This study will determine the role of four chemoattractant cytokines (MIPalpha, MCP-1, MIP-2, and CINC) in the development of acute lung injury (ALI) following hemorrhagic shock and will explore the impact of perfluorocarbon partial liquid ventilation on the expression of these inflammatory mediators. Acute lung injury (ALI) is a complication occurring in as many as 40 percent of traumatic, intraoperative peripartum, and other events associated with acute severe blood loss. The mechanism by which hemorrhage induces lung injury, specifically the recruitment of neutrophils into the lung, is poorly understood. Partial liquid ventilation (PLV, gas ventilation of partially perfluorocarbon- filled lungs) is currently used in patients with respiratory failure to improve gas exchanges and pulmonary mechanics. Our laboratory has generated a large body of animal data linking perfluorocarbon PLV with a lung-protective effect in the setting of acute lung injury. In a model of hemorrhagic shock, we have shown that PLV decreases neutrophil accumulation and capillary leak in the lung. We hypothesize that the development of acute lung injury in the setting of hemorrhagic shock is dependent on the expression of chemokines and that partial liquid ventilation will result in a reduction of these peptides. Using a rat model of hemorrhagic shock-induced lung injury, we intend to systematically determine the presence and relevance of neutrophil- attracting cytokines following acute blood loss. As lung injury following hemorrhage may be a result of circulating or local mediator activity, both serum and lung chemokine expression will be analyzed. ELISA and Northern Blot analysis will be used to quantify cytokine and chemokine up- regulation. Intravenous and intratracheal blocking antibody studies will be performed to assess each protein's contribution to neutrophil accumulation and capillary leak. Once the relevant chemokines are identified, we will examine the effect of partial liquid ventilation on the expression of these proteins. The expected results are better understanding of the role of chemokines in hemorrhagic shock-induced acute lung injury and greater insight into the anti-inflammatory effects of partial liquid ventilation. For the applicant, this program will provide a period of intense research training in an active academic environment with a focus on the scientific methodological and technical skills necessary for the study of acute lung injury and evaluation of new therapies for respiratory failure.
| Valencia, Gabriel; Sarma, J Vidya; Younger, John G (2005) Complement C5 and early oxygen kinetics during murine sepsis. Acad Emerg Med 12:275-81 |
| Shankar-Sinha, Sunita; Valencia, Gabriel A; Janes, Brian K et al. (2004) The Klebsiella pneumoniae O antigen contributes to bacteremia and lethality during murine pneumonia. Infect Immun 72:1423-30 |
| Younger, John G; Shankar-Sinha, Sunita; Mickiewicz, Marc et al. (2003) Murine complement interactions with Pseudomonas aeruginosa and their consequences during pneumonia. Am J Respir Cell Mol Biol 29:432-8 |
| Ko, Angela C; Hirsh, Emily; Wong, Andrew C et al. (2003) Segmental hemodynamics during partial liquid ventilation in isolated rat lungs. Resuscitation 57:85-91 |
| Younger, J G; Sasaki, N; Waite, M D et al. (2001) Detrimental effects of complement activation in hemorrhagic shock. J Appl Physiol 90:441-6 |
| Younger, J G; Sasaki, N; Delgado, J et al. (2001) Systemic and lung physiological changes in rats after intravascular activation of complement. J Appl Physiol 90:2289-95 |
| Fernandez, R; Sarma, V; Younkin, E et al. (2001) Exposure to perflubron is associated with decreased Syk phosphorylation in human neutrophils. J Appl Physiol 91:1941-7 |
