III

The University of Rochester is the regional referral center for patients with echo estimated pulmonary hypertension. We take care of ~170 patients with WHO Group 1 classified Pulmonary Arterial Hypertension. I was a lead enroller and study author in the Phase III pivotal trial for tadalafil, and we continue to make significant contributions to the development of oral treprostinil (Remodulin). We are actively participating in the Reveal registry. We use subcutaneous treprostinil (about 50 patients), inhaled iloprost, bosentan, ambrisentan, tadalafil and sildenafil in combinations best tailored to a particular patients needs. We provide a strong link to San Diego for our patients with chronic thromboembolic pulmonary hypertension.

The overall goal of my bench laboratory is to understand the vascular biology which causes severe pulmonary arterial hypertension. Our main approach is with a rat model that recapitulates the histopathology, severe hemodynamic alterations, and right ventricular heart failure seen in advanced human disease. This rat model employs pneumonectomy (promotes contralateral lung growth) and endothelial injury (monocrotaline) to cause lethal pulmonary hypertension in about 4 weeks. Our animals die earlier with a more severe phenotype, and we have presented the first report of plexiform lesions. We have developed a novel CT angiography to assess for vascular pruning during disease progression, and we are also utilizing invasive techniques to measure pressure and cardiac output in awake, behaving animals. We hypothesize that tissue factor (the membrane bound glycoprotein which initiates coagulation) is an important contributor to disease progression, and we are actively testing small molecule inhibitors of tissue factor and thrombin as novel therapies in this devastating disease.

A second line of investigation seeks to define the role of thrombin and the PAR1 receptor in PH. In endothelial cells isolated from the rat pulmonary microvasculature, PAR1 activation promotes migration, wound closure, and tube formation in in vitro angiogenesis assays. The migratory activity is dependent on the matrix (fibronectin or collagen) and the microvascular endothelial cells behave differently than those derived from the proximal pulmonary artery. We hypothesize that plexiform lesions result from exuberant proliferation after these cells migrate to sites of injury rich in a fibronectin matrix. This is the work of the recently graduated M.D. Ph.D. student in my laboratory, David Meoli.

• Pride DT, Salzman J, Haynes M, Rohwer F, Davis-Long C, White RA, Loomer P, Armitage GC, Relman DA. Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome. ISME J. 2012 May; 6(5):915-26.
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• Ferrantino M, White RJ. Inhaled treprostinil sodium for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2011 Nov; 12(16):2583-93.
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• White RA, Quake SR, Curr K. Digital PCR provides absolute quantitation of viral load for an occult RNA virus. J Virol Methods. 2012 Jan; 179(1):45-50.
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• Yee M, White RJ, Awad HA, Bates WA, McGrath-Morrow SA, O'Reilly MA. Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice. Am J Pathol. 2011 Jun; 178(6):2601-10.
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• Jiang N, Weinstein JA, Penland L, White RA, Fisher DS, Quake SR. Determinism and stochasticity during maturation of the zebrafish antibody repertoire. Proc Natl Acad Sci U S A. 2011 Mar 29; 108(13):5348-53.
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• Levin YD, White RJ. Novel therapeutic approaches in pulmonary arterial hypertension: focus on tadalafil. Drugs Today (Barc). 2011 Feb; 47(2):145-56.
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• White RJ, Hiremath J. Rationale for the judicious use of placebos in PAH trials. J Heart Lung Transplant. 2010 Jul; 29(7):826-7.
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• Meoli DF, White RJ. Thrombin induces fibronectin-specific migration of pulmonary microvascular endothelial cells: requirement of calcium/calmodulin-dependent protein kinase II. Am J Physiol Lung Cell Mol Physiol. 2009 Oct; 297(4):L706-14.
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• Weinstein JA, Jiang N, White RA, Fisher DS, Quake SR. High-throughput sequencing of the zebrafish antibody repertoire. Science. 2009 May 8; 324(5928):807-10.
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• White RA, Blainey PC, Fan HC, Quake SR. Digital PCR provides sensitive and absolute calibration for high throughput sequencing. BMC Genomics. 2009; 10:116.
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• Pang J, Hoefen R, Pryhuber GS, Wang J, Yin G, White RJ, Xu X, O'Dell MR, Mohan A, Michaloski H, Massett MP, Yan C, Berk BC. G-protein-coupled receptor kinase interacting protein-1 is required for pulmonary vascular development. Circulation. 2009 Mar 24; 119(11):1524-32.
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• Gough MS, White RJ. Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension. Liver Transpl. 2009 Jan; 15(1):30-6.
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• White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, Miller CM, Blaxall BC, Hall CM, Pierce RA, Cool CD, Taubman MB. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2007 Sep; 293(3):L583-90.
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• White RJ, Galaria II, Harvey J, Blaxall BC, Cool CD, Taubman MB. Tissue factor is induced in a rodent model of severe pulmonary hypertension characterized by neointimal lesions typical of human disease. Chest. 2005 Dec; 128(6 Suppl):612S-613S.
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