Skip to main content

Volume 15 Supplement 3

Sepsis 2011

Sepsis-induced lung fibrosis in baboons is reduced by the treatment with a complement inhibitor

Introduction

Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [1].

Methods

Here we used the baboon model described [1] in conjunction with detailed gene expression analysis, as well as biochemical and histological assays to determine if E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.

Results

Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post E. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity® pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table 1). Immunocytochemistry and pathway-oriented transcriptomics and phospho-proteomics analysis reveal changes of multiple processes mediated by transforming growth factor beta (TGF-β), connective tissue growth factor and other TGF-β controlled proteins. Immunostaining for cell proliferation markers demonstrates that compstatin treatment strongly reduces cell proliferation in fibroblastic foci. Moreover, biochemical analysis shows decreased production in the compstatin-treated group of two chemokines responsible for fibrocyte recruitment (CCL2 and CXCL12) and of the type 1 tissue inhibitor of metalloproteases that controls extracellular matrix remodeling.

Table 1 abstract P34

Conclusion

Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis.

References

  1. 1.

    Silasi-Mansat R, Zhu H, Popescu NI, Peer G, Sfyroera G, Magotti P, Ivanciu L, Lupu C, Mollnes TE, Taylor FB, et al.: Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 2010, 116: 1002-1010. 10.1182/blood-2010-02-269746

    PubMed Central  CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr Bart Frank (OMRF) for help with protein array scanning and quantitation. This work was supported by grants from the National Institutes of Health (GM097747-01 to FL and JL; 2P20RR018758-06A2 and 1RC1GM09739-02 to FL; AI068730 and GM062134 to JL).

Author information

Affiliations

Authors

Corresponding author

Correspondence to F Lupu.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Cite this article

Lupu, F., Zhu, H., Silasi-Mansat, R. et al. Sepsis-induced lung fibrosis in baboons is reduced by the treatment with a complement inhibitor. Crit Care 15, P34 (2011). https://doi.org/10.1186/cc10403

Download citation

Keywords

  • Pulmonary Fibrosis
  • Connective Tissue Growth Factor
  • Fibrotic Response
  • Complement Inhibitor
  • Cell Proliferation Marker