Acute respiratory distress syndrome (ARDS) is a serious clinical problem. ARDS is associated with organ system failure(MODS). This proposal models ARDS and MODS in a sheep that has a 40% 3rd degree burn with smoke inhalation injury. It has been shown that many of the systemic changes noted with the model are associated with the release of activated neutrophils (PMNs) from the lung into the systemic circulation and that this activation could be reversed by the administration of a monoclonal antibody to L-selectin. The hypothesis is that oxidants formed from smoke interact the tissues in the airway to cause the release of chemokines the latter activate PMNs by ligation of L-selectin. Activated PMNs are carried by the circulation to systemic organs and reduce blood flow to the organ by vasoconstriction, release reactive oxygen species (ROS) that combine with tissue nitric oxide to form NO/O2 reactant products such as peroxynitrite. The latter causes DNA strand breaks and activates poly (ADP-ribose) polymerase (PARP). PARP causes consumption of ATP and also up regulates P- and E-selectin and NF-kappaB. The latter up regulates iNOS and IL-8. The result is to attract more PMNs to the tissue to induce additional tissue injury. Some of the PMNs escape the systemic circulation and further damage the lung. The hypothesis will be tested in sheep operatively prepared for chronic study. After obtaining baseline data the animals are anesthetized and divided in groups (a burn alone, smoke alone, combined injury). There will be a sham group without injury.
Aim #1. Determine if an antibody to L-selectin will prevent the activation of blood PMNs, PARP and NF-kappaB and limit tissue damage seen in the lung, ileum, pancreas, skeletal muscle and liver after burn and inhalation injury.
Aim #2 To determine whether inhibitors of iNOS and PARP will prevent the activation of PARP and NF-kappaB, the loss of L-selectin from blood neutrophils and the expression of P and E selectins and limit tissue damage in the lung, ileum, pancreas, skeletal muscle and liver with bum and inhalation injuries.
Aim #3. To differentiate the role of the lung and peripheral areas by preventing the activation of neutrophils in the Jung by ablating the bronchial circulation with the various injuries.
These aims should result in a better understanding of the injury and reduce the mortalities of ARDS patients.
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