Bethany B. Moore, Ph.D.
Associate Professor,
Internal Medicine, Pulmonary Division

bmoore@umich.edu

My laboratory has two basic areas of interest. Our primary focus involves the pathogenesis of pulmonary fibrosis and the second interest involves bacterial complications of bone marrow transplantation. Pulmonary fibrosis is a disease, often of unknown etiology, that results in the progressive accumulation of extracellular matrix (collagen) deposition within the lung resulting in a loss of gas exchange and death from respiratory insufficiency. The excessive collagen deposition that occurs in fibrosis is the result of activation and differentiation of fibroblasts into cells called myofibroblasts. These myofibroblasts express certain smooth muscle cell proteins that allow the myofibroblasts to contract the lung architecture. The combination of this contractile phenotype with the increased collagen synthetic capacity of these cells makes them the pathologic entity in this disease process. Many clinical associations suggest that viral infections may be associated with fibrotic illness. To model this, we are using the murine gamma herpesvirus, MHV-68 which we have shown augments experimental pulmonary fibrosis. Current projects are seeking to identify the mechanisms involved in this process. We are looking at the types of cells in the lung that are infected, how infection alters the phenotype and functions of these cells, and whether lytic vs. latent infection is required. A second area of fibrosis research involves studying the origin of myofibroblasts in fibrotic disease. Fibroblasts are resident cells within the lung and the common belief was that fibrotic disease resulted from an inappropriate activation of the local lung fibroblasts. In general, circulation of mesenchymal cells was not well appreciated. However, we have recently demonstrated that a population of bone-marrow-derived circulating precursor cells called fibrocytes can give rise to myofibroblasts within fibrotic lung. We have been able to demonstrate that these cells are recruited to the lung in response to chemokine signals (CCL2) and that this chemokine can cause the activation of collagen secretion by fibrocytes. We are currently working to understand how fibrocytes differentiate into myofibroblasts within fibrotic lungs. This work is particularly exciting to us because it provides a link between the inflammatory response to lung injury and the fibrotic outcomes. Of interest, MHV-68 infection recruits fibrocytes to the lung.

The other area of interest in our laboratory involves studying bacterial infections following bone marrow transplantation. Following syngeneic bone marrow transplantation, mice are more susceptible to infection with the nosocomial pathogen Pseudomonas aeruginosa despite bone marrow reconstitution. We have determined that this increased susceptibility relates to phagocytic defects in the bone-marrow transplant derived lung macrophages. Thus, we are currently examining the role that cytokines and chemokines play in recruiting and activating lung macrophages in response to infection in our transplanted and control mice. Our preliminary results suggest that transplant conditioning alters the ability of the lung to produce INF gamma in response to infection, and thus there is a deficiency in phagocyte activation. We have also found significant differences in PGE2 and leukotriene levels in the BMT mice which could explain the phagocytic defects in the alveolar macrophages. We have also observed that BMT mice are more susceptible to viral infections, thus we are exploring adaptive immune defects in these mice.

Recent Publications

Moore, BB, R Paine, III, PJ Christensen, S Sitterding, TA Moore, R Ngan, CA Wilke, WA Kuziel, GB Toews. Protection from Pulmonary Fibrosis in the Absence of CCR2 Receptor Signaling. 2001. J. Immunol. 167:4368-4377.

Peters-Golden,M, M. Baile, T Marshall, C Wilke, S Phan, GB Toews and BB Moore. Protection from Pulmonary Fibrosis in Leukotriene Deficient Mice. 2002. Am J. Resp. Crit. Care Med. 165:229-235.

Moore, BB, Peters-Golden, M, Christensen, PJ, Lama, V, Kuziel, WA, Paine, R, and GB Toews. Alveolar Epithelial Cell Inhibition of Fibroblast Proliferation is Regulated by MCP-1/CCR2 and Mediated by PGE2. 2003. Am. J. Physiol. Lung Cell Mol. Physiol. 284(2):L342-9.

Charbenneau R.P., Christensen, P.J., Chrisman, C.J., Paine, R. III, Toews, G.B. Peters-Golden, M. and B.B. Moore. 2003 Defective Production of PGE2 by Lung Fibroblasts and Alveolar Epithelial Cells from GM-CSF -/- Mice: Implications for Fibroproliferation. Am. J. Physiol. Lung Cell Mol Physiol. 284:L1103-1111.

Kolodsick, J.E., Peters-Golden, M., Larios, J., Toews, G.B., Thannickal, V.J., and Moore, BB. 2003. PGE2 Inhibits Myofibroblast Differentiation via EP2 Signaling and cAMP Elevation . Am J. Resp. Cell Mol. Biol. 29: 537-544

Ojielo, CI, Cooke, D., Mancuso, P., Moore, TA, Standiford, TJ, Olkiewicz, KM, Toews, GB, and BB Moore. 2003, Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation J. Immunol. 171:4416-4424

Kolodsick, JE, Toews, GB, Jakubzick, C, Hogaboam, C, Moore, TA, McKenzie, A, Wilke, CA, Chrisman, CJ and BB Moore. 2004. Protection from FITC-Induced Fibrosis in IL-13 Deficient, but not IL-4 Deficient Mice Results from Impaired Collagen Synthesis by Fibroblasts. J. Immunol. 172; 4068-4076.

Moore, BB, JE Kolodsick, VJ Thannickal, K Cooke, T.A. Moore, C Hogaboam, CA Wilke and GB Toews. 2005. CCR2-mediated recruitment of fibrocytes to the alveolar space following fibrotic injury and their differentiation into effector fibroblasts. Am. J. Pathol. 166:675-684.

Moore, BB, Ballinger, MN, Green, M, Podsiad, A, Wilke , CA , Toews, GB and M.Peters-Golden. 2005. Changes in Fibroblast E Prostanoid (EP) Receptor Profiles Alter Responsiveness to PGE 2 During Experimental Pulmonary Fibrosis. J. Immunol.174(9):5644-9.

Ballinger, MN , Paine, R., Serazani, C. H., Aronoff, D, M., Choi, E.S., Standiford, TJ, Toews, GB and BB Moore. 2006. Role of GM-CSF During Gram Negative Lung Infection with Pseudomonas aeruginosa . Am. J. Resp. Cell Mol. Biol. 34(6):766-774.

Moore, BB, Murray, LA , Das, A., Wilke, CA , Herrygers, AB and GB Toews. 2006. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am. J. Resp. Cell Mol. Biol. 35:175-181

Ballinger , MN , Aronoff, DM, McMillan, TR, Cooke, KR, Olkiewicz, K, Toews, GB, Peters-Golden, M and BB Moore. 2006. Critical Role of Prostaglandin E 2 Overproduction in Impaired Pulmonary Host Response Following Bone Marrow Transplantation. J. Immunol . 177:5499-5508.

Ballinger, MN , McMillan, TR and BB Moore. 2006. Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantation. Arch. Immunol. Ther. Exp. 55:1-12.