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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060688-06
Application #
7125581
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1999-12-01
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
6
Fiscal Year
2006
Total Cost
$287,531
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L et al. (2012) Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury. Burns 38:1072-8
Hamahata, Atsumori; Enkhbaatar, Perenlei; Lange, Matthias et al. (2012) Administration of a peroxynitrite decomposition catalyst into the bronchial artery attenuates pulmonary dysfunction after smoke inhalation and burn injury in sheep. Shock 38:543-8
Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda et al. (2012) Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis. Am J Physiol Heart Circ Physiol 303:H1245-54
Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L et al. (2011) Preclinical evaluation of epinephrine nebulization to reduce airway hyperemia and improve oxygenation after smoke inhalation injury. Crit Care Med 39:718-24
Sousse, Linda E; Yamamoto, Yusuke; Enkhbaatar, Perenlei et al. (2011) Acute lung injury-induced collagen deposition is associated with elevated asymmetric dimethylarginine and arginase activity. Shock 35:282-8
Maybauer, Dirk M; Maybauer, Marc O; Szabo, Csaba et al. (2011) The peroxynitrite catalyst WW-85 improves microcirculation in ovine smoke inhalation injury and septic shock. Burns 37:842-50
Lange, Matthias; Szabo, Csaba; Enkhbaatar, Perenlei et al. (2011) Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury. Am J Physiol Lung Cell Mol Physiol 300:L167-75
Morita, Naoki; Enkhbaatar, Perenlei; Maybauer, Dirk M et al. (2011) Impact of bronchial circulation on bronchial exudates following combined burn and smoke inhalation injury in sheep. Burns 37:465-73

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