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 poo r lung function. Unfortunately, oxygen itself is toxic and incites res piratory cell damage and inflammation. Therapies for oxygen-induced lu ng damage are nonexistent. Employing a mouse model of hyperoxic lung i njury, a monoclonal anti-CD40 ligand (L) antibody (MR1), which disrupt s CD40-CD40L interactions, was tested for the ability to reduce pulmon ary injury. Intraperitoneal administration of MR1, either before or af ter oxygen exposure, was remarkably effective in reducing and in many cases preventing lung injury. The pro-inflammatory enzyme cyclooxygena se-2 (Cox-2), responsible for prostaglandin production, is massively u p-regulated in the lungs after hyperoxic exposure. Immunohistochemical staining for Cox-2 revealed that MR1 greatly reduces the oxygen-induc ed induction of Cox-2. The remarkable effectiveness of MR1 in blunting hyperoxic lung injury in this preclinical model may be relevant to th e hundreds of thousands of patients who require treatment with high ox ygen 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 respira tory distress syndrome and other inflammatory lung disorders.