Basic Science Research
Pulmonary vascular disease is a growing problem in many systemic diseases. In disease states, such as systemic sclerosis and hemolytic anemias, in which patient survival has increased dramatically in recent years, pulmonary complications, especially vascular ones, have become the leading cause of morbidity and mortality.
The mechanisms involved in development of pulmonary hypertension (PH) regardless of etiology is not well-understood. The object of our studies is to define pathogenic mechanisms, essential for the development of these vascular abnormalities and use them to try to direct new therapies. Lastly, each of these entities can be associated with relative or absolute hypoxemia; thus, we have been investigating the effects of hypoxia on pulmonary vascular endothelium and methods to mitigate its effect.
The projects in our research group are linked by the underlying pulmonary vascular abnormalities they engender:
Sickle cell anemia:
Approximately 6-10% of adults with sickle cell disease have pulmonary hypertension which is an independent risk factor for mortality. We have been interested in studying genetic modulators of sickle cell disease that place patients at risk for the development of PH. We are in the process of performing genome wide association studies of the largest cohort of prospectively collected SCD patients with cardiopulmonary phenotypes (the SickleGen consortium) to determine genetic variants associated with PH. We have begun to undertake functional studies of these genes within the endothelium. Additionally, we have continued our collaborations with the Cardiovascular Proteomics Center to develop technologies to use the plasma proteome to better understand the biology of PH of SCD and to develop novel biomarkers for diagnosis.
Systemic sclerosis (SSc) is characterized by autoimmunity, a small-vessel vasculopathy, and eventually fibrosis producing damage in multiple organ systems PH is a well-described complication of SSc and occurs in 10-50% of patients depending on the study and the mode of diagnosis. The incidence of PH increases with duration of disease, later age of onset , and is greater in male patients and in those with limited SSc. Moreover, PH is a leading cause of mortality in SSc patients and may be increasing due to longer life span of these patients. Unlike the PH resulting from parenchymal lung disease and hypoxemia observed in diffuse SSc, the histology of PH associated with limited SSc is identical to other forms of PAH and is suggestive of dysregulated angiogenesis. In contrast to the evidence for excessive angiogenesis in vascular lesions of PAH, early vascular damage in SSc is characterized by EC apoptosis. In addition, serum from SSc patients contains factors such as anti-endothelial cell antibodies that not only can induce EC apoptosis but also are associated with the presence and severity of PH. These observations raise the intriguing possibility that PAH in SSc arises from an initial induction of EC apoptosis, selection of an apoptosis-resistant population of EC and the subsequent excessive angiogenesis observed in the vascular lesions of established SSc-PAH. Using genomic and proteomic technology, we are investigating the hypotheses that: 1) the vascular changes in SSc-PAH result from EC dysfunction, apoptosis and subsequent excessive angiogenesis; and 2) that specific markers of apoptosis and/or angiogenesis define distinct phenotypes in the SSc population that predict development of PAH and response to treatment.
Adiponectin is an adipose tissue-derived hormone that is secreted at high concentrations into the serum of lean healthy individuals but paradoxically decreases with increasing body fat. Interest in this hormone relates to its multi-functional role in metabolism, immune regulation and vascular homeostasis. We recently showed that adiponectin binds to the pulmonary endothelium in mice under basal, non-stressed conditions and that targeted gene deletion leads to development of spontaneous lung abnormalities characterized by activated endothelium, peri-vascular inflammatory cell infiltration and elevated pulmonary artery pressures. In addition, we showed in response to select agonists, adiponectin deficient mice are at increased risk for developing acute lung injury, and this occurs, at least in part, because of exaggerated inflammatory responses in lung endothelium. Ongoing studies are investigating the downstream signaling pathways mediating adiponectin’s anti-inflammatory and tissue protective effects on lung vascular cells. The long-term goals of this work are to identify new avenues of research in lung vascular biology and to lay the foundation for the rational design of clinical trials examining the role of adiponectin and its signaling pathways in lung vascular disease.
Current research projects:
- Understanding the role of adiponectin in modulating pulmonary vascular disease
- Genomics of pulmonary hypertension related to sickle cell disease
- The use of plasma proteomics to identify plasma peptides and oxidative post-translational modifications associated with pulmonary arterial hypertension of sickle cell disease
- Use of genomics and proteomics to identify genetic abnormalities associated with PH of systemic sclerosis
- Harrison W. Farber
- Elizabeth S. Klings
- Surinder Safaya
- Clinton T. Baldwin
- Jean-Bosco Tagne
- Robert Lafyatis
- Robert Simms
- Ross Summers
- Christmann RB, Hayes E, Pendergrass S, Padilla C, Farina G, Affandi AJ et al. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum 2011; 63(6):1718-1728.
- Pendergrass SA, Hayes E, Farina G, Lemaire R, Farber HW, Whitfield ML et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One 2010; 5(8):e12106.
- Safaya S, Klings ES, Odhiambo A, Li G, Farber HW, Steinberg MH. Effect of Sodium Butyrate on TNFSF15 (Vascular Endothelial Growth Inhibitor, TL1A) Expression in Lung Endothelium: Cell-Specific and Sequence-Selective Expression of TNFSF15. Cytokine 2009;46:72-78.
- Akinsheye I, Klings ES. Sickle Cell Anemia and Vascular Dysfunction: the Nitric Oxide Connection. J Cell Physiol 2010; 224:620-625. PMID: 20578237.
- Dworkis DA, Klings ES, Solovieff N, Li G, Milton JN, Hartley SW, Melista E, Parente J, Sebastiani P, Steinberg MH, Baldwin CT. Role of Tumor Necrosis-Alpha Signaling in Sickle Cell Disease: Elevated Biomarker Levels and Genetic Associations with Disease Severity. Am J Hematol 2011; 86:220-3.
- Dworkis DA, Klings ES, Shenouda S, Solovieff N, Melista E, Giovannucci C, Safaya S, Li G, Vita J, Steinberg MH, Baldwin CT. Endothelial response to TNF-α in an ARFGEF2 siRNA knockdown model: Enhanced expression of ICAM1, VCAM1 and Transgelin. 2011 (manuscript under review).
- Konter, J., Li, S., Parker, J., Ouchi, N., Fine, A., Walsh, K., Summer, R. Adiponectin attenuates LPS-induced acute lung injury in mice. Journal of Immunology., Under review
- Walkey, A., Rice, T., Konter, J., Ouchi, N., Shibata, R., Walsh, K., deBoisblanc, B., Summer, R. Plasma Adiponectin and Clinical Outcomes in Critically Ill Subjects with Respiratory Failure. Critical Care Medicine 2010 Dec;38(12):2415-6. Editorial focus
- Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Amstrup Pedersen A, Kalthoff C, Tullin S, Sams A, Summer R, Walsh K. Adiponectin promotes macrophage polarization towards an anti-inflammatory phenotype. J Biol Chem. 2009 Dec 22.
- Summer, R., Fiack, C.A., Farber, H., Dwyer, D., Fine, A., Ouchi, N., Yasumasa, I., Walsh, K., Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol. Accepted June 2009. Editorial focus.
- Summer, R., Little, F, Ouchi, N, Takemura,Y, Aprahamian, T., Dwyer, D, Fitzsimmons, K., Suki, B., Parameswaran, H., Fine, A., Walsh, K. Alveolar macrophage activation and an emphysema-like phenotype in adiponectin deficient mice. Am J Physiol Lung Cell Mol Physiol. Jun;294(6):L1035-42.2008. Editorial focus.
- Murphy, J., Summer, R., Wilson, A., Kotton, D., Fine, A. The Prolonged Life-span of Alveolar Macrophages Am J Respir Cell Mol Biol. 2008 Apr;38(4):380-5. 2008.
- Takemura Y, Ouchi N, Shibata R, Aprahamian T, Kirber MT, Summer R., Kihara S, Walsh K. Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J Clin Invest. 2007 Feb;117(2):375-86.