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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108797-03
Application #
8484430
Study Section
Special Emphasis Panel (ZHL1-PPG-A (M1))
Program Officer
Moore, Timothy M
Project Start
2011-08-17
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$2,045,899
Indirect Cost
$639,861
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Jiang, Xinguo; Sung, Yon K; Tian, Wen et al. (2014) Graft microvascular disease in solid organ transplantation. J Mol Med (Berl) 92:797-810
Khan, Mohammad Afzal; Nicolls, Mark R; Surguladze, Besiki et al. (2014) Complement components as potential therapeutic targets for asthma treatment. Respir Med 108:543-9
Rabinovitch, Marlene; Guignabert, Christophe; Humbert, Marc et al. (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165-75
Beraud, Anne-Sophie; Guillamet, Cristina Vazquez; Hammes, Jessie L et al. (2014) Efficacy of transthoracic echocardiography for diagnosing heart failure in septic shock. Am J Med Sci 347:295-8
Jiang, Xinguo; Tian, Wen; Sung, Yon K et al. (2014) Macrophages in solid organ transplantation. Vasc Cell 6:5
Singh, Amar Bahadur; Li, Hai; Kan, Chin Fung Kelvin et al. (2014) The critical role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein d in 3' untranslated region-mediated decay of low-density lipoprotein receptor mRNA in liver tissue. Arterioscler Thromb Vasc Biol 34:8-16
Tian, Wen; Jiang, Xinguo; Sung, Yon K et al. (2014) Leukotrienes in pulmonary arterial hypertension. Immunol Res 58:387-93
Sawada, Hirofumi; Saito, Toshie; Nickel, Nils P et al. (2014) Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med 211:263-80
Jiang, Xinguo; Nicolls, Mark R (2014) Working toward immune tolerance in lung transplantation. J Clin Invest 124:967-70
Jiang, Xinguo; Malkovskiy, Andrey V; Tian, Wen et al. (2014) Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. Biomaterials 35:803-13

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