Kasotakis – Medicine/Surgery/Critical Care
Options: Volunteer Basis, Potential for UROP Funding
HISTONE DEACETYLASE INHIBITION IN MOUSE MODELS OF ACUTE LUNG INJURY AND SEPSIS
Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) represent a spectrum of severe pulmonary disease, which manifest clinically as respiratory failure necessitating prolonged pulmonary support and mechanical ventilation. The syndrome, caused by an exaggerated host immune response, is most commonly triggered by lung infections and afflicts more than 100,000 patients annually worldwide, carrying a mortality as high as 55% in its most severe form.
Similarly, sepsis, an uncontrolled systemic response to infection, afflicts more than 18 million patients every year with mortality in excess of 35%.
Despite advances in critical care over the last few decades, treatment for both ALI/ARDS and sepsis remains supportive and anti-inflammatory therapies have failed to improve clinically relevant outcomes, including survival in human clinical trials. Preliminary studies using rodent models of ALI/ARDS and sepsis have recently demonstrated mitigation of the pulmonary and systemic inflammatory profile pretreated with Histone Deacetylase Inhibitors (HDACI), as well as improved survival. However, the studies published to date have not answered many critical questions that require addressing prior to porting HDACI to clinical use, namely the effect of HDAC inhibition on wound healing and infection control (an inflammatory response is required for wound healing and to combat infection); optimal dosing, frequency and route of administration; effect on pulmonary, liver and immune function; interaction with other comorbid conditions frequently present in patients with sepsis or ALI/ARDS.
The goal of the research is to further elucidate the role of HDACI in the management of ALI/ARDS and sepsis, and pave the way for clinical use, in an attempt to improve clinically relevant outcomes in human subjects and save millions of lives.