Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.
The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. We sought comprehensive integration of gene expression data in experimental acute lung injury (ALI) in rodents compared with humans. We performed two separate gene expression multicohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. We identified 21 animal lung tissue datasets and three human lung injury bronchoalveolar lavage datasets. We show that the metasignatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, ventilator-induced lung injury, LPS) are significantly correlated with human models of lung injury (Pearson r = 0.33-0.45, P < 1E-16). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.
1 Stanford Institute for Immunity, Transplantation and Infection.|2 Biomedical Informatics Research, and.
Timothy E
0000-0002-3596-1093
TE
Sweeney
1 Stanford Institute for Immunity, Transplantation and Infection.|2 Biomedical Informatics Research, and.
Shane
S
Lofgren
1 Stanford Institute for Immunity, Transplantation and Infection.|2 Biomedical Informatics Research, and.
Purvesh
P
Khatri
3 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California.
Angela J
AJ
Rogers
D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics*; D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D066264:Datasets as Topic; D004195:Disease Models, Animal; D055808:Drug Discovery; D015507:Drugs, Investigational; D053263:Gene Regulatory Networks; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000378:metabolism; D051379:Mice / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010126:Ozone / Q000633:toxicity; D051381:Rats / Q000235:genetics* / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D046888:Tissue Array Analysis; D059467:Transcriptome; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
D015507:Drugs, Investigational; D008024:Ligands; D008070:Lipopolysaccharides; D010126:Ozone
acute lung injury; acute respiratory distress syndrome; animal model; gene expression; human