Grant: Operating Grant

Acute Respiratory Distress Syndrome (ARDS) is a common and devastating problem affecting many patients in the intensive care unit. This syndrome is characterized by severe lung inflammation which prevents patients from breathing independently - so most patients need to be placed on life support. Although mechanical ventilation in these patients can be life saving, studies have shown that repeated lung stretch that occurs during artificial ventilation can also increase lung injury and promote further inflammation. This is called ventilator induced lung injury (VILI). VILI contributes significantly to the mortality and long term morbidity of ARDS patients. There are no known specific treatments for ARDS. The only strategy shown to decrease mortality in these patients is the use of lower tidal volumes - which minimizes lung stretch. My lab is dedicated to understanding how the ventilator causes this type of injury and using this knowledge to develop new therapeutic approaches to reduce lung injury. Using novel genomic technology we have identified a new transcription factor (a molecule that regulates the function of other molecules) that we believe may be important in protecting the lungs from mechanical injury. The mechanism of this protection is unknown. Therefore, in this grant we propose to identify the mechanisms by which ATF3 may protect lungs from VILI. We will use both in-vivo (animal) and in-vitro (cell) models to determine which cells (circulating vs. tissue) play a major role; and which mechanisms (inflammation, cell death [apoptosis] or/and oxidative stress) enable ATF3 to protect lungs from lung injury. This is very important because identifying and understanding novel mechanisms of lung protection is fundamental to developing novel treatment approaches for these and possibly all other patients on life support.