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

Abstract

The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A 2/2 mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthmaassociated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A 2/2 mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

“…Of interest, trimeric fragments of human SP-A have been used successfully to neutralize RSV infection in an in vitro model of human bronchial epithelial cells (66). Furthermore, in animal models and human epithelial cells, exogenous SP-A is shown to attenuate asthma-related factors and protect against IL-13-induced inflammation in asthma (170).…”

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

“…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 .…”

Regulation of Immune Responses by Nonhematopoietic Cells in Asthma

“…These peptides can act directly to kill bacteria and also promote immune responses, in part by binding to the chemokine receptor, CCR6, that is expressed on immature DCs (74). Surfactants not only prevent collapse of the alveoli during exhalation, but also have innate immune functions in the airways, including modulating LPS-, IL-13-, and aeroallergeninduced inflammation (75)(76)(77). The epithelium is also a rich source of innate immune cytokines.…”