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Editorial |

Surfactant Protein-D and Asthma FREE TO VIEW

Patrick D. Mitchell, MB; Paul M. O’Byrne, MB, FCCP
Author and Funding Information

CORRESPONDENCE TO: Paul M. O’Byrne, MB, FCCP, Room 3W10, McMaster University Medical Center, 1280 Main St W, Hamilton, Ontario, L8S 4K1, Canada


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(5):1121-1122. doi:10.1016/j.chest.2015.12.038
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Much of the recent research in asthma has focused on delineating the causative factors that contribute to the pathobiology of both airway eosinophilia and neutrophilia, and steroid-refractory disease. The distal airway, once thought to be a sterile environment, is now known to be a complex arena of microorganisms, termed the lung microbiome. Complementary and counterbalancing mechanisms are essential to maintaining homeostasis in this environment. An altered lung microbiome has been well described in asthma, with a higher burden of bacteria and differing species seen in asthmatic lungs compared with normal lungs, and these differences are more marked in severe asthma. There are likely several different mechanisms that account for these differences, including the usage of inhaled or oral corticosteroids and the higher prevalence of antimicrobial prescription in patients with more severe asthma.

FOR RELATED ARTICLE SEE PAGE 1165

In this issue of CHEST, Mackay et al provide us with information about the relationship between airway eosinophilia and neutrophilia, and both quantitative and functional assays of surfactant protein (SP) -D in normal healthy control subjects and in patients with mild asthma and severe asthma. The initial interest in surfactant focused on its ability to reduce surface tension in the lung. This feature of surfactant was historically best demonstrated in preterm neonates. Surfactant is enriched with a relatively unique phospholipid, dipalmitoylphosphatidylcholine, and with four surfactant-associated proteins, SP-A, SP-B, SP-C, and SP-D. SP-B and SP-C, together with dipalmitoylphosphatidylcholine, provide surface tension-lowering properties to the material. The more hydrophilic surfactant-associated proteins, SP-A and SP-D, are involved in innate immunity in lungs. SP-D is synthesized and secreted by alveolar type II cells and club cells, and it binds to surface glycoconjugates and oligosaccharides expressed by a wide variety of microorganisms and associated with the surface of various complex organic antigens.

Allergic asthma and animal models of airway inflammation have previously been associated with increased SP-D levels in airway tissue, bronchoalveolar lavage (BAL), and serum, suggesting that SP-D is involved in responses to both allergic inflammation and inflammatory responses to pathogens. Mackay et al demonstrated that BAL concentrations of myeloperoxidase, IL-8, and eosinophilic cationic protein were increased in patients with severe asthma compared with patients with mild asthma and healthy control subjects. Others have shown that neutrophil elastase levels were also significantly increased in BAL from patients with severe asthma compared with healthy control subjects and patients with mild asthma. Mackay et al have now shown that BAL SP-D concentrations from patients with severe asthma are significantly decreased compared with both healthy control subjects and patients with mild asthma. Interestingly, patients with severe asthma had significantly increased SP-D concentrations in serum compared with both healthy control subjects and patients with mild asthma. The authors have suggested that the higher SP-D concentration found in the serum compared with BAL levels in patients with severe asthma may be attributable to impaired airway epithelium integrity allowing increased permeability and leakage into peripheral blood. It may also result from the heavier burden of gram-negative bacteria seen in the airways of patients with severe asthma that SP-D binds to, thus reducing the amount of SP-D available for detection in the BAL enzyme-linked immunosorbent assay quantification.,

This study also looked at SP-D via a functional Western blot assay. It surprisingly identified that the SP-D in severe asthma has 50 kDa forms, but also fragmented bands at 17 kDa and 38 kDa in BAL and 17 kDa, 28 kDa, and 30 kDa bands in serum. Importantly, this was not seen in either the normal or mild asthmatic groups. As the authors suggest, this cleaving of SP-D most likely is caused by increased burden of both bacterial proteases and neutrophil serine proteinases in the severe asthmatic group. It would be most informative to know whether this can be replicated in the severe asthma group without airway neutrophilia. These proteases may inactivate SP-D, reducing its immunomodulatory effects in the lung, but this remains unproven, as these cleaved fragments may have either enhanced or muted biologic activity.

Emmanouil et al described significantly higher levels of SP-D in the sputum and BAL in patients with severe refractory asthma compared with patients with mild or moderate asthma and healthy control subjects and identified concentrations of SP-D in the BAL not seen in this study. Factors that may have confounded the results of both studies are the small numbers of patients with severe asthma in each study, which may have also included other phenotypes of severe asthma (ie, neutrophilic vs nonneutrophilic asthma). Other factors such as BMI, prior antibiotic exposure, dose of inhaled or oral corticosteroid, and the smoking history in the severe asthma groups in both studies is not well described and may also have had a significant influence on the findings.,,,

SP-D has many important immunologic functions in the lungs. The research done by Mackay et al has enhanced our understanding of its potential importance in severe asthma. The decreased level found in the BAL in patients with severe asthma may be the result of a consumptive process or cleavage by proteases. SP-D increases bronchial epithelial permeability, facilitating the migration of immune cells such as eosinophils or neutrophils into the airways when needed; this may allow SP-D to “leak” into the serum, causing its elevated levels in this compartment. Further research is needed to assess the mechanistic properties of SP-D and cleaved fragments in patients with severe asthma and to ascertain whether they collectively influence steroid-refractory asthma.

References

Han M.K. .Huang Y.J. .Lipuma J.J. .et al Significance of the microbiome in obstructive lung disease. Thorax. 2012;67:456-463 [PubMed]journal. [CrossRef] [PubMed]
 
Mackay R.-M.A. .Grainge C.L. .Lau L.C. .Barber C. .Clark H.W. .Howarth P.H. . Airway surfactant protein D deficiency in adults with severe asthma. Chest. 2016;149:1165-1172 [PubMed]journal
 
Whitsett J.A. .Weaver T.E. . Alveolar development and disease. Am J Respir Cell Mol Biol. 2015;53:1-7 [PubMed]journal. [CrossRef] [PubMed]
 
Crouch E.C. . Surfactant protein-D and pulmonary host defense. Respir Res. 2000;1:93-108 [PubMed]journal. [CrossRef] [PubMed]
 
Fakih D. .Pilecki B. .Schlosser A. .et al Protective effects of surfactant protein D treatment in 1,3-β-glucan-modulated allergic inflammation. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1333-L1343 [PubMed]journal. [PubMed]
 
Jatakanon A. .Uasuf C. .Maziak W. .Lim S. .Chung K.F. .Barnes P.J. . Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160:1532-1539 [PubMed]journal. [CrossRef] [PubMed]
 
Kuan S.F. .Rust K. .Crouch E. . Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage. J Clin Invest. 1992;90:97-106 [PubMed]journal. [CrossRef] [PubMed]
 
Hilty M. .Burke C. .Pedro H. .et al Disordered microbial communities in asthmatic airways. PLoS One. 2010;5:e8578- [PubMed]journal. [CrossRef] [PubMed]
 
Emmanouil P. .Loukides S. .Kostikas K. .et al Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma. Allergy. 2015;70:711-714 [PubMed]journal. [CrossRef] [PubMed]
 
Sorensen G.L. .Hjelmborg J.V. .Leth-Larsen R. .et al Surfactant protein D of the innate immune defence is inversely associated with human obesity and SP-D deficiency infers increased body weight in mice. Scand J Immunol. 2006;64:633-638 [PubMed]journal. [CrossRef] [PubMed]
 
Noverr M.C. .Noggle R.M. .Toews G.B. .Huffnagle G.B. . Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect Immun. 2004;72:4996-5003 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Han M.K. .Huang Y.J. .Lipuma J.J. .et al Significance of the microbiome in obstructive lung disease. Thorax. 2012;67:456-463 [PubMed]journal. [CrossRef] [PubMed]
 
Mackay R.-M.A. .Grainge C.L. .Lau L.C. .Barber C. .Clark H.W. .Howarth P.H. . Airway surfactant protein D deficiency in adults with severe asthma. Chest. 2016;149:1165-1172 [PubMed]journal
 
Whitsett J.A. .Weaver T.E. . Alveolar development and disease. Am J Respir Cell Mol Biol. 2015;53:1-7 [PubMed]journal. [CrossRef] [PubMed]
 
Crouch E.C. . Surfactant protein-D and pulmonary host defense. Respir Res. 2000;1:93-108 [PubMed]journal. [CrossRef] [PubMed]
 
Fakih D. .Pilecki B. .Schlosser A. .et al Protective effects of surfactant protein D treatment in 1,3-β-glucan-modulated allergic inflammation. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1333-L1343 [PubMed]journal. [PubMed]
 
Jatakanon A. .Uasuf C. .Maziak W. .Lim S. .Chung K.F. .Barnes P.J. . Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160:1532-1539 [PubMed]journal. [CrossRef] [PubMed]
 
Kuan S.F. .Rust K. .Crouch E. . Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage. J Clin Invest. 1992;90:97-106 [PubMed]journal. [CrossRef] [PubMed]
 
Hilty M. .Burke C. .Pedro H. .et al Disordered microbial communities in asthmatic airways. PLoS One. 2010;5:e8578- [PubMed]journal. [CrossRef] [PubMed]
 
Emmanouil P. .Loukides S. .Kostikas K. .et al Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma. Allergy. 2015;70:711-714 [PubMed]journal. [CrossRef] [PubMed]
 
Sorensen G.L. .Hjelmborg J.V. .Leth-Larsen R. .et al Surfactant protein D of the innate immune defence is inversely associated with human obesity and SP-D deficiency infers increased body weight in mice. Scand J Immunol. 2006;64:633-638 [PubMed]journal. [CrossRef] [PubMed]
 
Noverr M.C. .Noggle R.M. .Toews G.B. .Huffnagle G.B. . Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect Immun. 2004;72:4996-5003 [PubMed]journal. [CrossRef] [PubMed]
 
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