Grant: Project Grant

Acute lung injury (ALI) is a leading cause of death in critically ill patients. Sepsis, a life-threatening complication of infection, is the major cause of ALI. Approximately 50% of patients with sepsis are implicated with the lipopolysaccharide (LPS), a toxic substance bound to the Gram-negative bacterial cell wall and released when the bacterium ruptures or disintegrates. LPS consists of endotoxin and lipoproteins. LPS triggers a network of inflammation resulting in lung injury or ARDS. Large clinical trials, focusing on the therapeutic potential by removal of LPS from blood or by blocking the activities of inflammation, were disappointing. Another large clinical study showed that the blockage of the LPS receptor (toll-like receptor 4) on the surface of white blood cells failed to treat patients. These results have forced us to re-examine the whole concept of immunotherapy. We have obtained substantial pilot data demonstrating that LPS can be internalized into the lung mediated by a cell adhesion molecule to produce LPS signal resulting in continuation of inflammatory responses and sustained lung injury. We will examine the mechanisms how LPS gets into the cells and how they send signal to cause lung injury using specific genome editing technique. We will then propose a new adjuvant therapy targeting LPS signal not only in bloodstream but also inside cells for sepsis associated ALI.