Causes of failure in acute respiratory distress syndrome modeling and treatment in animal research and new approaches

Table 1 Animal models of acute respiratory distress syndrome

Direct lung injury	Intratracheal or intranasal delivery of bacteria or bacterial product such as lipopolysaccaride
	Hydrochloric acid or gastric particles to create acid aspiration
	High inspired fraction of oxygen
	Surfactant depletion (0.9% NaCl lavage)
	Lung ischemia/reperfusion
	Mechanical ventilation at high tidal volumes
Indirect lung injury	Cecal ligation and puncture
	Intravenous bacteria or LPS administration
	Mesenteric ischemia/reperfusion
	Oleic acid model
Combination models	Cecal ligation and puncture followed by hemorrhage
	Saline lavage after mechanical ventilation
	Intraperitoneal LPS injection after intravenous oleic acid

LPS: Lipopolysaccharide.

Table 2 Limitations of acute respiratory distress syndrome models

Experiment period	The formation of pathology takes hours or days in humans, whereas the monitored period is shorter in animal models (monitoring difficulties)
Ventilation and fluid management	Ventilation and fluid management supports are lacking in animal experiments (these are crucial in humans)
The degree of pathology	Experimental models generally have milder pathology compared to human pathology
The species and the size of the animals	Larger animals (primates) can more easily mimic human disease, but these experiments require expertise. Smaller animals (mice) are much more widely used (this may allow for the study of complex pathways and genetic studies)
Treatment time	Therapeutic agents in experimental studies are usually given before the onset of acute respiratory distress syndrome, whereas the clinical diagnosis and treatment of ARDS is delayed
Animal age	Animal experiments are performed on young animals with no comorbidities; however, patients with ARDS are mostly elderly and may have many medical problems such as cardiovascular diseases, kidney or liver failure
Changes in response to therapy	The effects of therapeutic agents on survival in humans and animals are different. An agent may be effective on animal survival, but may not be effective in humans (there are many anatomical and physiological differences between animals and humans)
Coagulation and fibrinolytic status	Animal models cannot mimic the coagulation and fibrinolytic system changes during lung injury in humans
Correlation between biochemical markers and their biological activities	Biochemical markers measured in bronchoalveolar lavage fluid, plasma and edema fluid may not correlate with their biological activities
Combination treatment	Combined treatment should be developed. Combined treatment approaches are applied to a lesser extent in experimental models

ARDS: Acute respiratory distress syndrome.