ACUTE RESPIRATORY STRESS SYNDROME

CLINICAL CONCEPT & PATHOGENIC MECHANISM

MAJOR FEATURES OF ARDS PATHOGENESIS

ARDS CURRENT MODEL SYSTEM AND CHALLENGES

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

Alveolar epithelial injury

Inflammatory cell reflux

COMMON CHALLENGES TO MODELLING ARDS

A loss of the alveolar - cappilary barrier

Activation of coagulation & inhibition of fibrinolysis

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

FUTURE RESEARCH DIRECTION

Limited ability to provide critical care to small animals

Animal model do not replicate key pathogenic features of human disease

Lack of good surrogate endpoint

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

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

Introduction

Ineffective anti-inflammatory therapies that have been tred in ARDS indicate that effectiveness in these models does not easily translate into successful human trials

Presence of hyaline membrane

Direct result of intra alveolar fibrin polymerization

Cause

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

Loss of ability to activate protein C which is a key anti-coagulant protein

Consumption of platelets and resulting in microvascular thrombosis that causes an increase in the dead space in the lungs

Cause

Direct injury to the lung as a response to systemic inflammation and cytokine production

Aspiration of gastric content

Cause

Example

Macrophages and lymphocytes recruited to the lung and produce large amounts of both pro and anti inflammatory cytokines

1st Model

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

2nd Model

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

Challenges in providing hemodynamic support

Patient in shock and require aggressive fluid resuscitation and a cardiovascular support with vasopressors

Development of unilateral lung injury model

Solution

Unilateral acid aspiration

Example

through

In need of models that replicate the coagulation and fibrinolytic abnormalities that are key to ARDS pathogenesis

Solution

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

Solution

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

Results in

Caused by

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

Radiographic analysis

Tachypnea and hypoxemia

Clinical signs

Development

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

Indirect

Pneumonia, aspiration,contusion

Sepsis,trauma,pancreatitis

Occurence

Heterogeneity of causes make sthe studying of pathogenesis of the syndrome and potential therapies complicated

In 1994, ARDS Is defined by :

  1. Acute onset of bilateral infiltrates on chest imaging
  2. Acute onset of hypoxemia
  3. Absence of left heart failure

Cause