Bruce D. Uhal, Ph.D.
Biomedical Physical Sciences Building
567 Wilson Rd Rm 3197
Department of Physiology
Michigan State University
East Lansing, MI 48824
Area of Research Interest (PDF)
Idiopathic Pulmonary Fibrosis (IPF) is the most frequent Interstitial Lung Disease seen by physicians specializing in pulmonary medicine. Despite years of research, there is unfortunately no effective therapy for IPF, and lung transplantation is often the only option. Although it was once thought to be an “inflammatory disease”, IPF is now recognized to be a disorder of “epithelial-mesenchymal imbalance” that results from persistent epithelial damage and activation followed by myofibroblast accumulation and deposition of interstitial collagens types I and III. Our laboratory was among the first to demonstrate that lung epithelial cells in patients with IPF have an unusually high rate of apoptosis (cell suicide), despite being traditionally described by pulmonary pathologists as “hyperplastic”. Apoptosis of lung epithelial cells is now recognized as one of the hallmark features of the histopathology of the IPF lung.
More recently, research in our lab is designed to elucidate the mechanisms that control apoptosis of lung epithelial cells. Experimental models currently in use include mouse and rat models of lung fibrosis, pathologic specimens from patients with IPF and other fibrotic lung diseases, and cell culture models including primary cell isolates of lung epithelial and mesenchymal cells. In all these models, the peptide angiotensin II (ANGII) and its degradation product ANG1-7 were found to be potent regulators of epithelial cell apoptosis and the subsequent fibrotic response. Current work in the lab is focused on the enzyme ACE-2, which degrades ANGII, and the receptor for ANG1-7 (mas) which inhibits the proapoptotic and profibrotic actions of ANGII. This work has provided the basis for several ongoing clinical trials of angiotensin blockers in patients with IPF. It is also identifying potential molecular targets from which new experimental therapeutics will be designed in the future.
Uhal BD, Dang M, Li X, Abdul-Hafez, A. Angiotensinogen gene transcription in pulmonary fibrosis. (Invited Review) Int J Pept. 2012;2012:875910. PMID:22500179.
Uhal B, Li X, Piasecki C and Molina-Molina M. Angiotensin Signalling In Pulmonary Fibrosis (Invited Review). Int J Biochem Cell Biol 44:465– 468, 2011.
Uhal BD, Li X, XueA, Gao X, and Abdul-Hafez A. Regulation Of Alveolar Epithelial Cell Survival By The ACE-2/Angiotensin 1-7/Mas Axis. Am J Physiol, 301: L269-L274, 2011.
Ivanov V, Gewolb I and Uhal BD. A New Look at the Pathogenesis of the Meconium Aspiration Syndrome: A role for fetal pancreatic proteolytic enzymes in epithelial cell detachment. Pediatric Research, 68(3):221-224, 2010.
Abdul-Hafez A, R Shu and BD Uhal. JunD and HIF-1a mediate transcriptional activation of angiotensinogen by TGF-b1 in human lung fibroblasts. FASEB J 23(6):1655-1662, 2009.
Uhal B and A Abdul-Hafez. Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome. (Invited Review) J Perinatology 28:S108-S112, 2008.
Uhal BD. The role of apoptosis in pulmonary fibrosis (Invited Review) Eur Respir Rev 17: 109, 138–143, 2008.
Molina-Molina M, Li X, Abdul-Hafez A, Friderici K, Fu W, Pereda J, Serrano-Mollar A, Casanova A, Rodríguez-Becerra E, Morell F, Ancochea J, Picado C, Xaubet X, Uhal BD. Angiotensinogen gene G-6A polymorphism influences disease progression in idiopathic pulmonary fibrosis. Eur Resp J 32(4):1004-1008, 2008.