Tumor Necrosis Factor-Alpha (TNF) is an inflammatory mediator implicated in the pathogenesis of sepsis syndrome and Adult Respiratory Distress Syndrome (ARDS). We have demonstrated that TNF induces edema mediated by neutrophils (PMN) in lungs isolated from guinea pigs pretreated with TNF. Our preliminary data suggest that the edema is mediated by Platelet Activating Factor (PAF), Thromboxane A2 (TxA2), Reactive Oxygen Species (ROS) and the activation of Protein Kinase C (PKC). The central hypothesis of the proposal is that TNF induces a sequence of mediators which result in pulmonary edema. TNF induces endothelial PAF, which may cause (i) endothelial PKC activation, (ii) lung TxA2 generation, (iii) PMN production of reactive oxygen species (ROS), and (iv) PMN production of additional PAF. Endothelial PKC activation may be induced directly by TNF through activation of phospholipase C (PLC), and may also be mediated indirectly by PAF. Endothelial PKC activation may lead to PAF release and cytoskeletal abnormalities with associated increases in vascular permeability. The increased permeability, in conjunction with the TxA2-mediated increase in capillary pressure, results in pulmonary edema. The isolated perfused guinea pig and rat lung will be used to study the changes in pulmonary hemodynamics (capillary filtration coefficient, vascular compliance, arterial and capillary pressures), lung permeability to albumin, lung weight gain, PMN uptake, in situ actin morphology and releases of mediators (PAF, TxA2, ROS). The pulmonary arterial endothelial monolayer (PAEM) will be used to characterize the cellular mechanisms of TNF-induced pulmonary edema (PKC activation, PAF and TxA2 generation). The isolated lung and the PAEM are well-characterized; however, studies using PAEM will be limited to specific questions focused on endothelial function based on preliminary data and correlated with data obtained using the isolated lung. The studies proposed in this research plan will define the physiologic and biochemical mechanisms of TNF-induced pulmonary edema and will fill further the understanding of the mechanisms of inflammatory pulmonary edema and the vascular effects of TNF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL048406-01
Application #
3367545
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-09-06
Project End
1994-08-31
Budget Start
1991-09-06
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Bove, K; Neumann, P; Gertzberg, N et al. (2001) Role of ecNOS-derived NO in mediating TNF-induced endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 280:L914-22
Gertzberg, N; Clements, R; Jaspers, I et al. (2000) Tumor necrosis factor-alpha-induced activating protein-1 activity is modulated by nitric oxide-mediated protein kinase G activation. Am J Respir Cell Mol Biol 22:105-15
Ferro, T; Neumann, P; Gertzberg, N et al. (2000) Protein kinase C-alpha mediates endothelial barrier dysfunction induced by TNF-alpha. Am J Physiol Lung Cell Mol Physiol 278:L1107-17
Ferro, T J; Gertzberg, N; Selden, L et al. (1997) Endothelial barrier dysfunction and p42 oxidation induced by TNF-alpha are mediated by nitric oxide. Am J Physiol 272:L979-88
Johnson, A; Ferro, T J (1996) Nitrovasodilator repletion increases TNF-alpha-induced pulmonary edema. J Appl Physiol 80:2151-5
Phelps, D T; Ferro, T J; Higgins, P J et al. (1995) TNF-alpha induces peroxynitrite-mediated depletion of lung endothelial glutathione via protein kinase C. Am J Physiol 269:L551-9
Johnson, A; Phelps, D T; Ferro, T J (1994) Tumor necrosis factor-alpha decreases pulmonary artery endothelial nitrovasodilator via protein kinase C. Am J Physiol 267:L318-25
Serfilippi, G; Ferro, T J; Johnson, A (1994) Activation of protein kinase C mediates altered pulmonary vasoreactivity induced by tumor necrosis factor-alpha. Am J Physiol 267:L282-90
Ferro, T J; Parker, D M; Commins, L M et al. (1993) Tumor necrosis factor-alpha activates pulmonary artery endothelial protein kinase C. Am J Physiol 264:L7-14
Ferro, T J; Hocking, D C; Johnson, A (1993) Tumor necrosis factor-alpha alters pulmonary vasoreactivity via neutrophil-derived oxidants. Am J Physiol 265:L462-71

Showing the most recent 10 out of 12 publications