ARDS ) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs . Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin coloration (cyanosis). For those who survive, a decreased quality of life

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1140-609: A mouse model and a human fibroblast cell culture model of prostate cancer. Cellular internalization of large oncosomes can reprogram non-neoplastic brain cells to divide and migrate in primary tissue culture, and higher numbers of large oncosomes isolated from blood samples from glioblastoma patients were correlated with more advanced disease progression. Exophers are a class of large EV, approximately four microns in diameter, observed in model organisms ranging from Caenorhabditis elegans to mice. When genetically modified to express aggregating proteins, neurons were observed to sequester

1235-461: A nexus for therapeutic intervention was paralleled by formation of companies and funding programs focused on development of EVs as biomarkers or therapies of disease, the founding of an International Society for Extracellular Vesicles (ISEV), and establishment of a scientific journal devoted to the field, the Journal of Extracellular Vesicles . Evidence for the existence of EVs and their functions

1330-629: A permitted rise in blood carbon dioxide levels and collapse of alveoli because of their inherent tendency to increase shunting within the lung. Physiologic dead space cannot change as it is ventilation without perfusion. A shunt is a perfusion without ventilation within a lung region. Low tidal volume ventilation was the primary independent variable associated with reduced mortality in the NIH-sponsored ARDSNet trial of tidal volume in ARDS. Plateau pressure less than 30 cm H 2 O

1425-465: A positive effect on cardiac output (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion and potential for increased urine output secondary to increased kidney perfusion. A patient with ARDS, on average, spends between 8 and 11 days on a mechanical ventilator; APRV may reduce this time significantly and thus may conserve valuable resources. Positive end-expiratory pressure (PEEP)

1520-401: A potentially unrecognized contributor to PEEP in intubated individuals. When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). iPEEP has been measured in very few formal studies on ventilation in ARDS, and its contribution is largely unknown. Its measurement

1615-490: A result of this phenomenon and acute respiratory distress syndrome (ARDS) results. Leukocyte filters may prevent TRALI for those patients whose lung injury is due to leukoagglutination of the donor white blood cells, but because most TRALI is due to donor antibodies to leukocytes, filters are not helpful in TRALI prevention. Transfused plasma (from any component source) may also contain antibodies that cross-react with platelets in

1710-549: A significant reduction of TRALI reports. In TRALI, first-hit risk factors include long-term excessive alcohol use, shock, liver surgery, current smoking, higher peak airway pressure while undergoing mechanical ventilation, positive intravascular fluid balance, low levels of interleukin-10 , and systemic inflammation . Systemic inflammation may be reflected in the plasma cytokine profiles but also via increased levels of C-reactive protein (CRP), an acute-phase protein that rapidly increases during acute infections and inflammation and

1805-523: A specific size range for accurate quantitation, and very small EVs (<100 nm diameter) are not detected by many technologies. Molecular "fingerprints" of populations can be obtained by "omics" technologies like proteomics, lipidomics, and RNomics, or by techniques like Raman spectroscopy . Overall levels of unique molecules can also be measured in the population, such as tetraspanins , phosphatidylserine , or species of RNA. It has been proposed that purity of an EV preparation can be estimated by examining

1900-495: A transfusion of EVs from younger animals. It is therefore believed that EVs hold promise as an anti-aging treatment in humans. Studies indicate that EVs may have a procoagulant effect in various diseases. EVs can express phosphatidylserine (PS) on their surface. PS is an anionic phospholipid and PS+ EVs therefore provide a negatively charged surface which may facilitate formation of coagulation complexes. Under pathological conditions, EVs can sometimes express tissue factor (TF). TF

1995-471: Is supportive care . Oxygen supplementation is employed in all reported cases of TRALI, and 72% of patients require aggressive respiratory support. To support blood pressure, intravenous administration of fluids, as well as vasopressors , are essential. In treating TRALI, diuretics are to be avoided, although they are indicated in the management of transfusion associated circulatory overload . Corticosteroids can be beneficial. The true incidence of TRALI

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2090-399: Is a form of fluid accumulation in the lungs not explained by heart failure (noncardiogenic pulmonary edema). It is typically provoked by an acute injury to the lungs that results in flooding of the lungs' microscopic air sacs responsible for the exchange of gases such as oxygen and carbon dioxide with capillaries in the lungs. Additional common findings in ARDS include partial collapse of

2185-640: Is a recombinant human IFN beta-1a drug, developed by the Finnish company Faron Pharmaceuticals , which is undergoing international phase-III clinical trials after an open-label, early-phase trial showed an 81% reduction-in-odds of 28-day mortality in ICU patients with ARDS. The drug is known to function by enhancing lung CD73 expression and increasing production of anti-inflammatory adenosine, such that vascular leaking and escalation of inflammation are reduced. Aspirin has been studied in those who are at high risk and

2280-605: Is an uncommon syndrome, that is due to the presence of leukocyte antibodies in transfused plasma. It is believed to occur in approximately one in every 5000 transfusions. Leukoagglutination and pooling of granulocytes in the recipient's lungs may occur, with release of the contents of leukocyte granules, and resulting injury to cellular membranes, endothelial surfaces, and potentially to lung parenchyma. In most cases leukoagglutination results in mild dyspnea and pulmonary infiltrates within about 6 hours of transfusion, and spontaneously resolves. Occasionally more severe lung injury occurs as

2375-407: Is associated with a death rate between 35 and 50%. Globally, ARDS affects more than 3 million people a year. The condition was first described in 1967. Although the terminology of "adult respiratory distress syndrome" has at times been used to differentiate ARDS from " infant respiratory distress syndrome " in newborns, the international consensus is that "acute respiratory distress syndrome"

2470-697: Is based on a PaO 2 /FiO 2 ratio (ratio of partial pressure arterial oxygen and fraction of inspired oxygen) of less than 300 mm Hg despite a positive end-expiratory pressure (PEEP) of more than 5 cm H 2 O. Cardiogenic pulmonary edema , as the cause, must be excluded. The primary treatment involves mechanical ventilation together with treatments directed at the underlying cause. Ventilation strategies include using low volumes and low pressures. If oxygenation remains insufficient, lung recruitment maneuvers and neuromuscular blockers may be used. If these are insufficient, extracorporeal membrane oxygenation (ECMO) may be an option. The syndrome

2565-452: Is common. Causes may include sepsis , pancreatitis , trauma , pneumonia , and aspiration . The underlying mechanism involves diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs , surfactant dysfunction, activation of the immune system , and dysfunction of the body's regulation of blood clotting . In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide . Adult diagnosis

2660-583: Is considered one of the important signs for diagnosing TRALI, in some cases high blood pressure can occur. Delayed TRALI occurs 6 to 72 hours after transfusion completion. It is associated with a higher rate of mortality . The cause of TRALI is currently not fully understood. 80–85% of cases are thought to be immune mediated. Antibodies directed toward human leukocyte antigens (HLA) or human neutrophil antigens (HNA) have been implicated, with transfused antibodies shown to bind antigens expressed on pulmonary endothelial cells to initiate acute inflammation in

2755-666: Is difficult to assess the underlying pathology directly. EVs facilitate communication between different parts of the CNS, and therefore, EVs found in the blood of neurological patients contain molecules implicated in neurodegenerative diseases. EVs carrying myeloid cargo, for example, have long been recognized as a biomarker of brain inflammation. Furthermore, nucleic acids corresponding to APP, Aβ42, BACE1, and tau protein biomarkers were found to be associated with different neurodegenerative diseases. Using EVs to profile RNA expression patterns could therefore help diagnose certain diseases before

2850-453: Is generally believed to increase with age due to DNA or mitochondrial damage and lipid peroxidation. It has been demonstrated that exosomes released by senescent cells have a miRNA content that contributes to aging. miRNAs play an essential role in senescence by negatively regulating the suppressors of p53, for example.   Furthermore, EVs play a role in overall chronic inflammation. The interorgan shuttling of EVs can mean that one disease

2945-709: Is likely to promote the advancement of another, as is the case with NAFLD and the development of atherosclerosis. EVs released from steatosis-affected hepatocytes induce the release of inflammatory molecules from endothelial cells co-cultured with them. The co-cultured cells also show increased NF-κB activity. It has thus been demonstrated that EVs released by hepatocytes under NAFLD conditions cause vascular endothelial inflammation and promote atherosclerosis. EVs also have senolytic potential. EVs harvested from cardio-sphere-derived cells in young rats have been shown to reverse senescent processes in aged rats. The older rats’ endurance and cardiovascular function improved when they received

Transfusion-related acute lung injury - Misplaced Pages Continue

3040-655: Is no evidence that inhaled nitric oxide decreases morbidity and mortality in people with ARDS. Furthermore, nitric oxide may cause kidney damage and is not recommended as therapy for ARDS regardless of severity. Alvelestat (AZD 9668) had been quoted according to one review article. Extracorporeal membrane oxygenation (ECMO) is mechanically applied prolonged cardiopulmonary support. There are two types of ECMO: Venovenous which provides respiratory support and venoarterial which provides respiratory and hemodynamic support. People with ARDS who do not require cardiac support typically undergo venovenous ECMO. Multiple studies have shown

3135-576: Is poor, with mortality rates of approximately 40%. Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important sequelae of ARDS. The annual rate of ARDS is generally 13–23 people per 100,000 in the general population. It is more common in people who are mechanically ventilated with acute lung injury (ALI) occurring in 16% of ventilated people. Rates increased in 2020 due to COVID-19 , with some cases also appearing similar to HAPE . Worldwide, severe sepsis

3230-411: Is recommended in the treatment of people who have ARDS, especially when using high-frequency (oscillatory/jet) ventilation . The position of lung infiltrates in acute respiratory distress syndrome is non-uniform. Repositioning into the prone position (face down) might improve oxygenation by relieving atelectasis and improving perfusion. If this is done early in the treatment of severe ARDS, it confers

3325-420: Is some residual plasma in the packed cells. Incidents have also been reported with other blood products including " cryoprecipitate , granulocytes , intravenous immune globulin , allogeneic and autologous stem cells". It is a diagnosis upon examination of clinical manifestations that appear within 6 hours of transfusion, such as acute respiratory distress, tachypnea, hypotension, cyanosis, and dyspnea. TRALI

3420-468: Is the best term because ARDS can affect people of all ages. There are separate diagnostic criteria for children and those in areas of the world with fewer resources. The signs and symptoms of ARDS often begin within two hours of an inciting event, but have been known to take as long as 1–3 days; diagnostic criteria require a known insult to have happened within 7 days of the syndrome. Signs and symptoms may include shortness of breath , fast breathing , and

3515-416: Is the most common trigger causing ARDS. Other triggers include mechanical ventilation, sepsis, pneumonia, Gilchrist's disease, drowning, circulatory shock, aspiration , trauma —especially pulmonary contusion —major surgery, massive blood transfusions , smoke inhalation , drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy. However,

3610-506: Is the most potent initiator of the coagulation cascade and is under normal conditions mainly contained to subvascular tissue. EVs are believed to play a role in the spreading of different diseases. Studies have shown that tumor cells send EVs to send signal to target resident cells, which can lead to tumor invasion and metastasis. In vitro studies of Alzheimer's disease have shown that astrocytes that accumulate amyloid beta release EVs that cause neuronal apoptosis . The content of

3705-513: Is to maintain acceptable gas exchange to meet the body's metabolic demands and to minimize adverse effects in its application. The parameters PEEP (positive end-expiratory pressure, to keep alveoli open), mean airway pressure (to promote recruitment (opening) of easily collapsible alveoli and predictor of hemodynamic effects), and plateau pressure (best predictor of alveolar overdistention) are used. Previously, mechanical ventilation aimed to achieve tidal volumes ( V t ) of 12–15 ml/kg (where

3800-541: Is uncertain whether or not treatment with corticosteroids improves overall survival. Corticosteroids may increase the number of ventilator-free days during the first 28 days of hospitalization. One study found that dexamethasone may help. The combination of hydrocortisone, ascorbic acid, and thiamine also requires further study as of 2018. Inhaled nitric oxide (NO) selectively widens the lung's arteries which allows for more blood flow to open alveoli for gas exchange . Despite evidence of increased oxygenation status, there

3895-486: Is unknown because of the difficulty in making the diagnosis and because of underreporting. It is estimated to occur in 1:1300 to 1:5000 transfusions of plasma-containing products. TRALI is the leading reported cause of death related to transfusion in the United States; more than 20 cases were reported per year from 2003 to 2005. The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has

Transfusion-related acute lung injury - Misplaced Pages Continue

3990-477: Is used in mechanically ventilated people with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli that are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas exchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimens. The recruitable alveoli represent

4085-580: Is usually treated with mechanical ventilation in the intensive care unit (ICU) . Mechanical ventilation is usually delivered through a rigid tube which enters the oral cavity and is secured in the airway (endotracheal intubation), or by tracheostomy when prolonged ventilation (≥2 weeks) is necessary. The role of non-invasive ventilation is limited to the very early period of the disease or to prevent worsening respiratory distress in individuals with atypical pneumonias , lung bruising , or major surgery patients, who are at risk of developing ARDS. Treatment of

4180-422: Is widely used clinically as a biomarker of inflammation. CRP has been shown to be elevated in TRALI patients and, in a mouse model , to functionally enable the first hit in the development of TRALI by increasing the accumulation in the lungs of a neutrophil homologous to interleukin-8 . Another factor that can predispose patients to TRALI is pre-existing lung injury, which causes white blood cells to localize in

4275-628: The AABB (formerly the American Association of Blood Banks) has recommended that those blood components with a high volume of plasma not be used for transfusion, but for further processing into other therapeutic products. To mitigate the risk of TRALI, female donors are excluded from fresh frozen plasma donation in Germany as of 2009 if they have a history of pregnancy and there are no HLA/HNA screening results available, which has resulted in

4370-503: The Tamm-Horsfall protein (uromodulin) in urine, or proteins of the nucleus , Golgi apparatus , endoplasmic reticulum , or mitochondria in eukaryotic cells. The latter proteins may be found in large EVs or indeed any EVs, but are expected to be less concentrated in the EV than in the cell. A wide variety of biological functions have been ascribed to EVs. EVs have been implicated in senescence. Extracellular vesicle secretion

4465-495: The bat during arousal from hibernation , suggesting the possible involvement of EVs in endocrine processes. Reports of EVs in intestinal villi samples and, for the first time, in material from human cancer ( adenoma ) referred back to even earlier publications that furnished similar evidence, although conclusions about EV release had not then been drawn. EVs were also described in bovine serum and cell culture conditioned medium with distinctions made between "vesicles of

4560-409: The pathophysiology has evolved. The international consensus criteria for ARDS were most recently updated in 2012 and are known as the "Berlin definition". In addition to generally broadening the diagnostic thresholds, other notable changes from the prior 1994 consensus criteria include discouraging the term "acute lung injury", and defining grades of ARDS severity according to degree of decrease in

4655-659: The plasma membrane or surface of the cell, but also by fusion of the multivesicular body with the plasma membrane. During this time, EVs were described by many names, sometimes in the same manuscript, such as "shedding vesicles," "membrane fragments," "plasma membrane vesicles," "micro-vesicles/microvesicles," "exosomes," (previously used for mobile, transforming DNA elements in model organisms Drosophila and Neurospora ), "inclusion vesicles," and more, or referred to by organ of origin, such as "prostasomes" that were found to enhance sperm motility in semen. The involvement of EVs in immune responses became increasingly clear in

4750-531: The 1990s with findings of the group of Graça Raposo and others. A clinical trial of dendritic cell-derived EVs was performed in France just before the turn of the century. Cells of the immune system were found capable of transferring transmembrane proteins via EVs. For example, the HIV co-receptors CCR5 and CXCR4 could be transferred from an HIV-susceptible cell to a refractory cell by "microparticles," rendering

4845-695: The Berlin Definition of ARDS was devised by the European Society of Intensive Care Medicine, and was endorsed by the American Thoracic Society and the Society of Critical Care Medicine . These recommendations were an effort to both update classification criteria in order to improve clinical usefulness and to clarify terminology. Notably, the Berlin guidelines discourage the use of the term "acute lung injury" or ALI, as

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4940-497: The EV-enriched or -depleted markers are proteins that can be detected by Western blot, flow cytometry, ELISA, mass spectrometry, or other widely-available methods. Assaying for depleted markers is thought to be particularly important, as otherwise the purity of an EV preparation cannot be claimed. However, most studies of EVs prior to 2016 did not support claims of the presence of EVs by showing enriched markers, and <5% measured

5035-403: The EVs was also affected by the exposure to amyloid beta and higher ApoE was found in EVs secreted by astrocyte exposed to amyloid beta. An oncogenic mechanism illustrates how extracellular vesicles are produced by proliferative acute lymphoblastic leukemia cells and can target and compromise a healthy hematopoiesis system during leukemia development. The fate of T cells can be determined by

5130-771: The PM to a surface. Exosome biogenesis begins with pinching off of endosomal invaginations into the multivesicular body (MVB), forming intraluminal vesicles (ILVs). If the MVB fuses with the plasma membrane, the ILVs are released as "exosomes." The first publication to use the term "exosome" for EVs presented it as a synonym for "micro-vesicle." The term has also been used for EVs within specific size ranges, EVs separated using specific methods, or even all EVs. Apoptotic bodies are EVs that are released by dying cells undergoing apoptosis . Since apoptotic cells tend to display phosphatidylserine (PS) in

5225-399: The accumulation of bioactive lipids in stored blood components ( red cells , platelets , or plasma ) that are capable of priming neutrophils. TRALI is typically associated with plasma products such as fresh frozen plasma . TRALI can also occur in recipients of packed red blood cells , whether adult or pediatric patients. Due to the higher risk of TRALI resulting from donations by females,

5320-447: The aggregates into a portion of the cell and release them within a large EV called an exopher . They are hypothesized to be a mechanism for disposal of unwanted cellular material including protein aggregates and damaged organelles. Exophers can remain connected to the cell body by a thin, membranous filament resembling a tunneling nanotube . Migrasomes are large membrane-bound EVs, ranging from 0.5 to 3 microns in diameter, that form at

5415-458: The alveoli ( atelectasis ) and low levels of oxygen in the blood ( hypoxemia ). The clinical syndrome is associated with pathological findings including pneumonia, eosinophilic pneumonia , cryptogenic organizing pneumonia , acute fibrinous organizing pneumonia, and diffuse alveolar damage (DAD) . Of these, the pathology most commonly associated with ARDS is DAD, which is characterized by a diffuse inflammation of lung tissue. The triggering insult to

5510-491: The beneficial and adverse effects of PEEP is inevitable. The 'best PEEP' used to be defined as 'some' cm H 2 O above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli—and, more importantly, the overdistension of aerated units—occur throughout

5605-932: The bewildering and sometimes contradictory definitions of different EV subtypes, the current scientific consensus is that "extracellular vesicle" and variations thereon are the preferred nomenclature unless specific biogenetic origin can be demonstrated. Subtypes of EVs may be defined by: "a) physical characteristics of EVs, such as size ("small EVs" (sEVs) and "medium/large EVs" (m/lEVs), with ranges defined, for instance, respectively, <100nm or <200nm [small], or >200nm [large and/or medium]) or density (low, middle, high, with each range defined); b) biochemical composition (CD63+/CD81+- EVs, Annexin A5-stained EVs, etc.); or c) descriptions of conditions or cell of origin (podocyte EVs, hypoxic EVs, large oncosomes , apoptotic bodies)." The terms "ectosome," "microvesicle" (MV), and "microparticle" (MP) refer to particles released from

5700-584: The blood recipient must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. A two-hit hypothesis has been suggested wherein pre-existing pulmonary pathology (i.e., the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema . A proposed mechanism for non-antibody-mediated TRALI involves

5795-486: The definitions recommended a classification as "acute lung injury" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary Pa O 2 thresholds without systematic data. In 2012,

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5890-428: The diagnostic criteria have been expanded over time to accept CT and ultrasound findings as equally contributory. Generally, radiographic findings of fluid accumulation (pulmonary edema) affecting both lungs and unrelated to increased cardiopulmonary vascular pressure (such as in heart failure) may be suggestive of ARDS. Ultrasound findings suggestive of ARDS include the following: Acute respiratory distress syndrome

5985-837: The discovery that EVs could transfer nucleic acids such as RNA from cell to cell. Associated with EVs from certain cells or tissues , nucleic acids could be easily amplified as markers of disease and also potentially traced back to a cell of origin, such as a tumor cell . When EVs are taken up by other cells, they may alter the behaviour of the recipient cell, for instance EVs released by colorectal cancer cells increase migration of fibroblasts and thus EVs are of importance in forming tumour landscapes. This discovery also implied that EVs could be used for therapeutic purposes, such as delivering nucleic acids or other cargo to diseased tissue. Conversely, pharmacological inhibition of EV release, through Calix[6]arene, can slow down progression of experimental pancreatic cancer. The growing interest in EVs as

6080-701: The effectiveness of ECMO in acute respiratory failure. Specifically, the CESAR (Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Acute Respiratory failure) trial demonstrated that a group referred to an ECMO center demonstrated significantly increased survival compared to conventional management (63% to 47%). As of 2019, there is no evidence showing that treatments with exogenous surfactants , statins , beta-blockers or n-acetylcysteine decreases early mortality, late all-cause mortality, duration of mechanical ventilation, or number of ventilator-free days. The overall prognosis of ARDS

6175-400: The ends of retraction fibers left behind when cells migrate in a process termed "migracytosis." Migrasomes can continue to fill with cytosol and expand even as the originating cell moves away. Migrasomes were first observed in rat kidney cell culture, but they are produced by mouse and human cells as well. Damaged mitochondria can be expelled from migrating cells inside of migrasomes, suggesting

6270-729: The field including establishment of the Journal of Extracellular Vesicles . A plethora of national and regional EV societies have also been formed. In 2012, the Director's Office of the US National Institutes of Health (NIH) announced a program for funding of EV and extracellular RNA studies, the Extracellular RNA Communication Consortium (ERCC), which subsequently invested >USD 100 million in EV research. A second round of funding

6365-554: The incidence and death of ARDS. In 1988, an expanded definition was proposed, which quantified physiologic respiratory impairment. In 1994, a new definition was recommended by the American-European Consensus Conference Committee which recognized the variability in severity of pulmonary injury. The definition required the following criteria to be met: If Pa O 2 :Fi O 2  < 300 mmHg (40 kPa), then

6460-472: The lungs' blood vessels. The second hit in TRALI may be conveyed by anti-leukocyte antibodies or other factors present in the transfusion product. In approximately 80% of cases, anti-HLA class I or II or anti-HNA antibodies are implicated as involved in triggering TRALI, although that figure may be even higher depending on the detection methods used. In the remaining 20% of TRALI cases, non–antibody factors or biological response modifiers are suggested to contribute

6555-414: The lungs. Women who are multiparous (have carried more than one pregnancy to viable gestational age ) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI. Previous transfusion or transplantation can also lead to donor sensitization. To be at risk of TRALI via this mechanism,

6650-432: The majority of patients with all these conditions mentioned do not develop ARDS. It is unclear why some people with the mentioned factors above do not develop ARDS and others do. Pneumonia and sepsis are the most common triggers, and pneumonia is present in up to 60% of patients and may be either causes or complications of ARDS. Alcohol excess appears to increase the risk of ARDS. Diabetes was originally thought to decrease

6745-463: The multivesicular body" and "microvesicles." These studies further noted the similarities of EVs and enveloped viruses. In the early- to mid-1980s, the Stahl and Johnstone labs forged a deeper understanding of the release of EVs from reticulocytes, while progress was also made on EVs shed from tumor cells. The reticulocyte research, in particular, showed that EVs could be released not only from

6840-637: The outer bilayer of the cell membrane, apoptotic bodies tend to externalize PS, although other EVs may also do so. Apoptotic bodies may be quite large (microns in diameter) but may also measure in the submicron range. In addition to the very large EVs released during apoptosis, micron-sized EVs may be produced by cancer cells, neurons, and other cells. When produced by cancer cells, these particles are termed "large oncosomes" and may reach 20 microns or more in diameter. Large oncosomes can attain sizes comparable to individual cells, but they do not contain full nuclei. They have been shown to contribute to metastasis in

6935-422: The oxygen content of the blood . According to the 2012 Berlin definition, adult ARDS is characterized by the following: The 2012 "Berlin criteria" are a modification of the prior 1994 consensus conference definitions (see history ). Radiologic imaging has long been a criterion for diagnosis of ARDS. Original definitions of ARDS specified that correlative chest X-ray findings were required for diagnosis,

7030-425: The presence of possible co-isolates/contaminants. Despite the high need, a list of EV contaminants is not yet available to the EV research community. A recent study suggested density-gradient-based EV separation from biofluids as an experimental set-up to compile a list of contaminants for EV, based upon differential analysis of EV-enriched fractions versus soluble protein-enriched fractions. Soluble proteins in blood,

7125-441: The ratio of "true" EV components to co-isolates. EV separation can also be influenced by pre-analytical variables. Separated or concentrated populations of EVs may be characterized by several means. Total concentration of molecules in categories such as protein , lipid or nucleic acid . Total particle counts in a preparation can also be estimated, for example by light-scattering techniques. Each measurement technology may have

7220-895: The ratio of one population-level measurement to another, e.g., the ratio of total protein or total lipid to total particles. Specialized methods are needed to study EVs at the single particle level. The challenge for any putative single-particle method is to identify the individual EV as a single, lipid-bilayer particle, and to provide additional information such as size, surface proteins, or nucleic acid content. Methods that have been used successfully for single-EV analysis include optical microscopy and flow cytometry (for large EVs, usually >200 nm), tunable resistive pulse sensing for evaluating EV size, concentration and zeta potential, as well as electron microscopy (no lower bound) and immuno electron microscopy, single-particle interferometric reflectance imaging (down to about 40 nm), and nano-flow cytometry (also to 40 nm). Some technologies allow

7315-558: The recipient cell susceptible to infection. Beginning in 2006, several laboratories reported that EVs contain nucleic acids and have the ability to transfer them from cell to cell. Nucleic acids including DNAs and RNAs were even found to be functional in the recipient cell. Whether carrying DNA, RNA, surface molecules, or other factors, the involvement of EVs in cancer progression aroused considerable interest, leading to hypotheses that specific EVs could target specific cells due to "codes" displayed on their surface; create or enhance

7410-719: The recipient, producing usually mild forms of posttransfusion purpura or platelet aggregation after transfusion. Another nonspecific form of immunologic transfusion complication is mild to moderate immunosuppression consequent to transfusion. This effect of transfusion is not completely understood, but appears to be more common with cellular transfusion and may result in both desirable and undesirable effects. Mild immunosuppression may benefit organ transplant recipients and patients with autoimmune diseases; however, neonates and other already immunosuppressed hosts may be more vulnerable to infection, and cancer patients may possibly have worse outcomes postoperatively. The mainstay of therapy in TRALI

7505-426: The risk of ARDS, but this has shown to be due to an increase in the risk of pulmonary edema. Elevated abdominal pressure of any cause is also probably a risk factor for the development of ARDS, particularly during mechanical ventilation. Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et al. Initially there was no clearly established definition, which resulted in controversy regarding

7600-565: The same time, H. Clarke Anderson and Ermanno Bonucci separately described the calcifying properties of EVs in bone matrix. Although the extracellular and vesicular properties of EVs had been recognized by numerous groups by the 1970s, the term "extracellular vesicle" was first used in a manuscript title in 1971. This electron microscopy study of the flagellate freshwater alga 'Ochromonas danica' reported release of EVs from membranes including those of flagella . Soon thereafter, EVs were seen to be released from follicular thyroid cells of

7695-450: The second hit, and these may possibly include lipid mediators, extracellular vesicles , and aged blood cells. TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it occurs within the first six hours following a transfusion. It is typically associated with plasma components such as platelets and fresh frozen plasma, though cases have been reported with packed red blood cells since there

7790-999: The size of the smallest physically possible unilamellar liposome (around 20-30 nanometers ) to as large as 10 microns or more, although the vast majority of EVs are smaller than 200 nm. EVs can be divided according to size and synthesis route into exosomes , microvesicles and apoptotic bodies. The composition of EVs varies depending on their parent cells, encompassing proteins (e.g., adhesion molecules, cytoskeletons , cytokines , ribosomal proteins, growth factors , and metabolic enzymes ), lipids (including cholesterol , lipid rafts, and ceramides ), nucleic acids (such as DNA , mRNA , and miRNA ), metabolites , and even organelles . Most cells that have been studied to date are thought to release EVs, including some archaeal , bacterial , fungal , and plant cells that are surrounded by cell walls . A wide variety of EV subtypes have been proposed, defined variously by size, biogenesis pathway, cargo, cellular source, and function, leading to

7885-465: The study of individual EVs without extensive prior separation from a biological matrix: to give a few examples, electron microscopy and flow cytometry. To demonstrate the presence of EVs in a preparation, as well as the relative depletion of non-EV particles or molecules, EV-enriched 'and' -depleted markers are necessary: For example, the MISEV2018 guidelines recommend: Usually, but not necessarily,

7980-416: The surface of cells. Technically, the platelets of certain vertebrates (which bud from megakaryocytes ), as well as red blood cells (e.g., of adult humans) also fulfill the consensus definition of EVs. Especially in the field of platelet research, MP has been the standard nomenclature. Formation of ectosomes may in some cases result from directed processes, and in others from shear forces or adherence of

8075-541: The term was commonly being misused to characterize a less severe degree of lung injury. Instead, the committee proposes a classification of ARDS severity as mild, moderate, or severe according to arterial oxygen saturation. The Berlin definitions represent the current international consensus guidelines for both clinical and research classification of ARDS. ARDS is the severe form of acute lung injury (ALI), and of transfusion-related acute lung injury (TRALI), though there are other causes. The Berlin definition included ALI as

8170-436: The tissue usually results in an initial release of chemical signals and other inflammatory mediators secreted by local epithelial and endothelial cells. Neutrophils and some T- lymphocytes quickly migrate into the inflamed lung tissue and contribute in the amplification of the phenomenon. The typical histological presentation involves diffuse alveolar damage and hyaline membrane formation in alveolar walls. Although

8265-410: The transfer of telomeres via EVs from APCs. T cells that acquire telomeres in such a manner regain stem-like characteristics, avoiding senescence. The creation of long-lived memory T cells via an EV injection of telomeres enhances long-term immunological memory. It has been suggested that EVs carrying nucleic acid cargo could serve as biomarkers for disease, especially in neurological disorders where it

8360-457: The triggering mechanisms are not completely understood, recent research has examined the role of inflammation and mechanical stress. One research group has reported that broncho-alveolar lavage fluid in later-stage ARDS often contains trichomonads , in an amoeboid form (i.e. lacking their characteristic flagellum) which makes them difficult to identify under the microscope. Diagnostic criteria for ARDS have changed over time as understanding of

8455-439: The underlying cause is crucial. Appropriate antibiotic therapy is started as soon as culture results are available, or if infection is suspected (whichever is earlier). Empirical therapy may be appropriate if local microbiological surveillance is efficient. Where possible the origin of the infection is removed. When sepsis is diagnosed, appropriate local protocols are followed. The overall goal of mechanical ventilation

8550-434: The weight is ideal body weight rather than actual weight). Recent studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma (secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a clinical trial that showed improved mortality when people with ARDS were ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes ( V t ) may cause

8645-507: The whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some to define the minimum PEEP to be applied to their patients. Some new ventilators can automatically plot a pressure-volume curve. PEEP may also be set empirically. Some authors suggest performing a 'recruiting maneuver'—a short time at a very high continuous positive airway pressure, such as 50 cm H 2 O (4.9 kPa)—to recruit or open collapsed units with

8740-930: Was a secondary goal, and subsequent analyses of the data from the ARDSNet trial and other experimental data demonstrate that there appears to be no safe upper limit to plateau pressure; regardless of plateau pressure, individuals with ARDS fare better with low tidal volumes. No particular ventilator mode is known to improve mortality in acute respiratory distress syndrome (ARDS). Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation include decreased airway pressures, decreased minute ventilation , decreased dead-space ventilation, promotion of spontaneous breathing, almost 24-hour-a-day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity),

8835-660: Was announced in 2018. Commercial investment in EV diagnostics and therapeutics also grew during this time. Extracellular vesicles and particles (EVPs) are released by cells in different shapes and sizes. Diverse EV subtypes have been proposed, with names such as ectosomes , microvesicles , microparticles , exosomes , oncosomes , apoptotic bodies, and more. These EV subtypes have been defined by various, often overlapping, definitions, based mostly on biogenesis (cell pathway, cell or tissue identity, condition of origin). However, EV subtypes may also be defined by size, constituent molecules, function, or method of separation. Because of

8930-466: Was first gathered by combined applications of ultracentrifugation , electron microscopy , and functional studies during the mid-20th century. Ultracentrifuged pellets from blood plasma were reported to have procoagulant properties by Erwin Chargaff and Randolph West in 1946. The platelet derivation and lipid-containing nature of these particles was further articulated by Peter Wolf . Around

9025-420: Was not found to be useful. An intravenous ascorbic acid treatment was tested in the 2019 RCT , in people with ARDS due to sepsis and there was no change in primary endpoints. Extracellular vesicles Extracellular vesicles ( EVs ) are lipid bilayer -delimited particles that are naturally released from almost all types of cells but, unlike a cell, cannot replicate EVs range in diameter from near

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