Acute Respiratory Distress Syndrome (ARDS) (Pathogenesis of ARDS: (2)…
Acute Respiratory Distress Syndrome
What is ARDS?
ARDS is acute respiratory distress syndrome that cause due to injury of the lung parenchyma.
-Aspiration of gastric contents
Setting of ARDS
Pathogenesis of ARDS:
2) Alveolar epithelial injury
-An early event of acute lung injury is injury to both type 1 and type 2 alveolar epithelial cells.
-Patient with ARDS have elevated levels of the receptor for advanced glycation end products (RAGE) a marker of type 1 alveolar epithelial cell injury in both the lung compartment and circulating in the plasma.
1) Loss of the alveolar-capillary barrier
-One of the abnormalities seen in injured lung.
-This is seen both ultrastructurally on histological analysis and clinically.
-As vascular leak with flooding of the alveolar space with protein-rich edema fluid.
3) Inflammatory cell influx
-Concurrent with injury with to the alveolar-capillary barrier, thereis massive inflammatory cell influx into the lungs.
-This can occur as a result of a direct injury to the lung or as are as response to systemic inflammation and cytokine production.
4) Activation of coagulation and inhibition of fibrinolysis
-Presence of hyaline membranes which are a direct result of intra-alveolar fibrin polymerization.
-Recently, there is evidence that resident lung cells, including alveolar epithelial cells, actively modulate alveolar fibrin deposition through upregulation and activation of tissue factor.
Due to ARDS making result difficult to generate, ARDS now is defined by:
Acute onset of bilateral infiltrates of chest imaging
The acute onset of hypoxemia with a partial pressureof arterial oxygen (PaO2) / fraction of inspired oxygen (FiO2) ratio <200
The absence of left heart failure
challenges to modelling ARDS into the animal
Limited ability to provide critical care to small animals
The injury induced in the mice model is not severe enough to accurately mimic disease in human due to limited ability to provide prolonged supportive care to small animals. Hence the animals die and cannot be studied further
Challenge in providing hemodynamic support. Patients with ARDS are often in shock and require aggressive fluid resuscitation and cardiovascular support with vasopressors
. To properly prepare these treatment and mimic human, a ‘mouse intensive care unit’ ICU is needed which is impossible for our current technology
. For primates, the ICU unit is only available in a very few laboratories throughout the world.
the development of unilateral lung injury models, such as unilateral acid aspiration, which may provide the ability to create a severe lung injury in one lung, while preserving a normal lung with which the animal can survive. However, this method has not been well studied.
lack of good surrogate endpoint
lack of good surrogate endpoint in patient with disorder which make it difficult to determine appropriate endpoint in preclinical study
for example, improvement in blood oxygenation, potentially delivered to tissue. however, multiple clinical study show that improvement in blood oxygenation without mortality benefit
develop better biomarkers for development and outcomes from the ARDS in human that can be translated back to animal models
clinical and basic research opporutnity
creating small animal ICU type condition to provide prolonged respiratory and hemodynamic support
create ARDS models that replicate coagulation and fibrinolysis abnormalities
define surrof=gate endpoint that are predictive of ARDS outcomes
identify biomarkers for ARDS
Animal models do not replicate key pathogenic features of human disease
Many commonly used mouse lung injury models do not replicate all of these key pathogenic abnormalities
the loss of the alveolar-capillary barrier
epithelial cell injury inflammatory cell influx
future research direction
Improvements in disease
may required the use of multiple modalitiesto recapitulate multiple feature of acute lung injury
better supportive care for animal during course of injury
focusing on previously underappreciated biological pathways such as coagulation and fibrinolysis may aid in modeling his complex syndrome
The successful identification of surrogate endpoints or biomarkers that are predictive of outcome and that can be used in human and animal studies of ARDS will probably require increased collaboration between clinical and basic researchers
model system for ARDS
the use of animal in studying complex animal pathogenesis
The goal of each model system used is to mimic human disease such as pneumonia and sepsis which are the most common predisposing condition to develop ARDS.
Larger animals that more closely replicate human disease, such as primates, are prohibitively expensive for most researchers to study and require specialized research facilities.
Smaller animals, such as mice, are much more widely accessible to researchers and are a very powerful research tool as they can be genetically manipulated in multiple ways to facilitate the detailed mechanistic study of complex pathways.
Modelled in mice by using the Gram-negative bacterial endotoxin LPS, which can be administered either directly to the lungs through intratracheal injection or inhalation, or given intraperitoneally or intravenously to incite a systemic inflammatory response.
Another commonly used model of lung injury is hyperoxia, where mice breathe a high partial pressure of oxygen that is highly toxic to the alveolar epithelium and causes extensive alveolar epithelial injury with only a modest amount of inflammation
Another method is by using a ventilator that cause ventilator-induced lung injury which correlates excellently to human ventilator-induced lung injury. However, in the absence of an additional stimulus or extremely high tidal volumes, this model does not induce substantial lung injury in mice.
First report of ARDS is in 1967 when Ashbaugh and colleaguedescribed 12 adult patient with:
-Bilateral infiltrates in chest x-rays