Laboratory of Pulmonary Molecular
Biology and Oxidative Stress

Duke University Medical Center

Molecular Mechanisms of Idiopathic Pneumonia Syndrome (IPS) and Delayed Pulmonary Toxicity Syndrome (DPTS)
Following Autologous Stem Cell Transplantation

"My group has long been interested in understanding why patients develop lung disease following stem cell transplant, predicting who is likely to develop lung toxicity, and in developing strategies to diagnose and treat them should they develop it. Ideally, in the future, we will prevent its occurrence."

RJF

Description:
High dose chemotherapy with autologous bone marrow transplantation and/or peripheral blood
progenitor cell support is becoming a well-established method for treating high risk primary
breast cancer with extensive lymph node involvement. One of the commonest
non-hematological complications of this therapy is pulmonary toxicity, with a reported
incidence of 39% to 64%, usually occurring weeks to months after chemotherapy. The
mechanism(s) by which this delayed pulmonary toxicity develops is not clear but may involve
direct oxidative injury to the lung followed by a delayed inflammatory response. Carmustine (or
BCNU), for example, is know to inhibit glutathione reductase resulting in elevations in oxidized
glutathione in the lung. To further test these hypotheses, we have been developing an animal
model patterned after the chemotherapy given to patients for advanced metastatic breast
cancer. Our clinical research program works closely with members of the Bone Marrow
Transplantation Program. Several clinical studies have involved examining bronchoalveolar
lavage fluid in patients undergoing high dose chemotherapy with autologous bone marrow
support.

Publications by our Group in chronological order:

Wanko, SO, G Broadwater, RJ Folz, NJ Chao. Diffuse alveolar hemorrhage: Retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid. Biology of Blood and Marrow Transplantation, in press, 2006.

Miller KL, Kocak Z, Kahn D, Zhou SM, Baydush A, Hollis D, Folz RJ, Tisch A, Clough R, Yu X, Light K, and Marks LB. Preliminary report of the 6-minute walk test as a predictor of radiation-induced pulmonary toxicity. Int J Radiat Oncol Biol Phys 62:1009-1013, 2005.

Folz RJ and JM Routes. Pulmonary complications of organ transplantation and primary immunodeficiencies. In: The Textbook of Respiratory Medicine. 4'th Edition. Chapter 76. JF Murray, JA Nadel, RJ Mason and VC Broaddus (eds). W.B. Saunders Company, Philadelphia, 2005.

Kocak, Z, ES Evans, SM Zhou, KL Miller, RJ Folz, TD Shafman and LB Marks. Challenges in defining radiation pneumonitis in patients with lung cancer. International Journal of Radiation Oncology, Biology, and Physics, 62:635-638, 2005.

Anscher MS, L Chen, Z Rabbani, S Kang, N Larrier, H Huang, TV Samulski, MW Dewhirst, DM Brizel, RJ Folz, Z Vujaskovic. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy. International Journal of Radiation Oncology, Biology, and Physics, 62:255-259, 2005.

Huang YC, O'brien SR, Vredenburgh J, Folz RJ, Macintyre NR. Intrabreath analysis of carbon monoxide uptake during exercise in patients at risk for lung injury. Respiratory Medicine, in press, 2005.

Crawford SW, RJ Folz, and KM Sullivan. Hematopoietic stem cell transplantation and graft-versus host disease. In: Principles of Critical Care. 3 rd Edition, Chapter 73. JB Hall, GA Schmidt, LDH Wood (eds). McGraw-Hill Companies, NY, 2005.

Kelley MJ, EM Glaser, JE Herndon II, F Becker, R Bhagat, Y-J Zhang, RM Santella, SG Carmella, SS Hecht, L Gallot, L Schilder, JA Crowell, M Perloff, RJ Folz and RC Bergan. Safety and efficacy of weekly oral oltipraz in chronic smokers.Cancer Epidemiol Biomarkers Prev, 14:892-899, 2005.

R Bhagat, DA Rizzieri, JJ Vredenburgh, NJ Chao, RJ Folz. Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence? Chest, 126:642-644, 2004.

RJ Folz. Allogeneic stem cel transplant, lung disease, and airflow obstruction. Am J Respir Crit Care Med, 168:146-147, 2003.

Stuart MJ, WP Peters, G Broadwater, A Hussein, M Ross, LB Marks, RJ Folz, GD Long, D Rizzieri, NJ Chao, JJ Vredenburgh. High-dose chemotherapy and hematopoietic support for patients with high-risk breast cancer and involvement of 4 to 9 lymph nodes. Biol Blood Marrow Transplant, 8:666-673, 2002.

Abushamaa AM, TA Sporn, RJ Folz. Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen. Am J Physiol Lung Cell Mol Physiol, 283:L336-L345, 2002.

Bhalla KS and RJ Folz. Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice. Am J Respir Crit Care Med, 166:1579-1589, 2002.

Garantziotis S, KS Bhalla, GD Long, JJ Vredenburgh, RJ Folz. Fatal re-expansion pulmonary edema associated with increased lung IL-8 levels follwoing high-dose chemotherapy and autologous stem cell transplant. Respiration, 69:351-354, 2002.

McGaughey DS, GD Long, JJ Vredenburgh, D Rizzieri, CA Smith, RJ Folz, G Broadwater and NJ Chao. Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing high-dose chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant, 7:274-278, 2001.

Wright JR, P Borron, K Brinker, and RJ Folz. Surfactant Protein A: Regulation of Innate and Adaptive Immune Responses in Lung Inflammation. Am J Respir Cell Mol Biol, 24:513-517, 2001.

Bhagat R, TA Sporn, GD Long, RJ Folz. Amiodarone and cyclophosphamide: Potential for Enhanced Lung Toxicity. Bone Marrow Tranplant, 27:1109-1111, 2001.

Maddox L, GD Long, JJ Vredenburgh, RJ Folz. Rhizopus presenting as an endobronchial obstruciton following bone marrow transplant. Bone Marrow Transplant, 28:634-636, 2001.

Bhalla KS, SW Wilczynski, AM Abushamaa, WP Petros, CS McDonald, JS Loftis, NJ Chao, JJ Vredenburgh, RJ Folz. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous stem cell support. Am J Resp Crit Care Med, 161:17-25, 2000.

Folz RJ. Mechanisms of lung injury following bone marrow transplantation. Am J Resp Cell Mol Biol, 20:1097-1099, 1999.

Folz, RJ and MA Elkordy. Coronavirus pneumonia following autologous bone marrow transplantation for breast cancer. Chest, 115:901-905, 1999.

Wilczynski SW, JJ Erasmus, WP Petros, JJ Vredenburgh, RJ Folz. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med, 157:565-573, 1998.
See these related press releases: article 1, article 2, article 3, article 4.

Contact me by Email at folz0001atduke.edu
or snail mail at
Duke University Medical Center
Box 2620
Durham, NC 27710
919-684-3539 (office)
919-681-8936 (fax)