The overall focus of the laboratory is to study genes that regulate lung development. The lung is a highly specialized organ that is derived from mesoderm and endoderm which through inductive interactions undergoes a series of branching morphogenetic events and cellular differentiation. The mature lung contains nearly 40 distinct cell types whose interactions are necessary for both normal homeostasis as well as response to injury with subsequent repair. Because hyperoxia causes substantial hypertrophy and cell death with repair processes that appear to recapitulate developmental processes observed during embryonic development, we have chosen to utilize this model to identify and characterize molecular signals that regulate pulmonary cell proliferation and differentiation.

The current research focuses on understanding molecular signals that regulate the cell cycle during and following exposure to hyperoxia. The two projects that are presently ongoing are to clarify the roles of transforming growth factor-b (TGF-b) and the tumor suppressor protein p53 in oxidant lung injury. TGF-b is a multifunctional cytokine which regulates cell proliferation and differentiation, production of extracellular matrix and genes involved in the inflammatory response. Expression of TGF-b is dynamic during normal lung development and is significantly increased during oxidant lung injury. The p53 gene product regulates cell growth and death in response to genotoxic stimuli. The importance of p53 in maintaining normal lung phenotype is exemplified by the observations that 90% of all pulmonary tumors have mutant forms of p53 and that p53 expression is induced during oxidant lung injury, as well as the proliferation and differentiation responses observed during the recovery period. These hypotheses are being tested with genetically manipulated (transgenic/knock-out) cell lines and mouse models that are exposed and recovered from hyperoxia.

O’Reilly MA 2001. DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair. Am J Physiol Lung Cell Mol Physiol Aug;281(2):L291-305

O’Reilly MA, Staversky RJ, Watkins RH, Reed CK, de Mesy Jensen KL, Finkelstein JN, Keng PC. 2001. The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress. Am J Respir Cell Mol Biol Jun;24(6):703-10.

Rancourt RC, Keng PC, Helt CE, and O’Reilly MA. 2001. The role of p21(CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol. Apr;280(4):L617-626.

O’Reilly MA, Staversky RJ, Huyck HL, Watkins RH, LoMonaco MB, D’Angio CT, Baggs RB, Maniscalco WM, and Pryhuber GS. 2000. Bcl-2 family gene expression during severe hyperoxia induced lung injury. Lab Invest. Dec;80(12):1845-54.

Johnston, C.J., Driscoll, K.E., Finkelstein, J.N., Baggs, R., O’Reilly, M.A., Carter, J., Gelein, R, and Oberdorster, G. 2000. Pulmonary Chemokine and Mutagenic Responses in Rats after Subchronic Inhalation of Amorphous and Crystalline Silica. Toxicol. Sci. 56(2):405-413.

O’Reilly, M.A., Staversky, R.J., Watkins, R.H., Maniscalco, W.M., and Keng, P.C. 2000. p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 278(3):L552-L559.

Pryhuber, G.S., Huyck, H.L., Staversky, R.J., Finkelstein, J.N., O’Reilly, M.A. 2000. Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2. Am. J. Respir. Cell Mol. Biol. 22(2):150-6.

Rancourt, R.C., Staversky, R.J., Keng, P.C.,and O’Reilly, M.A. 1999. Hyperoxia inhibits proliferation of Mv1Lu epithelial cells independent of TGF-beta signaling. Am. J. Physiol. 277(6 Pt 1):L1172-8.

O’Reilly, M.A., Staversky, R.J., Watkins, R.H., and Maniscalco, W.M. 1998. Accumulation of p21 Cip1/WAF1 during hyperoxic lung injury in mice. Am. J. Respir. Cell Mol. Biol. 19: 777-785

O’Reilly, M.A., Staversky, R.J., Stripp, B.R., and Finkelstein, J.N. 1997. Exposure to hyperoxia induces p53 expression in mouse lung epithelium. Am. J. Respir. Cell Mol. Biol. 18:43-50.

O’Reilly, M.A., Staversky, R.J., Flanders, K. C., Johnston, C.J., and Finkelstein, J.N. 1997. Temporal changes in expression of TGF-beta isoforms in mouse lung exposed to oxygen. Am. J. Physiol. (Lung Cell. Mol. Physiol.), L60-L67.

O’Reilly, M.A., Stripp, B.R., and Pryhuber G.S. 1997. Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury. 1997. Microsc Res Tech. 38(5):473-479.

Glick, A.B., Kulkarni, A., Tennenbaum, T., Hennings, H., Flanders, K.C., O’Reilly, M., Sporn, M. B., Karlsson, S., and Yuspa, S. H. 1993. Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc. Nat. Acad. Sci. USA, 90: 6076-6080.

Kim, S.-J., Wagner, S., Liu, F., O’Reilly, M.A., Robbins, P. D., and Green, M. R. 1992. Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Nature 358: 331-334.

O’Reilly, M.A., Geiser, A.G., Kim, S.-J., Bruggerman, L. A., Luu, A.X., Roberts, A.B., and Sporn, M. B. 1992. Identification of an activating transcription factor (ATF) binding site in the human transforming growth factor-beta 2 promoter. J. Biol. Chem. 267: 19938-19943.

O’Reilly, M.A., Danielpour, D., Roberts, A.B., and Sporn, M.B. 1992. Regulation of expression of transforming growth factor-beta 2 by transforming growth factor-beta isoforms is dependent upon cell type. Growth Factors, 6: 193-202.

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