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Human models of acute lung injury.

Proudfoot AG, McAuley DF, Griffiths MJ, Hind M - Dis Model Mech (2011)

Bottom Line: ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis.The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies.In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

View Article: PubMed Central - PubMed

Affiliation: Royal Brompton & Harefield NHS Foundation Trust, Adult Intensive Care Unit, London, UK.

ABSTRACT
Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

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Related in: MedlinePlus

Potential roles of human models of ALI in the development of new therapeutics. Experiments performed in ex vivo models guided by animal data and human in vivo observational data will allow safety and basic efficacy testing of novel therapies before Phase I clinical trials are carried out in healthy volunteers. LPS and cardiopulmonary bypass (CBP) in vivo models can be used to provide proof-of-concept early Phase II data, whereas the oesophagectomy surgical in vivo model has the potential to interrogate clinical outcomes.
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f2-0040145: Potential roles of human models of ALI in the development of new therapeutics. Experiments performed in ex vivo models guided by animal data and human in vivo observational data will allow safety and basic efficacy testing of novel therapies before Phase I clinical trials are carried out in healthy volunteers. LPS and cardiopulmonary bypass (CBP) in vivo models can be used to provide proof-of-concept early Phase II data, whereas the oesophagectomy surgical in vivo model has the potential to interrogate clinical outcomes.

Mentions: Where possible, human models of ALI (Table 1) should be used to develop and test novel therapeutic targets. In this section, we describe human in vivo models that will allow the testing of novel therapeutic compounds in Phase II proof-of-principle clinical studies, as well as describing human ex vivo models that might help to shed light on the pathogenesis of ALI (Fig. 2).


Human models of acute lung injury.

Proudfoot AG, McAuley DF, Griffiths MJ, Hind M - Dis Model Mech (2011)

Potential roles of human models of ALI in the development of new therapeutics. Experiments performed in ex vivo models guided by animal data and human in vivo observational data will allow safety and basic efficacy testing of novel therapies before Phase I clinical trials are carried out in healthy volunteers. LPS and cardiopulmonary bypass (CBP) in vivo models can be used to provide proof-of-concept early Phase II data, whereas the oesophagectomy surgical in vivo model has the potential to interrogate clinical outcomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046086&req=5

f2-0040145: Potential roles of human models of ALI in the development of new therapeutics. Experiments performed in ex vivo models guided by animal data and human in vivo observational data will allow safety and basic efficacy testing of novel therapies before Phase I clinical trials are carried out in healthy volunteers. LPS and cardiopulmonary bypass (CBP) in vivo models can be used to provide proof-of-concept early Phase II data, whereas the oesophagectomy surgical in vivo model has the potential to interrogate clinical outcomes.
Mentions: Where possible, human models of ALI (Table 1) should be used to develop and test novel therapeutic targets. In this section, we describe human in vivo models that will allow the testing of novel therapeutic compounds in Phase II proof-of-principle clinical studies, as well as describing human ex vivo models that might help to shed light on the pathogenesis of ALI (Fig. 2).

Bottom Line: ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis.The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies.In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

View Article: PubMed Central - PubMed

Affiliation: Royal Brompton & Harefield NHS Foundation Trust, Adult Intensive Care Unit, London, UK.

ABSTRACT
Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

Show MeSH
Related in: MedlinePlus