Critically ill and injured patients die from multiple organ dysfunction and the respiratory system is one that commonly fails. Acute respiratory distress syndrome (ARDS) is a fatal diagnosis in critical illness with mortality rates remaining greater than twenty percent despite numerous clinical trials. ARDS is also unique in that it is a common pathway that occurs after many disease processes that result in critical illness (shock from trauma or sepsis, burns, pancreatitis). As such, ARDS represents an ideal disease to understand the immunological mechanisms surrounding critical illness.
Immune regulatory proteins such as CTLA-4, PD-1, and BTLA provide a new target for therapies in sepsis and critical illness due to the promising results in murine models of sepsis, cecal ligation and puncture (CLP) and ARDS (hemorrhagic shock followed by poly-microbial septic challenge due to CLP) done in the Ayala laboratory. Soluble forms of these proteins, which are due to alternative splicing, not a separate gene expression, have been identified. The functions of these soluble forms are not yet established, but the presence of soluble forms complicates our understanding of the role of those proteins in the biology of critical illness.
Among human genes that contain multiple exons, over 90% have alternative splicing events. With such a high rate of variation from the transcribed gene to the produced protein, splicing must be under exquisite control. Splicing regulatory factors (SR protein and hnRNP) and the sequence and resulting structure of the mRNA for a specific protein can influence splicing of that gene. Physiologic derangements such as altered temperature and osmotic stress (both seen in critical illness) can influence both these mechanisms of splicing control.
With these things in mind our central hypothesis states alternative splicing of immune modulating proteins (PD-1, CTLA-4, BTLA) leads to soluble forms that are intentionally produced in times of stress, i.e., critical illness, in order to alter the biology/ signaling through the nascent (non-spliced) membrane bound isoforms. In so doing altering the development of ARDS.