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ACUTE RESPIRATORY STRESS SYNDROME (CLINICAL CONCEPT & PATHOGENIC…
ACUTE RESPIRATORY STRESS SYNDROME
CLINICAL CONCEPT & PATHOGENIC MECHANISM
Acute Respiratory Distress Syndrome(ARDS) is caused by injry on the lung parenchyma which is common and life threatening caise of respiratory failure and mortality
Spesis
Multiple trauma
Pneumonia
Aspiration of gastric content
Severe burns
Report in 1967 shows 12 adults with acute onset of respiratory distress, refractory hypoxemia and bilateral infiltrates in chest X-ray
Initially known as adult respiratory distress syndrome and eventually modified to acute respiratory distress syndrome on 1972 when was diagnosed in children
Direct
Pneumonia, aspiration,contusion
Indirect
Sepsis,trauma,pancreatitis
Heterogeneity of causes make sthe studying of pathogenesis of the syndrome and potential therapies complicated
In 1994, ARDS Is defined by :
Acute onset of bilateral infiltrates on chest imaging
Acute onset of hypoxemia
Absence of left heart failure
MAJOR FEATURES OF ARDS PATHOGENESIS
Alveolar epithelial injury
Early event in the pathogenesis of acute lung injury is injury to both type I and type II alveolar epithelial cells
Apoptosis and necrosis
Impairs surfactatnt production which in combination with the accumulation of pulmonary edema
Inhibits gas exhange and leads to
persistent hypoxemia
Inflammatory cell reflux
Direct injury to the lung as a response to systemic inflammation and cytokine production
Aspiration of gastric content
Macrophages and lymphocytes recruited to the lung and produce large amounts of both pro and anti inflammatory cytokines
A loss of the alveolar - cappilary barrier
Earliest abnormalities that can be seen in injured lung
Vascular leak with flooding of the alveolar space with protein rich edema fluid
Bilateral,fluffy alveolar infiltrate
Tachypnea and hypoxemia
Activation of coagulation & inhibition of fibrinolysis
Presence of hyaline membrane
Direct result of intra alveolar fibrin polymerization
Increase in procoagulant protein activity amd a decrease in fibrinolytic therapy favoring fibrin formation
Lung cells actively modulate alveolar fibrin deposition
Upregulation & activation of tissue factor
Consumption of platelets and resulting in microvascular thrombosis that causes an increase in the dead space in the lungs
Loss of ability to activate protein C which is a key anti-coagulant protein
ARDS CURRENT MODEL SYSTEM AND CHALLENGES
In mice by using Gram negative bacterial endotoxin LPS which can be adminitered directly to the lungs through intratracheal injection or inhalation or given intraperitoneally or intravenously to incite a systemic inflammatory response
Model of lung injury is hyperoxia where mice breathe a high partial pressure of oxygen that is highly toxic to the alveolar epithelium
Extensive alveolar epithelial injury with only a modest amount of inflammation
Model is ventilator-induced lung injury however in the absence of an additional stimulus or extremely high tidal volume. Does not induce substantial lung injury in mice
COMMON CHALLENGES TO MODELLING ARDS
Limited ability to provide critical care to small animals
Life saving mechanical ventilation is needed to provide adequate gas exchange (extraction of oxygen and elimination of carbon dioxide) during the period of acute illness
Development of unilateral lung injury model
Unilateral acid aspiration
Challenges in providing hemodynamic support
Patient in shock and require aggressive fluid resuscitation and a cardiovascular support with vasopressors
Animal model do not replicate key pathogenic features of human disease
Ineffective anti-inflammatory therapies that have been tred in ARDS indicate that effectiveness in these models does not easily translate into successful human trials
In need of models that replicate the coagulation and fibrinolytic abnormalities that are key to ARDS pathogenesis
Lack of good surrogate endpoint
Limitations of time,personnel,money or other resources makes it very difficult to determine appropriate endpoints in preclinical studies
Develop better biomarkers for developments and putcomes from ARDS in humans that can then be translated back into animal models
FUTURE RESEARCH DIRECTION
Require the use of multiple modalities
Underappreaciated biological pathways
Successful identification of surrogate endpoints or biomarlers that are predictive of outcome
Optimal use of these models, however, requires active and ongoing communication between basic and clinical researchers
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