This proposed project incorporates a phased career development plan for a candidate with a long-standinginterest in infectious disease research. Under this phased plan, the first two years will incorporate methodsdevelopment, preliminary experimentation, and professional development to further the candidate'sbackground in veterinary medicine and research. The following three years will be spent developingmethods to intensively investigate interactions between lung endothelial and epithelial cells in response tothe bovine respiratory agent Mannheimia haemolytica. Like the human respiratory condition acute respiratorydistress syndrome (ARDS), pneumonic pasteurellosis is associated with profound leakage of vascularcomponents into the airspaces. Vascular leakage is associated with neutrophil activation in the lung duringthe initial stage of infection, whereas lipopolysaccharide is likely a mediator of vascular leakage later ininfection. The central hypothesis is that LPS from M. haemolytica and neutrophil activation are both involvedin promoting plasma leakage.
The specific aims i nclude 1) determine the effect of LPS and neutrophilactivation on albumin leakage and apoptosis in a co-culture system consisting of alveolar epithelial cells andpulmonary microvascular endothelial cells, 2) determine the effect of lung epithelial cell activation onpulmonary microvascular endothelial cell cytokine production, and 3) characterize the expression of Toll-likereceptor 4 on alveolar epithelial cells after LPS and cytokine stimulation. Understanding the interactionsbetween neutrophils, LPS, epithelial cells, and endothelial cells during pneumonic pasteurellosis will result ina better understanding of the basic mechanisms of vascular leakage in the lung. Upon completion of thisproject, the candidate will have acquired new laboratory techniques, developed critical thinking skills, andgrown professionally as a scientist, leading to the candidate's progression into an independent investigator.
| McClenahan, David; Hillenbrand, Kati; Kapur, Arvinder et al. (2009) Effects of extracellular ATP on bovine lung endothelial and epithelial cell monolayer morphologies, apoptoses, and permeabilities. Clin Vaccine Immunol 16:43-8 |
| Kuckleburg, Christopher J; McClenahan, Dave J; Czuprynski, Charles J (2008) Platelet activation by Histophilus somni and its lipooligosaccharide induces endothelial cell proinflammatory responses and platelet internalization. Shock 29:189-96 |
| McClenahan, David; Hellenbrand, Katrina; Atapattu, Dhammika et al. (2008) Effects of lipopolysaccharide and Mannheimia haemolytica leukotoxin on bovine lung microvascular endothelial cells and alveolar epithelial cells. Clin Vaccine Immunol 15:338-47 |
