Disruption of the CD40-CD40 ligand system prevents an oxygen-induced respiratory distress syndrome.
Oxygen therapy is a mainstay treatment for infants and adults with poor lung function. Unfortunately, oxygen itself is toxic and incites respiratory cell damage and inflammation. Therapies for oxygen-induced lung damage are nonexistent. Employing a mouse model of hyperoxic lung injury, a monoclonal anti-CD40 ligand (L) antibody (MR1), which disrupts CD40-CD40L interactions, was tested for the ability to reduce pulmonary injury. Intraperitoneal administration of MR1, either before or after oxygen exposure, was remarkably effective in reducing and in many cases preventing lung injury. The pro-inflammatory enzyme cyclooxygenase-2 (Cox-2), responsible for prostaglandin production, is massively up-regulated in the lungs after hyperoxic exposure. Immunohistochemical staining for Cox-2 revealed that MR1 greatly reduces the oxygen-induced induction of Cox-2. The remarkable effectiveness of MR1 in blunting hyperoxic lung injury in this preclinical model may be relevant to the hundreds of thousands of patients who require treatment with high oxygen and who are at risk for developing severe pulmonary inflammation and consequent fibrosis. Strategies to disrupt CD40-CD40L interactions may offer a new mode of intervention for oxygen-induced acute respiratory distress syndrome and other inflammatory lung disorders.
Adawi
A
A
University of Rochester Cancer Center and Department of Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Zhang
Y
Y
Baggs
R
R
Finkelstein
J
J
Phipps
R P
RP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand; D006224:Cricetinae; D004195:Disease Models, Animal; D006801:Humans; D018496:Hyperoxia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008024:Ligands; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen