"Everything should be as simple as possible, but not simpler."

Albert Einstein

Overview and Rationale

Although much can be learned by investigating the response to injury in man, many of our current and future scientific and therapeutic advances in critical care medicine will continue to depend upon studies using experimental models designed to mimic the injury response in man. As a collaborative group in the initial funding period, the Model Validation Core (MVC) investigators used several well-defined experimental injury models as an approach to corroborate findings from human studies and to further advance our understanding of the host response to injury and inflammation.

As a collaborative effort with investigators studying the human response to injury and inflammation, the MVC determined whether experimental models of tissue injury, blood loss, and endotoxemia resemble the human inflammatory response to injury using state of the art genetic and analytical assays. Moreover, the investigators provided the scientific and clinical community with standardized methodologies for performing experimental injury models, genetic analyses, and analytical assays. Multiple laboratories with expertise in designing and using experimental models to address the host response to injury and inflammation were involved in these studies. Importantly, both the tissue injury and blood loss models supported the clinical findings that patients are more susceptible to infection following serious injury. Thus, it was important to extend these experimental models further by:

• Clarifying similarities and differences between results from the experimental models and observations from injured patients
• Comparing post-injury gene expression and protein production by peripheral immune cells from patient and experimental studies
• Comparing circulating immune cells with similar cells from organs such as liver, gut and the respiratory tract to elucidate issues of different compartmentalization responses

Functions of the Model Validation Core

The MVC used experimental models of tissue injury, blood loss, and acute inflammation to determine genomic and proteomic changes and characterize these in a fashion comparable to the human studies (proteomic and genomic expression analyses). The core examined specific patterns of expression of a cluster of genes in circulating immune cells and correlated these with the gene expression patterns in tissue-fixed immune cells and to the systemic release of regulatory proteins.

Such investigations developed a consensus-driven database from comparable experimental models of tissue injury, blood loss, and endotoxemia. This permitted investigators to evaluate alterations in gene expression and proteomics after injury in experimental models that simulate the two major injured patient groups studied in this large-scale collaborative program.

Progress

The Model Validation Core substantially accomplished what has been described in terms of development of comparable murine model Standard Operating Procedures (SOPs) and have collected sufficient model data, samples, and tissues for further study by analytical methods as they are developed in our data interpretation groups (DIGs) during at least the first two years of the renewal Program and likely beyond.

The Program has not funded further model experiments and feels that we have ample model data, samples, and tissues gathered in Years 1 – 5 to evaluate. However, the Program continues to support model studies by our DIG investigators well beyond Year 5 in our Program. The members of the MVC remain enthusiastic participants in the analytical phase of our program and continue to represent the relevance of the murine models to our human investigations.