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.

House Dust Mite-Induced Allergic Lung Inflammation Is Not Exacerbated in Sickle Cell Disease Mice

“…BALF cytokines in SCD mice with OVA-induced AAD have higher IL-5 [11], which is responsible for eosinophil chemotaxis and function. The lack of difference of IL-5 secretion in our study is supported by data from the study of Eiymo Mwa Mpollo et al [32], which also showed a lack of difference in IL-5 levelsbetween (chimeric) SCD and WT mice when exposed to HDM. Indeed, it has been shown that elevated IgE titers induce increased IL-5 production by helper T cells [33], and increased IL-5 levels can drive airway eosinophilia [34], possibly giving insight into a key difference between the models that may explain why OVA models induce more robust allergic inflammation in SCD mice, but HDM does not.…”

“…While this may at first seem to contrast with our findings, if taken together, it fits into the clinical hypothesis that children with SCD have impaired lung function but not more severe asthma phenotypes [24, 25]. Indeed, Eiymo Mwa Mpollo et al [32] observed that chimeric SCD mice have elevated airway resistance at baseline when compared to WT mice, thus supporting this hypothesis. This group was able to link increased levels of placenta growth factor in SCD mice with increased airway resistance.…”

“…Our lack of high IgE titers and the normal levels of lung inflammation in SCD mice after exposure to HDM support this hypothesis. Additionally, Eiymo Mwa Mpollo et al [32] found that chimeric SCD mice have greater airway resistance after exposure to HDM than WT mice do. While this may at first seem to contrast with our findings, if taken together, it fits into the clinical hypothesis that children with SCD have impaired lung function but not more severe asthma phenotypes [24, 25].…”

The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

“…Unfortunately, erythropoiesis is metabolically demanding, and increases procoagulant autophagic vesicles (4). In addition, developing erythroblasts produce a number of vasoactive signaling molecules, including placental growth factor, that are associated with airway hyperactivity, monocyte activation, and pulmonary hypertension (5).…”

New insights into sickle cell disease

“…2). Placenta growth factor, a VEGF family member overexpressed in SCD and now known to be stimulated by erythropoietin, heme iron and inflammatory cytokines, promotes to airway hyperreactivity in sickle cell mice via leukotrienes and IL-13 [44]. Thus, placenta growth factor appears to inflammatory pathways in the reactive airway disease frequently encountered in children with SCD.…”