Development of animal models for the acute respiratory distress syndrome

Abstract

Injury to the lung parenchyma results in the acute respiratory distress syndrome (ARDS), which is a common and life-threatening cause of respiratory failure and mortality that develops after a variety of insults, including sepsis, multiple trauma, pneumonia, aspiration of gastric contents and severe burns. The pathogenesis of ARDS is complex with loss of the alveolar-capillary barrier and flooding of the airspaces with protein-rich fluid; injury to the alveolar epithelium; an influx of neutrophils and macrophages; and fibrin deposition as a result of activation of coagulation and inhibition of fibrinolysis. These changes develop over hours to a few days after the initiating event and often take days or weeks to resolve. Despite decades of research, there is only one therapy (low tidal volume ventilation) that has been shown to reduce mortality in ARDS. Further research into the pathogenesis of this devastating condition is crucial for the development of novel and specific therapies that target specific disease mechanisms. Unfortunately, no single animal model of ARDS replicates the complex pathophysiological changes seen in patients. This is a severe limitation in the study of ARDS and has impaired scientific and therapeutic progress in this field. Here, we discuss the primary features of this syndrome, highlight limitations of current animal models and suggest new approaches to investigate key components of pathogenesis. Hopefully, as new technologies and approaches emerge, barriers to scientific progress in ARDS will be overcome.

A Myristoylated Alanine-Rich C Kinase Substrate–Related Peptide Suppresses Cytokine mRNA and Protein Expression in LPS-Activated Canine Neutrophils

“…Naturally occurring disease in veterinary species represents a novel approach to therapeutic discovery, because there is a growing recognition that induced animal models of disease (e.g., murine models) can result in an oversimplification of disease pathogenesis and thus provide limited utility in therapeutic evaluations (6,7). Further, regulatory barriers to the in vivo use of investigational therapeutics in veterinary patients are less extensive than in humans, making the use of these patients in therapeutic discovery a valuable resource to evaluate relevant clinical outcomes in affected patients.…”

Progress in modelling acute lung injury in a pre-clinical mouse model

“…Investigators have used a wide variety of small-and largeanimal models in order to understand the mechanisms of injury to both the lung endothelial and epithelial barriers, as well as to test novel therapeutic strategies [2][3][4]. All animal models are limited in their ability to model the complex clinical syndrome of ALI/ARDS because they cannot replicate several of the confounding factors, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors that may contribute to the clinical syndrome of ALI/ARDS [3].…”

“…All animal models are limited in their ability to model the complex clinical syndrome of ALI/ARDS because they cannot replicate several of the confounding factors, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors that may contribute to the clinical syndrome of ALI/ARDS [3]. Nevertheless, animal models have made important contributions to understanding several of the mechanisms responsible for the development of lung injury [4,5].In this issue of the European Respiratory Journal, PATEL et al [6] report a mouse model of ALI that reproduces several features of the pathophysiology of ALI. The authors used orotracheal instillation of hydrochloric acid to induce ALI, and then monitored the mice over 10 days to study both the development and the resolution of ALI.…”

“…All animal models are limited in their ability to model the complex clinical syndrome of ALI/ARDS because they cannot replicate several of the confounding factors, including the effects of age, chronic medical diseases such as liver and renal insufficiency, and the impact of genetic and environmental factors that may contribute to the clinical syndrome of ALI/ARDS [3]. Nevertheless, animal models have made important contributions to understanding several of the mechanisms responsible for the development of lung injury [4,5].…”

Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

“…To further test the macrophage immunomodulatory effects of Ad14p1 versus those of wt Ad14 CPE corpses, we contrasted their effects on HAM stimulated with LPS (Fig. 5B), a known inducer of macrophage, NF-B-dependent, cytokine responses (19). Ad14p1 CPE corpses enhanced the LPS-induced IL-1␤ macrophage response, but wt Ad14 CPE corpses had no such stimulatory effect.…”