|Chunhua Fu, PhD
Summary of Research
What contribution do bone marrow derived cells make to vascular remodeling in the lungs, enhancing the progression of pulmonary hypertension? Is there a cell population that could serve as a potential master regulator in coordinating the innate and adaptive immune responses that result in pulmonary vascular disease? Our lab’s most recent work supports such a role for myeloid-derived suppressor cells (MDSCs) in the pathogenesis of PH secondary to chronic lung disease such as COPD or idiopathic pulmonary fibrosis (IPF). These cells are known to facilitate immunosuppressive privileges within the tumor microenvironment, leading to growth of cancerous cells, and metastases. We have demonstrated that a particular sub-population of MDSCs that appear phenotypically and morphologically similar to immature granulocytes (granulocytic-MDSCs; G-MDSCs) are necessary for the development of the pulmonary hypertension in the bleomycin-induced pulmonary fibrosis, and chronic hypoxia, models of disease. They do so, at least in part, through CXCR2-coordinated cell trafficking to the lung, and upregulation of arginase-1 and iNOS. This discovery opens up a completely novel method of approaching the problem of pulmonary hypertension therapeutic development, shifting focus away from vasodilatory agents to those that influence accumulation and activation of circulating myeloid-cell populations.
Additionally, while it is known that hypoxic signaling through the transcription factor hypoxia-inducible factor (HIF) plays an important role in the development of pulmonary hypertension secondary to chronic hypoxia, the role of HIF in the development of elevated pulmonary pressure in response to chronic lung disease, such as idiopathic pulmonary fibrosis (IPF), was heretofore unknown. Our lab has developed a transgenic mouse model with deletion of HIF in the vascular endothelium, demonstrating protection against development of pulmonary hypertension in both a bleomycin-induced fibrosis, and chronic hypoxia, model of disease. This work is important for several reasons: (1) Establishment of the vascular endothelium as the cell type of interest in disease pathogenesis represents not only an innovative mechanism for pulmonary hypertension secondary to chronic lung disease, but a more specific target for pharmacotherapies, through currently available vector delivery systems. (2) HIF-regulated genes, such as connective tissue growth factor (CTGF), have readily available systemic therapies that can be studied in our disease models for significant translational impact. (3) Finally, our group demonstrated the direct relevance of HIF-signaling within the vascular endothelium to patients with IPF with pulmonary hypertension. In total, we demonstrate that vascular endothelial HIF signaling is necessary for development of both hypoxia and pulmonary fibrosis associated pulmonary hypertension. Thus, HIF and HIF-regulated targets represent a therapeutic target in these conditions.
Active Research Projects/Grants
- University of Florida Clinical and Translational Science Institute,“Vascular Hypoxic Signaling Regulation of Pulmonary Hypertension,” Pearson (P1), 01/16/2016-12/01/2017.
- Gilead Sciences Research Scholars Program in Pulmonary Hypertension“Role of myeloid-derived suppressor cell trafficking in development of pulmonary hypertension,” Bryant (PI), 01/17/2017-12/31/2018.
- American Lung Association — Biomedical Research Grant, “Role of CXCR2-mediated cell trafficking in pulmonary hypertension,” Bryant (PI), 07/01/2017-06/30/2018.
- Institutional Start-Up Funds. University of Florida College of Medicine, Gatorade Fund, Bryant (PI), 07/01/2014- 06/30/2018.
- Margaret Q. Landenberger Research Program, Bryant (PI) 01/31/2017-01/31/2019.
Completed Research Projects/Grants
- University of Florida Institute on Aging, UF OAIC Pilot Award, Leeuwenburgh (PI), 08/01/2015-03/31/2016.
- NIH/NHLBI, “Clinical and Translational Research Training Program in Pulmonary Medicine,” Bernard (PI), 041/01/2007-06/30/2014.
- American Thoracic Society $50,000, “Hypoxia Inducible Factor Regulation of Secondary Pulmonary Hypertension,” Bryant (PI), 01/15/13-01/14/14.
- Bryant AJ, Shenoy V, Fu Chunhua, Marek G, Lorentsen KJ, Herzog EL, Brantly ML, Avram D, Scott EW. Myeloid-derived suppressor cells are necessary for the development of pulmonary hypertension. Am J Respir Cell Mol Biol. 2017 (In press).
- Bryant AJ, Carrick RC, McConaha ME, Jones BR, Shay SD, Moore CS, Blackwell TR, Gladson S, Penner NL, Burman A, Tanjore H, Hemnes AR, Karwandyar AK, Polosukhin VV, Talati MA, Dong H-J, Gleaves LA, Carrier EJ, Gaskill C, Scott EW, Majka SM, Fessel JP, Haase VH, West JD, Blackwell TS, Lawson WE. Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 1;310(3):L249-62.
- Bryant AJ and Scott EW. “A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension. Receptors Clin Investig. 2016;3(1). pii: e1213. Epub 2016 Mar 14.
- Bryant AJ, Robinson LJ, Moore CS, Blackwell T, Gladson S, Penner NL, Burman A, McClellan LJ, Polosukhin V, Tanjore H, McConaha ME, Gleaves LA, Talati M, Hemnes AR, Fessel JP, Blackwell TS, Lawson WE, and West J. Expression of mutant BMPR2 worsens pulmonary hypertension secondary to pulmonary fibrosis. Pulm Circ. 2015 Dec;5(4):681-90.
- PubMed: https://www.ncbi.nlm.nih.gov/sites/myncbi/1nOMrXCyL6CkP/bibliography/48049119/public/?sort=date&direction=ascending