The neutrophil has been strongly implicated in the inflammatory lung injury occurring during both pulmonary and nonpulmonary infection. However, the neutrophil is also an important component in host defense during infection. Adhesion molecules present on the surface of neutrophils and endothelial cells appear essential in neutrophil function during both inflammation and infection. These molecules interacting together mediate neutrophil migration out of the vascular space, neutrophil activation and neutrophil phagocytosis. Therapies such as monoclonal antibodies (MAb's) directed at inhibiting the function of adhesion molecules, might be beneficial during sepsis in limiting neutrophil mediated inflammatory injury, but might also be detrimental by interfering with normal neutrophil host defense function. We have found that MAb's directed against the integrin family of adhesion molecules limit pulmonary injury and improve survival related to tumor necrosis function challenge. However, administration of integrin MAb's during bacterial peritonitis in a canine model limit serum endotoxin clearance and worsen cardiovascular function and survival. During pulmonary infection in rats, similar MAb's are beneficial in limiting pulmonary injury, but still worsen survival. In contrast, in this same model of pneumonia, we have now found that MAb's directed against endothelial receptor molecules (intracellular adhesion molecule-1) improve survival compared to integrin MAb's. In additional studies, we plan to directly compare the effects of MAb's to ICAM-1 and P-selectin antibodies. These studies are being done in collaboration with Dr. Robert Rothlein from Boehringer Ingelheim.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL000142-02
Application #
5201098
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code