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The paper “Challenges in the development of chronic pulmonary hypertension models in large animals” in Pulmonary Circulation, published online January 2016, by Abraham Rothman, Robert G. Wiencek, Stephanie Davidson, William N. Evans, Humberto Restrepo, Valeri Sarukhanov, and David Mann ” describes the challenges encountered in the creation of three large animal models of pulmonary hypertension for the purpose of helping other investigators select models, modifications, and techniques for their experimental PH endeavors. The limitations of each model are explained as well as the protocol and technical modifications that lead to more successful model development outcomes. Testing of Vascular BioSciences’ novel endoarterial biopsy catheter in pulmonary arteries with hypertension proved to be successful in all PH large animal models. From the biopsies obtained in these models, investigators can assess molecular and genetic changes and correlate these changes with the progression of the disease in order to develop improved therapies.
The article “A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension” in the upcoming issue of The American Journal of Pathology, Volume 184, Number 2, February 2014 by Michie Toba, Abdallah Alzoubi, Kealan O’Neill, Kohtaro Abe, Takeo Urakami, Masanobu Komatsu, Diego Alvarez, Tero A.H. Jarvinen, David Mann, Erkki Ruoslahti, Ivan F. McMurtry, and Masahiko Oka describes how co-administered CAR selectively enhanced the pulmonary vascular effects of i.v. vasodilators in a Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension (PAH) . A major limitation in the pharmacological treatment of PAH is the lack of pulmonary vascular selectivity. Previous studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues.Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. These results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.
The article “Vascular Histomolecular Analysis By Sequential Endoarterial Biopsy in a Shunt Model of Pulmonary Hypertension” in Pulmonary Circulation, Volume 3, Number 1, January to March 2013, pp. 50-57 by Abraham Rothman, Robert G. Wiencek, William N. Evans, Humberto Restrepo, Valeri Sarukhanov, Erkki Ruoslahti, Roy Williams, and David Mann details how endoarterial biopsy provides a new method of assessing pulmonary vascular histology and gene expression in pulmonary arterial hypertension (PAH). Percutaneous pulmonary endoarterial biopsy coupled with histologic and molecular analysis represents a potential new paradigm for diagnosis and potential treatment of PAH. Histomolecular analysis could become a routine component of the diagnostic information obtained in patients with pulmonary vascular diseases at the time of cardiac catheterization. In addition to obtaining pressures, cardiac output, calculation of pulmonary vascular resistance, angiography and vasodilator testing, endoarterial biopsy with histologic and molecular analysis would add a whole new dimension of biologic information to aid in diagnosis and choice of therapy. This analysis could identify novel applications for existing and new PAH drugs. The detection of stage- and disease-specific variation in gene expression could lead to individualized therapies.
The paper, “Peptide-Directed Highly Selective Targeting of Pulmonary Arterial Hypertension” in American Journal of Pathology 2011; 178(6): 2489-2495, by Takeo Urakami, Tero A.H. Järvinen, Michie Toba, Junko Sawada, Namasivayam Ambalavanan, David Mann, Ivan McMurtry, Masahiko Oka, Erkki Ruoslahti, and Masanobu Komatsu describes the first discovery of a highly selective PAH-targeting and tissue-penetrating cyclic peptide CARSKNKDC (CAR). Injection of CAR resulted in the accumulation of the peptide in induced hypertensive lungs but not healthy lungs or other organs of the PAH rats. CAR also accumulated in various regions of the pulmonary system that play a crucial role in the development and pathogenesis of PAH. These findings support the future utility of CAR in the targeted delivery of therapeutic compounds and imaging probes to PAH lungs.
The paper “Hemodynamic and Histologic Characterization of a Swine (Sus scrofa domestica) Model of Chronic Pulmonary Arterial Hypertension (PAH)” in Comparative Medicne, Volume 61, Number 3, June 2011 , pp. 258-262(5) by Abraham Rothman, Robert G. Wiencek, Stephanie Davidson, William N Evans, Humberto Restrepo, Valeri Sarukhanov, Amanda Rivera-Begeman, and David Mann, describes the use of an experimental endoarterial biopsy catheter to describe the hemodynamic, angiographic, and histologic progression of a swine aortopulmonary shunt model of chronic pulmonary hypertension. The animal model described in this paper showed hemodynamic, angiographic, and histologic characteristics of chronic pulmonary arterial hypertension that mimicked the arterial pulmonary hypertension of systemic-to-pulmonary arterial shunts in humans. The use of the endoarterial biopsy catheter allowed for sequential pulmonary vascular biopsy procedures as the PAH model developed. This PAH large animal model can be used to test therapeutic agents or interventions at several hemodynamic and disease stages, including at baseline prior to shunt surgery, during the initial high-flow but low-pressure state, and during the development of PAH. Experimental data obtained using this and other models and application of an in vivo endoarterial biopsy technique may aid in understanding mechanisms and developing therapies for experimental and human pulmonary arterial hypertension.
The paper “Target seeking antifibrotic compund enhances wound healing and surpresses scar formation in mice” in the Proceedings of the National Academy of Sciences 2010: Vol. 107, No. 50, 21671-21676, by Tero A.H. Järvinen and Erkki Ruoslahti describes a systemically administered, target-seeking biotherapeutic for scar prevention. The biotherapeutic consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin to prevent tissue fibrosis and promote tissue regeneration to reduce scarring.
The paper, “Molecular Changes in the Vasculature of Injured Tissues” in The American Journal of Pathology 2007: Vol. 171, No. 2, 702-711, by Tero A.H. Järvinen and Erkki Ruoslahti describes the initial discovery of the CAR cell penetrating peptide, its wound homing properties and usefulness in delivering treatments into regenerating tissues.
An animal model of lung transplantation was created in order to determine if VCAM mRNA in pulmonary arterial biopsy samples could be a marker of transplant rejection. Please see Increased Expression of Endoarterial Vascular Cell Adhesion Molecule-1 mRNA in an Experimental Model of Lung Transplant Rejection: Diagnosis by Pulmonary Arterial Biopsy by A. Rothman, D. Mann et. al. Transplantation. Vol. 75, No. 7. April 15, 2003. This animal model was developed to demonstrate that endoarterial biopsy samples obtained in a lung transplant model of organ transplant rejection would show an increase in VCAM mRNA levels with increasing rejection. RT-PCR analysis of endoarterial biopsy specimens assessed the allo-immune response on the pulmonary vasculature, which is the first point of contact between the recipient’s immune system and the donor organ. Endoarterial biopsy samples could be useful in the surveillance and early diagnosis of lung transplant rejection.
An animal model of pulmonary hypertension was created by monthly infusions of ceramic microspheres to occlude pulmonary vessels and increase pulmonary arterial pressure. Please see Percutaneous Pulmonary Endoarterial Biopsy in an Experimental Model of Pulmonary Hypertension by A. Rothman, M.D., D. Mann et. al. Chest. Vol. 114, No. 1. July 1998: 241-250. This animal model was developed in order to test the safety and effectiveness of the device at elevated pressures and to study the progressive changes that occur in pulmonary vasculature through the use of a new tool, the endoarterial biopsy catheter.
The endoarterial biopsy catheter was tested in the pulmonary arteries of normotensive animals in order to determine initial feasibility, safety and effectiveness of the device at normal arterial pressures. Please see Transvenous Procurement of Pulmonary Artery Smooth Muscle and Endothelial Cells Using a Novel Endoarterial Biopsy Catheter in a Canine Model by A. Rothman, M.D., D. Mann et. al. Journal of American College of Cardiology. Vol. 27, No. 1. January 1996: 218-224.