We bring together physician scientists to pursue exciting pre-clinical data indicating that the endogenous neutrophil elastase inhibitor, elafin, is a highly effective therapy for three very challenging lung conditions, pulmonary hypertension (PAH), ventilator induced injury of the immature lung and lung transplant rejection. Project I pursues preliminary data supporting the premise that elafin can reverse the endothelial and smooth muscle cell dysfunction in patients with PAH, to allow regeneration of distal blood vessels and regression of obliterative lesions. The previous successful use of elastase inhibitors to reverse experimentally-induced PAH will be extended by assessing whether elafin can cause regression of a rodent pathology that more closely reproduces the hemodynamic and structural features of human disease. We will also determine whether the action of elafin will be enhanced by apelin, since apelin levels are reduced by dysfunctional BMPRII signaling. Project II pursues the successful use of elafin in protecting the mechanically ventilated newborn mouse lung, by reducing TGFB activation, lung cell apoptosis and impaired alveolar formation. Project II determines whether the action of elafin can be enhanced by direct blockade of enhanced TGFIS activity using an antibody or losartan. Project III shows, in exciting preliminary data, that elafin can protect the microcirculation in the murine tracheal transplant model, and prevent airway ischemia associated with bronchiolitis obliterans. This project further investigates the efficacy of combining elafin with low dose immunosuppression or of achieving high levels of elafin by adenoviral mediated gene therapy applied directly to the transplant. In all three projects, biomarkers of elastin degradation are investigated as a tool to judge elafin responsiveness. We will investigate the efficacy of these biomarkers in stratifying patients most likely to respond to elafin. A strong Biomarker Core of skilled clinical investigators coordinates the bioassays, the patient database and the physiological studies of lung and vascular function. The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle.
Our proposal emanates from exciting pre-clinical data indicating that the elastase inhibitor elafin can be used to treat three of the most challenging lung conditions, pulmonary hypertension, ventilator induced injury of the immature lung and lung transplant rejection. We will assess enhancing olefin's action with additional therapies tailored to these conditions. Biomarkers will be developed to help select elafin-responsive patiients.
|Hsu, Joe L; Manouvakhova, Olga V; Clemons, Karl V et al. (2018) Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation. Sci Transl Med 10:|
|Alejandre Alcazar, Miguel A; Kaschwich, Mark; Ertsey, Robert et al. (2018) Elafin Treatment Rescues EGFR-Klf4 Signaling and Lung Cell Survival in Ventilated Newborn Mice. Am J Respir Cell Mol Biol 59:623-634|
|Lin, Y-C; Sung, Y K; Jiang, X et al. (2017) Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. Am J Transplant 17:1229-1241|
|Saito, Toshie; Miyagawa, Kazuya; Chen, Shih-Yu et al. (2017) Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation 136:1920-1935|
|Lama, Vibha N; Belperio, John A; Christie, Jason D et al. (2017) Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight 2:|
|Maron, Bradley A; Hess, Edward; Maddox, Thomas M et al. (2016) Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 133:1240-8|
|Nicolls, Mark R; Hsu, Joe L; Jiang, Xinguo (2016) Microvascular injury after lung transplantation. Curr Opin Organ Transplant 21:279-84|
|Milla, Carlos E; Moss, Richard B (2015) Recent advances in cystic fibrosis. Curr Opin Pediatr 27:317-24|
|Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert et al. (2015) Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice. Am J Physiol Lung Cell Mol Physiol 308:L464-78|
|Nickel, Nils P; Spiekerkoetter, Edda; Gu, Mingxia et al. (2015) Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling. Am J Respir Crit Care Med 191:1273-86|
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