Genetic Variation in Surfactant Protein-A2 Delays Resolution of Eosinophilia in Asthma

Abstract

Surfactant protein-A (SP-A) is an important mediator of pulmonary immunity. A specific genetic variation in SP-A2, corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 of the lectin domain, was shown to alter the ability of SPA to inhibit eosinophil degranulation. Because a large subgroup of asthmatics have associated eosinophilia, often accompanied by inflammation associated with delayed clearance, our goal was to define how SPA mediates eosinophil resolution in allergic airways and whether genetic variation affects this activity. Wild-type, SPA knockout (SP-A KO) and humanized (SP-A2 223Q/Q, SP-A2 223K/K) C57BL/6 mice were challenged in an allergic OVA model, and parameters of inflammation were examined. Peripheral blood eosinophils were isolated to assess the effect of SPA genetic variation on apoptosis and chemotaxis. Five days postchallenge, SPA KO and humanized SP-A2 223K/K mice had persistent eosinophilia in bronchoalveolar lavage fluid compared with wild-type and SP-A2 223Q/Q mice, suggesting an impairment in eosinophil resolution. In vitro, human SPA containing either the 223Q or the 223K allele was chemoattractant for eosinophils whereas only 223Q resulted in decreased eosinophil viability. Our results suggest that SPA aids in the resolution of allergic airway inflammation by promoting eosinophil clearance from lung tissue through chemotaxis, independent of SP-A2 Q223K, and by inducing apoptosis of eosinophils, which is altered by the polymorphism.

Myeloid-associated differentiation marker is a novel SP-A-associated transmembrane protein whose expression on airway epithelial cells correlates with asthma severity

“…Eosinophils from the blood of IL-5 transgenic mice were isolated and purified as previously described 16 , 20 . Briefly, blood was collected by cardiac puncture through the left ventricle, after which red blood cells were lysed and eosinophils isolated by negative selection.…”

“…SP-A is also known to modulate cytokines, IgE and eosinophil levels in the setting of type 2-associated allergic inflammation 17 , 18 and treatment with exogenous SP-A in mouse models of asthma significantly reduces tissue eosinophilia 19 . We have determined that SP-A contributes to the resolution of eosinophilia by promoting eosinophil migration out of the lung tissue, and more remarkably, promoting eosinophil apoptosis in the lung lumen 20 . In addition to these phenotypes associated with resolution of eosinophilia, our group has also shown that SP-A inhibits eosinophil peroxidase release, a toxic product that can compromise the integrity of the airway epithelia 16 .…”

“…In addition to these phenotypes associated with resolution of eosinophilia, our group has also shown that SP-A inhibits eosinophil peroxidase release, a toxic product that can compromise the integrity of the airway epithelia 16 . Furthermore, a genetic variation in the carbohydrate recognition domain of SP-A2 occurring at position 223, which results in a glutamine (Q) to a lysine (K) substitution, alters regulatory functions of SP-A in apoptosis and degranulation of eosinophils 11 , 20 .…”

Genetic variation in surfactant protein-A2 alters responses to ozone

“…Therefore this higher frequency of a less protective SP-A allele within the African American population may be a contributing factor to the increased incidence and severity of asthma in this subgroup and should be further explored [ 28 ]. Additionally, in a recent study Dy et al demonstrated that SP-A is involved in the resolution of allergic airway inflammation by inducing eosinophil apoptosis, and expression of the 223K variant in SP-A2 results in diminished SP-A functionality and would therefor likely impact asthma [ 29 ].…”

Surfactant Protein-A Protects against IL-13–Induced Inflammation in Asthma

“…SP-A 2/2 mice have increased hallmarks of asthma including BAL eosinophilia, mucin production, IL-4, IL-5, and IgE as compared with WT mice (47). On a mechanistic level, SP-A has been shown to bind to eosinophils (Ca2+ dependent and receptormediated) and prevent degranulation (23) while promoting their apoptosis (48). In this investigation, we determined that SP-A modulates IL-13-driven signaling in both mice and human airway BECs via reduced phosphorylation and activation of STAT3, a critical mediator in allergic disease (36), while having little to no effect on STAT6 signaling.…”