Professor of Physiology and Environmental Medicine
Professor of Medicine
Director, Institute for Environmental Medicine

Research Interests

Membrane protein and phospholipid trafficking in lung epithelial cells; control of lung lipoprotein synthesis and secretion; lipid and protein oxidation in ischemia-reperfusion injury.

Research Techniques

Cell isolation and culture; isolated lung perfusion; biosynthesis of radiolabelled surfactant; enzyme isolation and characterization; isolation of subcellular organelles; metabolic flux measurement; lipid analysis.

Summary of Research Program

Lung surfactant is a lipoprotein secretory product of alveolar epithelium that serves to stabilize lung alveoli during the respiratory cycle. Our studies are directed towards understanding regulation of the cellular processing of lung surfactant. Current projects include evaluation of granular pneumocyte receptors for surfactant-associated proteins; mechanisms for endocytosis of lung surfactant; coupling of endocytosis to secretion; and pathways for intracellular trafficking and degradation of internalized surfactant components. Major emphasis is directed toward study of the role and properties of a novel Ca++-independent phospholipase A2 that we have isolated from lung epithelium. Delineation of the pathways of surfactant metabolism will provide important information for understanding the respiratory distress syndrome including its treatment by the administration of exogenous surfactant. A second area of research is the study of mechanisms for lung injury associated with decreased organ bloodflow. Ischemia/reperfusion injury is evaluated using in vivo and isolated perfused rat lung models. Lipid peroxidation and protein oxidation under varying conditions of oxygenation are correlated with alterations of lung function and with anti-oxidant capacity of tissue. This program investigates mechanisms for initiation of oxygen-derived radical production, the roles of Fe++ and peroxynitrite as oxidants, the pathways for protein oxidation, and novel methods for treatment with anti-oxidants. A goal of these studies is to develop methods for prevention and treatment of ischemia-mediated lung injury.

 

SELECTED PUBLICATIONS   (past 4 years)

Fisher, A.B., C.Dodia. Role of phospholipase A2 enzymes in degradation of dipalmitoylphosphatidylcholine by granular pneumocytes. J. Lipid Res. 37:1057-1064, 1996.

Chen, Q., S.R. Bates, A.B. Fisher. Secretagogues increase the expression of SP-A receptors on lung type II cells. J. Biol. Chem. 271:25277-25283, 1996.

Kim, T-S., Sundaresh, C.S., Feinstein, S.I., Dodia, C., Skatch, W., Jain, M., Nagase, T., Seki, N., Ishikawa, K., Nomura, N. and Fisher, A.B. Identification of a human cDNA clone for lysosomal-type Ca++-independent phospholipase A2 and properties of the expressed protein. J. Biol. Chem., 272:2542-2550, 1997


Al-Mehdi, A.B., H. Shuman,, A.B. Fisher. Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia. Am. J. Physiol. 272 (Lung Cell. Mol. Physiol. 16):L294-L300, 1997.


Al-Mehdi, A.B., Shuman, H. and Fisher, A.B. Oxidant generation with K+-induced depolarization in the isolated perfused lung. Free Rad. Biol. Med., 23:47-56, 1997.


Zhao, G., Al-Mehdi, A.B. and Fisher, A.B. Anoxia-reoxygenation versus ischemia in isolated rat lungs. Am. J. Physiol. (Lung Cell. Mol. Physiol. 17), 273:L1112-L1117, 1997.


Al-Mehdi, A.B., Zhao, G. and Fisher, A.B. ATP-independent membrane depolarization with ischemia in the oxygen-ventilated isolated rat lung. Am. J. Respir. Cell Mol. Biol., 18:653-661, 1998.


Kim, T-S., Dodia, C., Chen, X., Hennigan, B.B., Jain, M., Feinstein, S.I. and Fisher, A.B. Cloning and expression of rat lung acidic Ca2+-independent PLA2 and its organ distribution. Am. J. Physiol. (Lung Cell. Mol. Physiol. 18), 274:L750-L761, 1998.


Zen, K., Notarfrancesco, K., Oorschot, V., Slot, J.W., Fisher, A.B. and Shuman, H. Generation and characterization of monoclonal antibodies to alveolar type II cell lamellar body membrane. Am. J. Physiol. (Lung Cell. Mol. Physiol. 19), 275:L172-L183, 1998.


Chen, Q., Fisher, A.B., Strayer, D.S. and Bates, S. Mechanism for secretagogue-induced surfactant protein-A binding. Am. J. Physiol. (Lung Cell. Mol. Physiol. 19), 275:L38-L46, 1998.


Akiba, S. Dodia, C., Chen, X. and Fisher, A.B. Characterization of acidic Ca2+-independent phospholipase A2 of bovine lung. Comp. Biochem. Physiol., 120:393-404, 1998.


Al-Mehdi, A., Zhao, G., Dodia, C., Tozawa, K., Costa, K., Muzykantov, V., Ross, C., Bleecha, F., Dinauer, M. and Fisher, A.B. Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+. Circulation Research, 83:730-737, 1998.


Cajal, Y., Dodia, C., Fisher, A.B. and Jain, M.K. Calcium triggered selective intermembrane exchange of phospholipids by the lung surfactant protein SP-A. Biochemistry, 37:12178-12188, 1998.


Tozawa, K., Al-Mehdi, A.B., Muzykantov, V. and Fisher, A.B. In situ imaging of intracellular calcium with ischemia in lung subpleural microvascular endothelial cells. Antioxidants and Redox Signaling, 1:145-153, 1999.


Fisher, A.B., Dodia, C., Manevich, Y., Chen, J-W. and Feinstein, S.I. Phospholipid hydroperoxides are substrates for non-selenium glutathione peroxidase. J. Biol. Chem., 274:21326-21334, 1999.


Wei, Z., Costa, K., Al-Mehdi, A.B., Dodia, C., Muzykantov, V. and Fisher, A.B. Simulated ischemia in flow-adapted endothelial cells leads to generation of reactive oxygen species and cell signaling. Circ. Res., In press, 1999.