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977 Placenta Growth Factor Links the IL-13 Response and the Leukotriene Pathway to Augment Airway Hyper-Responsiveness

Hemoglobinopathies, Excluding Thalassemia – Basic and Translational Science
Program: Oral and Poster Abstracts
Session: 113. Hemoglobinopathies, Excluding Thalassemia – Basic and Translational Science: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Marthe-Sandrine Eiymo Mwa Mpollo, PhD1*, Eric Brandt, PhD2*, Shiva Kumar Shanmukhappa, DVM, PhD3*, Paritha Arumugam, PhD4*, Swati Tiwari5*, Anastacia Loberg5*, Tilat Rizvi, PhD6*, Mark Lindsey2*, Bart Jonckx, PhD7*, Peter Carmeliet, Prof MD, PhD8*, Vijay Kalra9*, Timothy Lecras, PhD10*, Nancy Ratner, PhD6*, Marsha wills-Karp, PhD11*, Gurjit Khurana hershey, MD, PhD2* and Punam Malik, MD12

1Cincinnati Children's Medical center, Cincinnati, OH
2Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati
3Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati
4Translational Pulmonary Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
5Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati
6Division of Experimental Hematology and Cancer and Blood Institute, Cincinnati Children's Hospital Medical Center, Cincinnati
7ThromBogenics, Leuven, Belgium
8Laboratory of Angiogenesis and Neurovascular Link, VIB - Katholieke Universiteit Leuven, Vesalius Research Center, LEUVEN, Belgium
9University of Southern California, Los Angeles
10Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati
11Johns Hopkins Bloomberg School of Public Health., baltimore
12Divisions of Hematology, Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Airway hyper-responsiveness (AHR) affects 55-77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the underlying mechanisms of this highly prevalent AHR in a hemoglobinopathy remain unknown. We hypothesized that Placenta Growth Factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates this AHR. We studied AHR in allergen-exposed PlGF-/- and SCD mice. Sickle mice genetically deficient in PlGF were not viable. PlGF augmented AHR, lung inflammation and blood/lung eosinophilia via IL-13 (a Th2-cytokine) and increased 5-lipoxygenase (a leukotriene synthetic enzyme) expression. AHR, or pulmonary inflammation and leukotriene levels were blunted in PlGF-/- mice or in PlGFWT mice treated with anti-PlGF-Ab, and was rescued by intratracheal administration of leukotrienes to PlGF-/- mice.  Notably, Th2-mediated Stat-6 activation further increased PlGF expression from lung epithelium, eosinophils and macrophages, linking the PlGF-leukotriene pathway in a positive feedback loop. Th2 response is classically seen in asthma, and indeed, expression of PlGF and its downstream genes was increased in respiratory epithelial cells of asthma patients. Like patients with SCD, sickle hematopoietic chimeras developed increased AHR and had higher leukotriene levels; and both were abrogated by anti-PlGF-Ab or zileuton (5-lipoxygenase inhibitor) phenocopying the blunted AHR in PlGF-/- mice, and indicating that sickle erythroid-cells/RBC potentiate AHR. Overall, PlGF exacerbates AHR and uniquely links the leukotriene and Th2 pathways in asthma. Both zileuton, licensed for asthma and anti-PlGF-Ab, in clinical trials for cancer, could be promising therapies to reduce the pulmonary morbidity in SCD.

Disclosures: Jonckx: ThromboGenics: Employment .

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