Sickle cell disease (SCD) with associated sickle cell lung injury (SCLI) can lead to the development of chronic sickle cell lung disease (CSCLD). CSCLD is characterized as chronic interstitial lung disease with secondary pulmonary hypertension and fibrosis. The discovery of circulating fibrocytes (CD45+Col1+) has now changed our view on the pathogenesis of pulmonary fibrosis. Fibrocytes play a role in mediating pulmonary fibrosis in pre-clinical models. Fibrocytes are found elevated in the circulation and lungs of IPF patients, and the magnitude of their circulating levels is associated with a worse prognosis in these patients. Extending these findings to SCD, we found using a preclinical transgenic mouse model of human SCD that CXC chemokine receptor 4 (CXCR4) expressing fibrocytes play a significant role in promoting pulmonary fibrosis related to the expression of lung-derived CXCL12. In addition, we found that CXCR4+ fibrocytes were elevated in the circulation of patients with SCD. Based on our preliminary data, we generated an overall hypothesis that fibrocytes play a critical role in mediating the pathogenesis of SCLI and development of CSCLD. To test this postulate, we designed the following specific aims to assess fibrocyte biology at the molecular, cellular, pre-clinical animal model, and patient levels to determine if these cells contribute to SCLI and the development of CSCLD: 1. Correlation of fibrocyte localization in SCD mice with fibrosis and vascular remodeling, and elucidation of the role of CXCL12/CXCR4 in promoting BM expansion, BM mobilization, and extravasation of these cells into the lung during the pathogenesis of SCLI: 2. Determination of mTOR inhibition results in down-regulation of CXCL12/CXCR4 and impairment of fibrocyte extravasation in the lungs that directly correlates with attenuation of the pulmonary vascular remodeling and fibrosis during the pathogenesis of SCLI in transgenic SCD animals. 3. Determine whether fibrocyte number and activated phenotype (i.e., (SMA+ and pSmad2/3+ fibrocytes) are associated with restrictive lung disease in adult SCD patients. Long-term objectives of this project will establish that fibrocytes are critical cells in promoting the pathogenesis of SCLI. These findings will support the notion that strategies to target fibrocytes will lead to novel therapies to attenuate their biology in the pathogenesis of CSCLD.

Public Health Relevance

Sickle cell disease is the most common inherited disorder in African-Americans. While improved patient care in Sickle cell disease has led to increased survival of these patients, they unfortunately experience an increase frequency of chronic organ problems, especially related to the lung. These patients can develop a chronic lung condition that is associated with elevated blood pressure and formation of scar tissue in their lungs. The studies in this proposal will focus on the role of a special cell found in the circulation of patients with sickle cell disease that may contribute to the problems we see in the lungs of these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Goldsmith, Jonathan C
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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