title: Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13.
abstract: Airway hyperresponsiveness (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 mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR. In allergen-exposed mice, loss of Plgf dampened AHR, reduced inflammation and eosinophilia, and decreased expression of the Th2 cytokine IL-13 and the leukotriene-synthesizing enzymes 5-lipoxygenase and leukotriene-C4-synthase. Plgf-/- mice treated with leukotrienes phenocopied the WT response to allergen exposure; conversely, anti-PlGF Ab administration in WT animals blunted the AHR. Notably, Th2-mediated STAT6 activation further increased PlGF expression from lung epithelium, eosinophils, and macrophages, creating a PlGF/leukotriene/Th2-response positive feedback loop. Similarly, we found that the Th2 response in asthma patients is associated with increased expression of PlGF and its downstream genes in respiratory epithelial cells. In an SCD mouse model, we observed increased AHR and higher leukotriene levels that were abrogated by anti-PlGF Ab or the 5-lipoxygenase inhibitor zileuton. Overall, our findings indicate that PlGF exacerbates AHR and uniquely links the leukotriene and Th2 pathways in asthma. These data also suggest that zileuton and anti-PlGF Ab could be promising therapies to reduce pulmonary morbidity in SCD.
authors.forename: Marthe-Sandrine
authors.initials: MS
authors.lastname: Eiymo Mwa Mpollo
authors.forename: Eric B
authors.initials: EB
authors.lastname: Brandt
authors.forename: Shiva Kumar
authors.initials: SK
authors.lastname: Shanmukhappa
authors.forename: Paritha I
authors.initials: PI
authors.lastname: Arumugam
authors.forename: Swati
authors.initials: S
authors.lastname: Tiwari
authors.forename: Anastacia
authors.initials: A
authors.lastname: Loberg
authors.forename: Devin
authors.initials: D
authors.lastname: Pillis
authors.forename: Tilat
authors.initials: T
authors.lastname: Rizvi
authors.forename: Mark
authors.initials: M
authors.lastname: Lindsey
authors.forename: Bart
authors.initials: B
authors.lastname: Jonck
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kalra
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: Marsha
authors.initials: M
authors.lastname: Wills-Karp
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D015289:Leukotrienes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D018793:Interleukin-13; D015289:Leukotrienes; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C063449:zileuton; D006918:Hydroxyurea