This proposed project incorporates a phased career development plan for a candidate with a long-standing interest in infectious disease research. Under this phased plan, the first 2 years will incorporate methods development, preliminary experimentation, and professional development to further the candidate's background in veterinary medicine and research. The following 3 years will be spent developing methods to intensively investigate interactions between lung endothelial and epithelial cells in response to the bovine respiratory agent Mannheimia haemolytica. Like the human respiratory condition acute respiratory distress syndrome (ARDS), pneumonic pasteurellosis is associated with profound leakage of vascular components into the airspaces. Vascular leakage is associated with neutrophil activation in the lung during the initial stage of infection, whereas lip polysaccharide is likely a mediator of vascular leakage later in infection. The central hypothesis is that LPS from M. haemolytica and neutrophil activation are both involved in promoting plasma leakage.
The specific aims i nclude 1) determine the effect of LPS and neutrophil activation on albumin leakage and apoptosis in a co-culture system consisting of alveolar epithelial cells and pulmonary micro vascular endothelial cells, 2) determine the effect of lung epithelial cell activation on pulmonary micro vascular endothelial cell cytokine production, and 3) characterize the expression of Toll-like receptor 4 (TLR4) on alveolar epithelial cells after LPS and cytokine stimulation. Understanding the interactions between neutrophils, LPS, epithelial cells, and endothelial cells during pneumonic pasteurellosis will result in a better understanding of the basic mechanisms of vascular leakage in the lung. Upon completion of this project, the candidate will have acquired new laboratory techniques, developed critical thinking skills, and grown 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 |
