Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease

Abstract

Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Barnes PJ, Burney PG, Silverman EK, Celli BR, Vestbo J, Wedzicha JA, et al. Chronic obstructive pulmonary disease. Nat Rev Dis Prim. 2015;1:15076.

    Article  Google Scholar 

  2. Cheng SL, Chan MC, Wang CC, Lin CH, Wang HC, Hsu JY, et al. COPD in Taiwan: a national epidemiology survey. Int J Chron Obstruct Pulmon Dis. 2015;10:2459–67.

    Google Scholar 

  3. Sullivan J, Pravosud V, Mannino DM, Siegel K, Choate R, Sullivan T. National and state estimates of COPD morbidity and mortality—United States, 2014-2015. Chronic Obstr Pulm Dis. 2018;5:324–33.

    Google Scholar 

  4. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20:1126–67.

    Article  CAS  Google Scholar 

  5. Cañadas O, Olmeda B, Alonso A, Pérez-Gil J. Lipid-protein and protein-protein interactions in the pulmonary surfactant system and their role in lung homeostasis. Int J Mol Sci. 2020;21:3708.

  6. Knudsen L, Ochs M, Mackay R, Townsend P, Deb R, Mühlfeld C, et al. Truncated recombinant human SP-D attenuates emphysema and type II cell changes in SP-D deficient mice. Respir Res. 2007;8:70.

    Article  Google Scholar 

  7. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5:58–68.

    Article  CAS  Google Scholar 

  8. Vandivier RW, Ogden CA, Fadok VA, Hoffmann PR, Brown KK, Botto M, et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J Immunol. 2002;169:3978–86.

    Article  CAS  Google Scholar 

  9. Knudsen L, Atochina-Vasserman EN, Massa CB, Birkelbach B, Guo CJ, Scott P, et al. The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice. Am J Physiol Lung Cell Mol Physiol. 2015;309:L959–69.

    Article  CAS  Google Scholar 

  10. Korfhagen TR, Sheftelyevich V, Burhans MS, Bruno MD, Ross GF, Wert SE, et al. Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. J Biol Chem. 1998;273:28438–43.

    Article  CAS  Google Scholar 

  11. Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T, Ross GF, et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci USA. 2000;97:5972–7.

    Article  CAS  Google Scholar 

  12. Levitan I, Volkov S, Subbaiah PV. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal. 2010;13:39–75.

    Article  CAS  Google Scholar 

  13. Hirama N, Shibata Y, Otake K, Machiya J, Wada T, Inoue S, et al. Increased surfactant protein-D and foamy macrophages in smoking-induced mouse emphysema. Respirology. 2007;12:191–201.

    Article  Google Scholar 

  14. Lian X, Yan C, Yang L, Xu Y, Du H. Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung. Am J Physiol Lung Cell Mol Physiol. 2004;286:L801–7.

    Article  CAS  Google Scholar 

  15. Nandy D, Sharma N, Senapati S. Systematic review and meta-analysis confirms significant contribution of surfactant protein D in chronic obstructive pulmonary disease. Front Genet. 2019;10:339.

    Article  CAS  Google Scholar 

  16. Ju CR, Liu W, Chen RC. Serum surfactant protein D: biomarker of chronic obstructive pulmonary disease. Dis Markers. 2012;32:281–7.

    Article  CAS  Google Scholar 

  17. Wang H, Li F, Huang H, Wu F, Chen L, Zhang D, et al. Serum surfactant protein D is a potential biomarker for chronic obstructive pulmonary disease: a systematic review and meta-analysis. Clin Lab. 2019;65. https://doi.org/10.7754/Clin.Lab.2019.190539.

  18. Obeidat M, Li X, Burgess S, Zhou G, Fishbane N, Hansel NN, et al. Surfactant protein D is a causal risk factor for COPD: results of Mendelian randomisation. Eur Respir J. 2017;50:1700657.

  19. Ou CY, Chen CZ, Hsiue TR, Lin SH, Wang JY. Genetic variants of pulmonary SP-D predict disease outcome of COPD in a Chinese population. Respirology. 2015;20:296–303.

    Article  Google Scholar 

  20. Zhu H, Jia Z, Zhang L, Yamamoto M, Misra HP, Trush MA, et al. Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress. Exp Biol Med. 2008;233:463–74.

    Article  CAS  Google Scholar 

  21. Kotlyarov S, Kotlyarova A. Molecular mechanisms of lipid metabolism disorders in infectious exacerbations of chronic obstructive pulmonary disease. Int J Mol Sci. 2021;22:7634.

  22. Azimzadeh Jamalkandi S, Mirzaie M, Jafari M, Mehrani H, Shariati P, Khodabandeh M. Signaling network of lipids as a comprehensive scaffold for omics data integration in sputum of COPD patients. Biochim Biophys Acta. 2015;1851:1383–93.

    Article  Google Scholar 

  23. Ko FW, Lau CY, Leung TF, Wong GW, Lam CW, Hui DS. Exhaled breath condensate levels of 8-isoprostane, growth related oncogene alpha and monocyte chemoattractant protein-1 in patients with chronic obstructive pulmonary disease. Respir Med. 2006;100:630–8.

    Article  Google Scholar 

  24. Bartoli ML, Novelli F, Costa F, Malagrinò L, Melosini L, Bacci E, et al. Malondialdehyde in exhaled breath condensate as a marker of oxidative stress in different pulmonary diseases. Mediators Inflamm. 2011;2011:891752.

    Article  CAS  Google Scholar 

  25. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med. 2000;162:1175–7.

    Article  CAS  Google Scholar 

  26. Miró O, Alonso JR, Jarreta D, Casademont J, Urbano-Márquez A, Cardellach F. Smoking disturbs mitochondrial respiratory chain function and enhances lipid peroxidation on human circulating lymphocytes. Carcinogenesis. 1999;20:1331–6.

    Article  Google Scholar 

  27. Ween MP, White JB, Tran HB, Mukaro V, Jones C, Macowan M, et al. The role of oxidised self-lipids and alveolar macrophage CD1b expression in COPD. Sci Rep. 2021;11:4106.

    Article  CAS  Google Scholar 

  28. Fessler MB. A new frontier in immunometabolism. Cholesterol in Lung health and disease. Ann Am Thorac Soc. 2017;14:S399–405.

    Article  Google Scholar 

  29. Morissette MC, Shen P, Thayaparan D, Stämpfli MR. Disruption of pulmonary lipid homeostasis drives cigarette smoke-induced lung inflammation in mice. Eur Respir J. 2015;46:1451–60.

    Article  CAS  Google Scholar 

  30. Fujii W, Kapellos TS, Baßler K, Händler K, Holsten L, Knoll R, et al. Alveolar macrophage transcriptomic profiling in COPD shows major lipid metabolism changes. ERJ Open Res. 2021;7:00915-2020.

  31. Baßler K, Fujii W, Kapellos TS, Horne A, Reiz B, Dudkin E, et al. Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease. bioRxiv. 2020. https://doi.org/10.1101/2020.05.28.121541.

  32. Fisher JH, Sheftelyevich V, Ho YS, Fligiel S, McCormack FX, Korfhagen TR, et al. Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice. Am J Physiol Lung Cell Mol Physiol. 2000;278:L365–73.

    Article  CAS  Google Scholar 

  33. Pilecki B, Wulf-Johansson H, Støttrup C, Jørgensen PT, Djiadeu P, Nexøe AB, et al. Surfactant protein D deficiency aggravates cigarette smoke-induced lung inflammation by upregulation of ceramide synthesis. Front Immunol. 2018;9:3013.

    Article  CAS  Google Scholar 

  34. Lara-Guzman OJ, Gil-Izquierdo Á, Medina S, Osorio E, Alvarez-Quintero R, Zuluaga N, et al. Oxidized LDL triggers changes in oxidative stress and inflammatory biomarkers in human macrophages. Redox Biol. 2018;15:1–11.

    Article  CAS  Google Scholar 

  35. Matsuura E, Hughes GR, Khamashta MA. Oxidation of LDL and its clinical implication. Autoimmun Rev. 2008;7:558–66.

    Article  CAS  Google Scholar 

  36. Malur A, Baker AD, Mccoy AJ, Wells G, Barna BP, Kavuru MS, et al. Restoration of PPARgamma reverses lipid accumulation in alveolar macrophages of GM-CSF knockout mice. Am J Physiol Lung Cell Mol Physiol. 2011;300:L73–80.

    Article  CAS  Google Scholar 

  37. Hafiane A, Gasbarrino K, Daskalopoulou SS. The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism. Metabolism. 2019;100:153953.

    Article  CAS  Google Scholar 

  38. Alzoubi A, Ghazwi R, Alzoubi K, Alqudah M, Kheirallah K, Khabour O, et al. Vascular endothelial growth factor receptor inhibition enhances chronic obstructive pulmonary disease picture in mice exposed to waterpipe smoke. Folia Morphol. 2018;77:447–55.

    Article  CAS  Google Scholar 

  39. Dodagatta-Marri E, Qaseem AS, Karbani N, Tsolaki AG, Waters P, Madan T, et al. Purification of surfactant protein D (SP-D) from pooled amniotic fluid and bronchoalveolar lavage. Methods Mol Biol. 2014;1100:273–90.

    Article  CAS  Google Scholar 

  40. Hsieh MH, Beirag N, Murugaiah V, Chou YC, Kuo WS, Kao HF, et al. Human surfactant protein D binds spike protein and acts as an entry inhibitor of SARS-CoV-2 pseudotyped viral particles. Front Immunol. 2021;12:641360.

    Article  CAS  Google Scholar 

  41. Assouvie A, Daley-Bauer LP, Rousselet G. Growing murine bone marrow-derived macrophages. Methods Mol Biol. 2018;1784:29–33.

    Article  CAS  Google Scholar 

  42. Hirai T, Fukui Y, Motojima K. PPARalpha agonists positively and negatively regulate the expression of several nutrient/drug transporters in mouse small intestine. Biol Pharm Bull. 2007;30:2185–90.

    Article  CAS  Google Scholar 

  43. Kang JH, Ko HM, Han GD, Lee SY, Moon JS, Kim MS, et al. Dual role of phosphatidylserine and its receptors in osteoclastogenesis. Cell Death Dis. 2020;11:497.

    Article  CAS  Google Scholar 

  44. Sekine S, Yao A, Hattori K, Sugawara S, Naguro I, Koike M, et al. The ablation of mitochondrial protein phosphatase Pgam5 confers resistance against metabolic stress. EBioMedicine. 2016;5:82–92.

    Article  Google Scholar 

  45. He X, Chen X, Wang L, Wang W, Liang Q, Yi L, et al. Metformin ameliorates Ox-LDL-induced foam cell formation in raw264.7 cells by promoting ABCG-1 mediated cholesterol efflux. Life Sci. 2019;216:67–74.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Laboratory Animal Center, College of Medicine, National Cheng Kung University and Taiwan Animal Consortium for the technical support in IVIS.

Funding

This work was supported by the Ministry of Science and Technology (MOST) of Taiwan (grant numbers 103-2321-B-006-030 and 104-2321-B-006-008), funding received in part from the Headquarters of University Advancement at the National Cheng Kung University, which is sponsored by the Ministry of Education in Taiwan, and a research grant (1JA8) from the Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.

Author information

Authors and Affiliations

Authors

Contributions

MHH, LSHW, and JYW developed the study concepts and aims. MHH, HYH, JCL, YSH, SDW, and WSK performed the experiments and data extraction. CWK collected the clinical BALF samples from COPD patients. MHH, WSK, HFK, and ZGL performed the data analysis. MHH, LSHW, and JYW drafted the manuscript. All authors provided important insight into data interpretation and contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Lawrence Shih-Hsin Wu or Jiu-Yao Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hsieh, MH., Chen, PC., Hsu, HY. et al. Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease. Cell Mol Immunol 20, 38–50 (2023). https://doi.org/10.1038/s41423-022-00946-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-022-00946-2

Keywords

  • Alveolar macrophages
  • Chronic obstructive pulmonary diseases
  • Surfactant protein D
  • Lipid metabolism
  • Ozone
  • Cigarettes

Search

Quick links